You searched for subject:(Synthetic lethality).
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University of Saskatchewan
1.
Sumi, Sharmin Sultana.
Characterization of PIK3CD as a Cancer Drug Target.
Degree: 2018, University of Saskatchewan
URL: http://hdl.handle.net/10388/11491 
► Peroxisome proliferator activated Receptors (PPARs) belong to the nuclear receptor super family and are ligand activated transcription factors regulating the expression of a wide variety…
(more)
▼ Peroxisome proliferator activated Receptors (PPARs) belong to the nuclear receptor super family and are ligand activated transcription factors regulating the expression of a wide variety of genes. On activation by a ligand, they bind to the PPAR-responsive regulatory elements (PPRE) and/or PPAR associated conserved motif (PACM) as obligate heterodimers with retinoid X recep¬tor (RXR). Recently, several reports have shown a consistent link between PPARγ activation and anti-tumorigenic effects in several tumor cell lines. Although several mechanisms have been proposed for this anti-tumorigenic effect on PPARγ activation, one of the potential mechanisms is the inhibition of telomerase activity and modulation of hTERT expression through the Myc/Mad/Max genes that are downstream targets of PPARγ. This mechanism is very interesting because hTERT expression is upregulated in 90% of the cancer cells. Our lab has computationally predicted over 1100 genes that are potentially regulated by PPARγ. Several of these targets have been identified in a genome-wide screen that was driven to identify factors that selectively kill hTERT overexpressing cells. My project involves validation of these targets using metabolic, proliferation and expression assays. Finally, we validated one potential target of PPARγ that can selectively kill hTERT overexpressing cells. These investigations have applications in cancer therapeutics.
Advisors/Committee Members: Sakharkar, Meena, Vizeacoumar, Franco, Freywald, Andrew, Blackburn, David, Taghibiglou , Changiz.
Subjects/Keywords: PPARγ; PIK3CD; hTERT; Synthetic Dosages Lethality
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APA (6th Edition):
Sumi, S. S. (2018). Characterization of PIK3CD as a Cancer Drug Target. (Thesis). University of Saskatchewan. Retrieved from http://hdl.handle.net/10388/11491
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Sumi, Sharmin Sultana. “Characterization of PIK3CD as a Cancer Drug Target.” 2018. Thesis, University of Saskatchewan. Accessed April 14, 2021.
http://hdl.handle.net/10388/11491.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Sumi, Sharmin Sultana. “Characterization of PIK3CD as a Cancer Drug Target.” 2018. Web. 14 Apr 2021.
Vancouver:
Sumi SS. Characterization of PIK3CD as a Cancer Drug Target. [Internet] [Thesis]. University of Saskatchewan; 2018. [cited 2021 Apr 14].
Available from: http://hdl.handle.net/10388/11491.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Sumi SS. Characterization of PIK3CD as a Cancer Drug Target. [Thesis]. University of Saskatchewan; 2018. Available from: http://hdl.handle.net/10388/11491
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Alberta
2.
Mereniuk, Todd.
Synthetic lethal targeting of polynucleotide
kinase/phosphatase and its potential role in directed cancer
therapies.
Degree: PhD, Department of Oncology, 2012, University of Alberta
URL: https://era.library.ualberta.ca/files/c7p88cg67w
► Synthetic lethality arises when simultaneous disruption of two non-essential, non-allelic genes in the same cell causes lethality. This phenomenon has been shown to occur between…
(more)
▼ Synthetic lethality arises when simultaneous
disruption of two non-essential, non-allelic genes in the same cell
causes lethality. This phenomenon has been shown to occur between
proteins involved in DNA repair and much attention to date has
focused on poly(ADP-ribose) polymerase and the BRCA proteins.
Synthetic lethality holds great promise in the development of
tailor-made treatments for each specific patient and as such, there
exists a need to expand the repertoire of known synthetic lethal
associations in human cells. We intended to identify novel
synthetic lethal relationships and show these lethal combinations
need not solely rely on the interactions between two DNA repair
proteins. We performed an siRNA screen of Qiagen’s druggable genome
to identify synthetic lethal partnerships with another DNA repair
protein, polynucleotide kinase/phosphatase (PNKP). We identified 14
currently known tumor suppressors showing potential synthetic
lethality with PNKP, including the tyrosine-protein phosphatase
SHP-1, and the major tumor suppressor PTEN. SHP-1 has been shown to
be lost or diminished in ~90% of malignant prostate tissues, 95% of
malignant lymphomas and 100% of NK and T cell lymphomas tested,
whereas PTEN is the second most frequently lost tumor suppressor in
human sporadic cancers. Therefore, targeted disruption of PNKP may
be of benefit to a large subset of cancer sufferers. Further
investigation into the mechanisms underlying synthetic lethality
revealed that depletion of SHP-1 causes an increase in the
production of reactive oxygen species. This finding suggests a
possible mechanism for synthetic lethality beyond widely accepted
models seen with co-disruption of PARP and the BRCA proteins in
which reactive oxygen species enhance the level of unrepaired
strand breaks. We also demonstrated that PTEN’s cytoplasmic
phosphatase function is important to rescue the lethal phenotype
upon co-disruption with PNKP. Furthermore, loss of both the 3’
phosphatase and 5’ kinase function of PNKP in double-strand break
repair contribute to synthetic lethality. Since tumor suppressor
proficient cells can withstand PNKP disruption, only the suppressor
protein depleted cancer cells should be sensitive to PNKP
inhibition. This allows for the development of a highly selective
and patient-specific cancer therapy using the targeted disruption
of PNKP with either a small molecule inhibitor of PNKP, or siRNA.
Furthermore, since normal tissues should be minimally affected by
treatment, side effects typically associated with cancer therapies
should be minimized.
Subjects/Keywords: polynucleotide kinase/phosphatase; PTEN; synthetic lethality; SHP-1
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APA (6th Edition):
Mereniuk, T. (2012). Synthetic lethal targeting of polynucleotide
kinase/phosphatase and its potential role in directed cancer
therapies. (Doctoral Dissertation). University of Alberta. Retrieved from https://era.library.ualberta.ca/files/c7p88cg67w
Chicago Manual of Style (16th Edition):
Mereniuk, Todd. “Synthetic lethal targeting of polynucleotide
kinase/phosphatase and its potential role in directed cancer
therapies.” 2012. Doctoral Dissertation, University of Alberta. Accessed April 14, 2021.
https://era.library.ualberta.ca/files/c7p88cg67w.
MLA Handbook (7th Edition):
Mereniuk, Todd. “Synthetic lethal targeting of polynucleotide
kinase/phosphatase and its potential role in directed cancer
therapies.” 2012. Web. 14 Apr 2021.
Vancouver:
Mereniuk T. Synthetic lethal targeting of polynucleotide
kinase/phosphatase and its potential role in directed cancer
therapies. [Internet] [Doctoral dissertation]. University of Alberta; 2012. [cited 2021 Apr 14].
Available from: https://era.library.ualberta.ca/files/c7p88cg67w.
Council of Science Editors:
Mereniuk T. Synthetic lethal targeting of polynucleotide
kinase/phosphatase and its potential role in directed cancer
therapies. [Doctoral Dissertation]. University of Alberta; 2012. Available from: https://era.library.ualberta.ca/files/c7p88cg67w
Temple University
3.
Reed, Katherine Sullivan.
Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Cancers.
Degree: PhD, 2018, Temple University
URL: http://digital.library.temple.edu/u?/p245801coll10,507327
► Biomedical Sciences
PARP inhibitors (PARPi) have been used to induce synthetic lethality in BRCA-deficient tumors in clinical trials with limited success due to the development…
(more)
▼ Biomedical Sciences
PARP inhibitors (PARPi) have been used to induce synthetic lethality in BRCA-deficient tumors in clinical trials with limited success due to the development of resistance to PARPi. BRCA-deficient cells are unable to repair DNA double strand breaks by the accurate homologous recombination repair (HR), and therefore rely on alternative DNA repair pathways for survival. We hypothesized that RAD52-mediated DNA repair mechanisms remain active and are thus protecting some PARPi-treated BRCA-deficient tumor cells from apoptosis, and that targeting RAD52 should enhance the synthetic lethal effect of PARPi. We show here that RAD52 inhibitors (RAD52i) attenuated single-strand annealing (SSA) and residual HR activity in BRCA-deficient cells. Simultaneous targeting of PARP1 and RAD52 with small molecule inhibitors or via expression of dominant-negative mutants induced an accumulation of DSBs and selective eradication of BRCA-deficient solid tumor and leukemia cells, while BRCA-proficient cells were unaffected. Parp1-/-Rad52-/- transgenic mice are healthy and indistinguishable from wild-type mice due to the presence of the BRCA-pathway, and Parp1-/-Rad52-/- mice with inducible BRCA1-deficient leukemia displayed significantly prolonged survival when compared to Parp1-/- and Rad52-/- counterparts. Finally, PARPi + RAD52i selectively targeted BRCA1-deficient solid tumors in immunodeficient mice with minimal toxicity to normal cells and tissues which are protected by the BRCA-pathway, indicating minimal side effects. In conclusion, our data indicate that combination treatment of RAD52i and PARPi will significantly improve therapeutic outcome of BRCA-deficient malignancies compared to treatment with PARPi monotherapy, while leaving healthy cells and tissues unharmed.
Temple University – Theses
Advisors/Committee Members: Skorski, Tomasz;, Soprano, Dianne R., Grana-Amat, Xavier, Liebermann, Dan A., Pomerantz, Richard T., Johnson, Neil, Mazin, Alex;.
Subjects/Keywords: Oncology; Cellular biology;
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APA (6th Edition):
Reed, K. S. (2018). Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Cancers. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,507327
Chicago Manual of Style (16th Edition):
Reed, Katherine Sullivan. “Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Cancers.” 2018. Doctoral Dissertation, Temple University. Accessed April 14, 2021.
http://digital.library.temple.edu/u?/p245801coll10,507327.
MLA Handbook (7th Edition):
Reed, Katherine Sullivan. “Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Cancers.” 2018. Web. 14 Apr 2021.
Vancouver:
Reed KS. Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Cancers. [Internet] [Doctoral dissertation]. Temple University; 2018. [cited 2021 Apr 14].
Available from: http://digital.library.temple.edu/u?/p245801coll10,507327.
Council of Science Editors:
Reed KS. Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Cancers. [Doctoral Dissertation]. Temple University; 2018. Available from: http://digital.library.temple.edu/u?/p245801coll10,507327
University of Saskatchewan
4.
Paul, James 1986-.
Synthetic lethal interactions of EPHB6 in breast cancer cells.
Degree: 2016, University of Saskatchewan
URL: http://hdl.handle.net/10388/7663
► Sequencing of tumor genomes has shown that many loss-of-function alterations exist in cancer cells. Some of these alterations are a product of the cancerous progression…
(more)
▼ Sequencing of tumor genomes has shown that many loss-of-function alterations exist in cancer cells. Some of these alterations are a product of the cancerous progression of such cells, while others play a causative role. Unlike gain-of-function or overexpression alterations, these loss-of-function alterations are difficult to target directly, meaning that alternative approaches are necessary. In this case, such alterations can be specifically targeted through utilizing
synthetic lethal interactions, whereby simultaneous inhibition of a particular interacting partner gene causes
lethality in the context of a previously inactivated gene. Such a loss-of-function alteration occurs in the case of the EPHB6 receptor tyrosine kinase, which is downregulated in multiple cancer types. This downregulation of EPHB6, along with its inherent anti-malignant properties, make it a logical target for the
synthetic lethal approach. In my thesis, I describe the use of a large-scale genome-wide screen of EPHB6 in triple-negative beast caner cells to determine corresponding
synthetic lethal genes, which may be therapeutically targeted. The screen revealed the SRC kinase as a
synthetic lethal partner of EPHB6, whereby targeting of SRC in EPHB6-deficient cells results in
lethality. In addition, small molecule SRC inhibitors, such as KX2-391, were used to improve elimination of EPHB6-deficient triple-negative breast cancer cells in both monolayer culture, as well as in xenograft tumor models. This work reveals EPHB6 to be a biomarker for the use of SRC inhibitors in triple negative breast cancer, and it contributes to larger
synthetic lethal interaction maps of cancer as a whole.
Advisors/Committee Members: Vizeacoumar, Franco, Freywald, Andrew, Lee, Jeremy, Lukong, Erique, Chelico, Linda.
Subjects/Keywords: breast cancer; genetic interaction; synthetic lethality; EPHB6; SRC kinase; KX2-391
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APA (6th Edition):
Paul, J. 1. (2016). Synthetic lethal interactions of EPHB6 in breast cancer cells. (Thesis). University of Saskatchewan. Retrieved from http://hdl.handle.net/10388/7663
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Paul, James 1986-. “Synthetic lethal interactions of EPHB6 in breast cancer cells.” 2016. Thesis, University of Saskatchewan. Accessed April 14, 2021.
http://hdl.handle.net/10388/7663.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Paul, James 1986-. “Synthetic lethal interactions of EPHB6 in breast cancer cells.” 2016. Web. 14 Apr 2021.
Vancouver:
Paul J1. Synthetic lethal interactions of EPHB6 in breast cancer cells. [Internet] [Thesis]. University of Saskatchewan; 2016. [cited 2021 Apr 14].
Available from: http://hdl.handle.net/10388/7663.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Paul J1. Synthetic lethal interactions of EPHB6 in breast cancer cells. [Thesis]. University of Saskatchewan; 2016. Available from: http://hdl.handle.net/10388/7663
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Wesleyan University
5.
Zhang, Shu.
Masking DNA Single-Strand Break (SSB): a New Approach to Cancer Treatment.
Degree: Chemistry, 2014, Wesleyan University
URL: https://wesscholar.wesleyan.edu/etd_mas_theses/78
► Certain types of cancer have defective repair mechanisms, which can cause the accumulation of damaged DNA. The persistent DNA damage can stall replication process…
(more)
▼ Certain types of cancer have defective repair mechanisms, which can cause the accumulation of damaged DNA. The persistent DNA damage can stall replication process and cause cell death. This type of defect found in cancer cells allows the development of new cancer treatment by exploiting the weakness of repair pathways. One alternative approach is to hide the damaged DNA from the malfunction repair mechanism. The aim of the research is to discover drug-like molecules that could mask the damaged site on duplex DNA. Spermine, spermidine, tetralysine, hoechest33258, DAPI, netropsin, berenil, and ethidium bromide (EtBr) have been tested for this purpose. An improved hydroxyl radical cleavage protocol is used to cleave the DNA to obtain structural information of the damaged site in the presence and absence of ligand. The preliminary result indicates that EtBr discriminates the damaged site on DNA. Other ligands fail to produce binding specificity relative to the damaged site.
Advisors/Committee Members: Philip H. Bolton, Rex F. Pratt, Ishita Mukerji.
Subjects/Keywords: DNA damage; DNA damage repair; Synthetic Lethality; SSB; DSB
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APA (6th Edition):
Zhang, S. (2014). Masking DNA Single-Strand Break (SSB): a New Approach to Cancer Treatment. (Masters Thesis). Wesleyan University. Retrieved from https://wesscholar.wesleyan.edu/etd_mas_theses/78
Chicago Manual of Style (16th Edition):
Zhang, Shu. “Masking DNA Single-Strand Break (SSB): a New Approach to Cancer Treatment.” 2014. Masters Thesis, Wesleyan University. Accessed April 14, 2021.
https://wesscholar.wesleyan.edu/etd_mas_theses/78.
MLA Handbook (7th Edition):
Zhang, Shu. “Masking DNA Single-Strand Break (SSB): a New Approach to Cancer Treatment.” 2014. Web. 14 Apr 2021.
Vancouver:
Zhang S. Masking DNA Single-Strand Break (SSB): a New Approach to Cancer Treatment. [Internet] [Masters thesis]. Wesleyan University; 2014. [cited 2021 Apr 14].
Available from: https://wesscholar.wesleyan.edu/etd_mas_theses/78.
Council of Science Editors:
Zhang S. Masking DNA Single-Strand Break (SSB): a New Approach to Cancer Treatment. [Masters Thesis]. Wesleyan University; 2014. Available from: https://wesscholar.wesleyan.edu/etd_mas_theses/78
University of Toronto
6.
Lian, Huan.
Exploration of Essential Biological Processes by Construction of Conditional Alleles of Non-essential Genes in S. cerevisiae.
Degree: 2017, University of Toronto
URL: http://hdl.handle.net/1807/77842
► Conditional mutants in S. cerevisiae have been useful tools in studying essential gene functions. In this study, I describe a new method that makes use…
(more)
▼ Conditional mutants in S. cerevisiae have been useful tools in studying essential gene functions. In this study, I describe a new method that makes use of yeast deletion collections with a marker swap system to generate conditional temperature sensitive (TS) mutations in non-essential genes. I created TS mutants of BNI1, a non-essential formin gene, in various genetic backgrounds that BNI1 is essential for viability. I also constructed reciprocal TS alleles in five genes that are synthetic lethal with bni1 deletion. I screened for dosage suppressors in various synthetic lethal backgrounds of BNI1, covering different biological processes. I identified process-specific as well as common suppressors for each synthetic lethal pair. I also constructed morphological marker strains that are compatible with my system. My studies demonstrate the feasibility of construction TS mutant alleles of non-essential genes, and their utility for exploring synthetic lethal phenotypes.
M.Sc.
Advisors/Committee Members: Andrews, Brenda, Boone, Charlie, Molecular and Medical Genetics.
Subjects/Keywords: Budding yeast; Dosage suppression; Genetic interactions; Mutagenesis; Synthetic lethality; 0369
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APA ·
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APA (6th Edition):
Lian, H. (2017). Exploration of Essential Biological Processes by Construction of Conditional Alleles of Non-essential Genes in S. cerevisiae. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/77842
Chicago Manual of Style (16th Edition):
Lian, Huan. “Exploration of Essential Biological Processes by Construction of Conditional Alleles of Non-essential Genes in S. cerevisiae.” 2017. Masters Thesis, University of Toronto. Accessed April 14, 2021.
http://hdl.handle.net/1807/77842.
MLA Handbook (7th Edition):
Lian, Huan. “Exploration of Essential Biological Processes by Construction of Conditional Alleles of Non-essential Genes in S. cerevisiae.” 2017. Web. 14 Apr 2021.
Vancouver:
Lian H. Exploration of Essential Biological Processes by Construction of Conditional Alleles of Non-essential Genes in S. cerevisiae. [Internet] [Masters thesis]. University of Toronto; 2017. [cited 2021 Apr 14].
Available from: http://hdl.handle.net/1807/77842.
Council of Science Editors:
Lian H. Exploration of Essential Biological Processes by Construction of Conditional Alleles of Non-essential Genes in S. cerevisiae. [Masters Thesis]. University of Toronto; 2017. Available from: http://hdl.handle.net/1807/77842
Texas Medical Center
7.
Huang, Shaoyi.
Induction of synthetic lethality in mutant KRAS cells for non-small cell lung cancers chemoprevention and therapy.
Degree: PhD, 2013, Texas Medical Center
URL: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/396
► Lung cancer is the leading cause of cancer death in both men and women in the United States and worldwide. Despite improvement in treatment…
(more)
▼ Lung cancer is the leading cause of cancer death in both men and women in the United States and worldwide. Despite improvement in treatment strategies, the 5-year survival rate of lung cancer patients remains low. Thus, effective chemoprevention and treatment approaches are sorely needed. Mutations and activation of KRAS occur frequently in tobacco users and the early stage of development of non-small cell lung cancers (NSCLC). So they are thought to be the primary driver for lung carcinogenesis. My work showed that
KRAS mutations and activations modulated the expression of TNF-related apoptosis-inducing ligand (TRAIL) receptors by up-regulating death receptors and down-regulating decoy receptors. In addition, we showed that KRAS suppresses cellular FADD-like IL-1β-converting enzyme (FLICE)-like inhibitory protein (c-FLIP) expression through activation of ERK/MAPK-mediated activation of c-MYC which means the mutant
KRAS cells could be specifically targeted via TRAIL induced apoptosis. The expression level of Inhibitors of Apoptosis Proteins (IAPs) in mutant
KRAS cells is usually high which could be overcome by the second mitochondria-derived activator of caspases (Smac) mimetic. So the combination of TRAIL and Smac mimetic induced the
synthetic lethal reaction specifically in the mutant-KRAS cells but not in normal lung cells and wild-type
KRAS lung cancer cells. Therefore, a
synthetic lethal interaction among TRAIL, Smac mimetic and
KRAS mutations could be used as an approach for chemoprevention and treatment of NSCLC with
KRAS mutations. Further data in animal experiments showed that short-term, intermittent treatment with TRAIL and Smac mimetic induced apoptosis in mutant
KRAS cells and reduced tumor burden in a KRAS-induced pre-malignancy model and mutant
KRAS NSCLC xenograft models. These results show the great potential benefit of a selective therapeutic approach for the chemoprevention and treatment of NSCLC with
KRAS mutations.
Advisors/Committee Members: Xiangwei Wu, Carlos Caulin, Bingliang Fang.
Subjects/Keywords: NSCLC; KRAS; Synthetic lethality; Chemoprevention; Medicine and Health Sciences
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APA ·
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MLA ·
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APA (6th Edition):
Huang, S. (2013). Induction of synthetic lethality in mutant KRAS cells for non-small cell lung cancers chemoprevention and therapy. (Doctoral Dissertation). Texas Medical Center. Retrieved from https://digitalcommons.library.tmc.edu/utgsbs_dissertations/396
Chicago Manual of Style (16th Edition):
Huang, Shaoyi. “Induction of synthetic lethality in mutant KRAS cells for non-small cell lung cancers chemoprevention and therapy.” 2013. Doctoral Dissertation, Texas Medical Center. Accessed April 14, 2021.
https://digitalcommons.library.tmc.edu/utgsbs_dissertations/396.
MLA Handbook (7th Edition):
Huang, Shaoyi. “Induction of synthetic lethality in mutant KRAS cells for non-small cell lung cancers chemoprevention and therapy.” 2013. Web. 14 Apr 2021.
Vancouver:
Huang S. Induction of synthetic lethality in mutant KRAS cells for non-small cell lung cancers chemoprevention and therapy. [Internet] [Doctoral dissertation]. Texas Medical Center; 2013. [cited 2021 Apr 14].
Available from: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/396.
Council of Science Editors:
Huang S. Induction of synthetic lethality in mutant KRAS cells for non-small cell lung cancers chemoprevention and therapy. [Doctoral Dissertation]. Texas Medical Center; 2013. Available from: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/396
University of California – Irvine
8.
Thompson, Jordan Michael.
Identifying Synthetic Lethal Interactions in VHL-Deficient CC-RCC.
Degree: Biological Sciences, 2017, University of California – Irvine
URL: http://www.escholarship.org/uc/item/9fw83435
► Clear Cell Renal Cell Carcinoma (CC-RCC) is a devastating disease in its metastatic manifestation with a 5-year survival rate of 11.7%. The loss of the…
(more)
▼ Clear Cell Renal Cell Carcinoma (CC-RCC) is a devastating disease in its metastatic manifestation with a 5-year survival rate of 11.7%. The loss of the tumor suppressor von Hippel-Lindau (VHL) has been shown to drive the initiation and progression of CC-RCC. Since most of the currently approved FDA therapies act on a patient’s endothelial cells to reduce angiogenesis, instead of directly on the tumor, new targeted therapies are needed to treat this disease. One method for identifying targeted and tumor specific therapies is by identifying synthetic lethal interactions with the most common mutations in the cancer.We conducted an annotated chemical library screen in a CC-RCC cell line with and without VHL re-expressed and identified seven potential synthetic lethal interactions. Validation of these potential hits confirmed that inhibition of Rho Kinase (ROCK) 1 is synthetically lethal with VHL loss in CC-RCC. We then confirmed the interaction both genetically via siRNA knockdown and with multiple ROCK inhibitors. The synthetic lethality interaction effect between ROCK1 inhibition and VHL loss is dependent on the overactivation of HIFs that occurs upon VHL loss. Furthermore, treatment with the ROCK inhibitor Y-27632 inhibited tumor growth in vivo in a subcutaneous xenograft model using 786-O CC-RCC cells. While ROCK inhibitors have great potential to become CC-RCC therapeutics, with the exception of Fasudil approved in Japan and China for treating cerebral vasospasm and pulmonary hypertension, the existing inhibitors are currently limited to topical applications for glaucoma. Statins, HMG CoA Reductase inhibitors, can disrupt the Rho/ROCK pathway at doses administered for treating hypercholesterolemia. We have confirmed the synthetic lethal effect of statin treatment in VHL-deficient CC-RCC. The effect is cytostatic at low nanomolar doses and becomes cytotoxic as the dose is increased into the low micromolar. The addition of both Mevalonate and Geranylgeranyl pyrophosphate (GGPP) can fully rescue the effect. Increasing ROCK activity with arachidonic acid only partially rescues the effect suggesting that statins act through more synthetic lethal partners beyond the Rho/ROCK pathway. In vivo, treatment with Fluvastatin decreased tumor initiation and caused tumor regression in established tumors in subcutaneous xenograft models using 786-O CC-RCC cells. Combined, these studies identify ROCK inhibitors and HMG CoA Reductase inhibitors as promising new therapies for treating VHL-deficient CC-RCC and the biomarkers (VHL/HIF pathway) by which patients can be stratified for clinical trials.
Subjects/Keywords: Molecular biology; Biochemistry; CC-RCC; Rho Kinase; Statin; Synthetic Lethality; VHL
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APA ·
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APA (6th Edition):
Thompson, J. M. (2017). Identifying Synthetic Lethal Interactions in VHL-Deficient CC-RCC. (Thesis). University of California – Irvine. Retrieved from http://www.escholarship.org/uc/item/9fw83435
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Thompson, Jordan Michael. “Identifying Synthetic Lethal Interactions in VHL-Deficient CC-RCC.” 2017. Thesis, University of California – Irvine. Accessed April 14, 2021.
http://www.escholarship.org/uc/item/9fw83435.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Thompson, Jordan Michael. “Identifying Synthetic Lethal Interactions in VHL-Deficient CC-RCC.” 2017. Web. 14 Apr 2021.
Vancouver:
Thompson JM. Identifying Synthetic Lethal Interactions in VHL-Deficient CC-RCC. [Internet] [Thesis]. University of California – Irvine; 2017. [cited 2021 Apr 14].
Available from: http://www.escholarship.org/uc/item/9fw83435.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Thompson JM. Identifying Synthetic Lethal Interactions in VHL-Deficient CC-RCC. [Thesis]. University of California – Irvine; 2017. Available from: http://www.escholarship.org/uc/item/9fw83435
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Boston University
9.
O'Connor, Kevin William.
Molecular determinants of sensitivity to poly(ADP-ribose) polymerase inhibitors in epithelial ovarian cancer.
Degree: MS, Medical Sciences, 2016, Boston University
URL: http://hdl.handle.net/2144/16827
► Less than half of patients with epithelial ovarian cancer (EOC) survive five years following diagnosis, underscoring the imperative need for improved treatment. Many patients, including…
(more)
▼ Less than half of patients with epithelial ovarian cancer (EOC) survive five years following diagnosis, underscoring the imperative need for improved treatment. Many patients, including those with advanced disease, initially respond to platinum agents, which constitute the backbone of therapy. However, tumors ultimately become resistant, rendering further treatment ineffective. Additionally, the poor tolerability of these agents warrants the exploration of more targeted treatments – one such strategy is exploiting synthetic lethal genetic relationships. Recent genomic sequencing efforts have revealed that as many of half of EOCs have homologous recombination (HR) alterations. HR is a critical pathway for the repair of platinum-induced ICLs, thus compromised HR is hypothesized to explain the initial response to chemotherapy in many patients. Accordingly, women whose tumors harbor mutations in the critical HR genes, BRCA1 or BRCA2 (BRCA1/2), demonstrate improved prognosis. BRCA1/2 mutations also confer exquisite sensitivity to inhibitors of the enzyme, poly(ADP-ribose) polymerase 1 (PARPis), hence loss of BRCA1/2 and PARP1 is synthetic lethal. A number of models have been proposed to explain this synthetic lethality, yet a consensus model that accounts for the diverse cellular roles of BRCA1/2 and PARP1 has yet to be established. Delineating the precise molecular underpinnings of PARPi action in BRCA1/2-deficient cells will aid clinicians in identifying the appropriate population of women with EOC likely to benefit from PARPi treatment and provide insight into resistance mechanisms that arise in these patients. Combining this approach with retrospective analysis of PARPi clinical trials will best define the proper indication for PARPi in EOC and other human cancers.
Subjects/Keywords: Oncology; PARP inhibitors; Homologous recombination; Ovarian cancer; Synthetic lethality
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APA (6th Edition):
O'Connor, K. W. (2016). Molecular determinants of sensitivity to poly(ADP-ribose) polymerase inhibitors in epithelial ovarian cancer. (Masters Thesis). Boston University. Retrieved from http://hdl.handle.net/2144/16827
Chicago Manual of Style (16th Edition):
O'Connor, Kevin William. “Molecular determinants of sensitivity to poly(ADP-ribose) polymerase inhibitors in epithelial ovarian cancer.” 2016. Masters Thesis, Boston University. Accessed April 14, 2021.
http://hdl.handle.net/2144/16827.
MLA Handbook (7th Edition):
O'Connor, Kevin William. “Molecular determinants of sensitivity to poly(ADP-ribose) polymerase inhibitors in epithelial ovarian cancer.” 2016. Web. 14 Apr 2021.
Vancouver:
O'Connor KW. Molecular determinants of sensitivity to poly(ADP-ribose) polymerase inhibitors in epithelial ovarian cancer. [Internet] [Masters thesis]. Boston University; 2016. [cited 2021 Apr 14].
Available from: http://hdl.handle.net/2144/16827.
Council of Science Editors:
O'Connor KW. Molecular determinants of sensitivity to poly(ADP-ribose) polymerase inhibitors in epithelial ovarian cancer. [Masters Thesis]. Boston University; 2016. Available from: http://hdl.handle.net/2144/16827
University of Manitoba
10.
Guppy, Brent.
Characterizing and selectively targeting RNF20 defects within colorectal cancer cells.
Degree: Biochemistry and Medical Genetics, 2016, University of Manitoba
URL: http://hdl.handle.net/1993/31860
► By 2030, the global colorectal cancer burden is projected to approximately double. This highlights the immediate need to expand our understanding of the etiological origins…
(more)
▼ By 2030, the global colorectal cancer burden is projected to approximately double. This highlights the immediate need to expand our understanding of the etiological origins of colorectal cancer, so that novel therapeutic strategies can be identified and validated. The putative tumor suppressor gene RNF20 encodes a histone H2B mono-ubiquitin ligase and has been found altered/mutated in colorectal and numerous other cancer types. Several studies suggest that RNF20, and by extension mono-ubiquitinated histone H2B (H2Bub1), play important roles in maintaining genome stability in human cells. Indeed, hypomorphic RNF20 expression and/or function have been shown to underlie several phenotypes consistent with genome instability, making aberrant RNF20 biology a potential driver in oncogenesis.
Through an evolutionarily conserved trans-histone pathway, RNF20 and H2Bub1 have been shown to modulate downstream di-methylation events at lysines 4 (H3K4me2) and 79 (H3K79me2) of histone H3. Accordingly, understanding the biology associated with RNF20, H2Bub1, H3K4me2, and H3K79me2 is an essential preliminary step towards understanding the etiological origins of cancer-associated RNF20 alterations and identifying a novel therapeutic strategy to selectively kill RNF20-deficient cancers.
In this thesis, I employ single-cell imaging, and multiple biochemical techniques to investigate the spatial and temporal patterning and characterize the biology of RNF20, H2Bub1, H3K4me2 and H3K79me2 throughout the cell cycle. In addition, I employ the CRISPR-Cas9 genome editing system to generate RNF20-deficient HCT116 cells. Finally, I employ
synthetic lethal strategies to selectively kill RNF20-depleted cells.
In conclusion, the research chapters contained within this thesis have characterized putative drivers in cancer (Chapter 3), generated a valuable research reagent for CRISPR-Cas9
ii
genome editing experiments (Chapter 4), and identified a novel therapeutic strategy to selectively kill certain cancer cells (Chapter 5). This thesis has increased our understanding of the etiological origins of cancer and generated novel reagents and treatments strategies that after further validation and clinical studies, could be employed to reduce morbidity and mortality rates associated with cancer.
Advisors/Committee Members: McManus, Kirk (Biochemistry and Medical Genetics) (supervisor), Davie, James (Biochemistry and Medical Genetics) Mai, Sabine (Physiology) Kung, Sam (Immunology) Poirier, Guy (Proteomics) (examiningcommittee).
Subjects/Keywords: RNF20; H2Bub1; H3K79me2; H3K4me2; CRISPR-Cas9; Synthetic lethality; Colorectal cancer
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APA (6th Edition):
Guppy, B. (2016). Characterizing and selectively targeting RNF20 defects within colorectal cancer cells. (Thesis). University of Manitoba. Retrieved from http://hdl.handle.net/1993/31860
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Guppy, Brent. “Characterizing and selectively targeting RNF20 defects within colorectal cancer cells.” 2016. Thesis, University of Manitoba. Accessed April 14, 2021.
http://hdl.handle.net/1993/31860.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Guppy, Brent. “Characterizing and selectively targeting RNF20 defects within colorectal cancer cells.” 2016. Web. 14 Apr 2021.
Vancouver:
Guppy B. Characterizing and selectively targeting RNF20 defects within colorectal cancer cells. [Internet] [Thesis]. University of Manitoba; 2016. [cited 2021 Apr 14].
Available from: http://hdl.handle.net/1993/31860.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Guppy B. Characterizing and selectively targeting RNF20 defects within colorectal cancer cells. [Thesis]. University of Manitoba; 2016. Available from: http://hdl.handle.net/1993/31860
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Ottawa
11.
Wedge, Marie-Ève.
Tailoring Oncolytic Viruses for the Treatment of Pancreatic Cancer
.
Degree: 2020, University of Ottawa
URL: http://hdl.handle.net/10393/40384
► Pancreatic cancer (PC) is a highly aggressive disease with unmet therapeutic needs. Recent advances in the use of oncolytic viruses (OVs) as cancer therapeutic agents…
(more)
▼ Pancreatic cancer (PC) is a highly aggressive disease with unmet therapeutic needs. Recent advances in the use of oncolytic viruses (OVs) as cancer therapeutic agents bring new hope to fight the notorious disease that is PC. Although OVs have shown promising results in certain cancers, some tumors remain resistant to OV therapy due to their inherent residual antiviral mechanisms. We hypothesized that the use of OV-encoded artificial microRNAs (amiRNAs) could help target the cellular antiviral components associated with the observed OV resistance and could also sensitize neighboring tumor cells to OV therapy and small molecule inhibitors through the secretion of amiRNA-containing extracellular vesicles (EVs) from infected cells. To find such amiRNAs, a viral surrogate library encoding ~16,000 unique amiRNAs was passaged in pancreatic cancer cell lines to enrich for sequences that could enhance OV replication. An amiRNA that improves PC cell killing when expressed from an OV was identified. Target identification of this amiRNA (amiR-4) revealed ARID1A as a key player in resistance to OV therapy in pancreatic cancers. This target is of particular interest, since its downregulation acts in a synthetic lethal fashion with inhibition of the EZH2 methyltransferase. Combining VSV51-amiR-4 with a small molecule inhibitor of EZH2 enhances PC cell death. Moreover, amiR-4 is packaged in cancer cell-secreted EVs which can reach neighboring naïve cells to sensitize them to EZH2 inhibition-mediated cell death and to spread the OV-mediated tumor killing effect throughout the tumor. This data translates into tumor debulking and survival in animal models of highly aggressive PC. This work not only broadens our knowledge on the resistance of select tumors to oncolytic virotherapy and the EV-mediated bystander killing effect in OV-infected tumors, but it also establishes OVs as a novel tool to produce anti-cancer therapeutic EVs in situ to improve therapeutic gain. Ultimately, our work provides new hope for a cure to the grim disease that is PC.
Subjects/Keywords: Oncolytic virus;
Pancreatic cancer;
Extracellular vesicles;
microRNA;
Synthetic lethality;
Bystander effect
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APA ·
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MLA ·
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CSE |
Export
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APA (6th Edition):
Wedge, M. (2020). Tailoring Oncolytic Viruses for the Treatment of Pancreatic Cancer
. (Thesis). University of Ottawa. Retrieved from http://hdl.handle.net/10393/40384
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Wedge, Marie-Ève. “Tailoring Oncolytic Viruses for the Treatment of Pancreatic Cancer
.” 2020. Thesis, University of Ottawa. Accessed April 14, 2021.
http://hdl.handle.net/10393/40384.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Wedge, Marie-Ève. “Tailoring Oncolytic Viruses for the Treatment of Pancreatic Cancer
.” 2020. Web. 14 Apr 2021.
Vancouver:
Wedge M. Tailoring Oncolytic Viruses for the Treatment of Pancreatic Cancer
. [Internet] [Thesis]. University of Ottawa; 2020. [cited 2021 Apr 14].
Available from: http://hdl.handle.net/10393/40384.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Wedge M. Tailoring Oncolytic Viruses for the Treatment of Pancreatic Cancer
. [Thesis]. University of Ottawa; 2020. Available from: http://hdl.handle.net/10393/40384
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Universitat de Valencia
12.
Llorca Cardeñosa, Marta Jessica.
Genetic determinants of ATR inhibitor sensitivity and resistance in Gastric Cancer
.
Degree: 2019, Universitat de Valencia
URL: http://hdl.handle.net/10550/70728
► Synthetic lethal approaches in identifying genetic determinants of drug response is a powerful method in selecting patents for targeted cancer therapies. Ataxia-Telangiectasia Mutated (ATM) and…
(more)
▼ Synthetic lethal approaches in identifying genetic determinants of drug response is a powerful method in selecting patents for targeted cancer therapies. Ataxia-Telangiectasia Mutated (ATM) and Rad3-related protein kinase (ATR) is a valuable target to inhibit the DNA damage repair (DDR) pathway, that has been shown to be particularly effective in cancer cells harbouring other DDR defects, including truncating mutations in ARID1A, found in the 20% of gastric cancer (GC) patients. Although ATR inhibitors (ATRi) are emerging as promising cancer therapies, resistance mechanisms inevitably arise from these drugs as monotherapy, emphasising the importance of identifying genetic determinants of response and resistance to inform drug combinations that result in durable clinical responses.
In this thesis, an integrated functional genomics approach was undertaken in order to identify genetic determinants to ATRi sensitivity and resistance in GC. First, I show that ARID1A defective GCs in vitro and in vivo models exhibit enhanced sensitivity to ATRi. Second, I have comprehensively identified and validated genetic determinants of ATRi-resistance by undertaking a genome-wide (GW) CRISPR/Cas9 screen and created ATRi resistant isogenic models, including CDC25B, HUWE1, CARD10, SMG8, SMG9, SMG1, HNRNPF, IRF9, and STAT2. Lastly, I have shown for the first time that mutations in the ATR FAT domain cause resistance to ATRi.
These findings inform us about the biological mechanisms of ATRi sensitivity and resistance in GC. Furthermore, this data provides the preclinical rationale for assessing ATRi such as VX970, AZD6738 or M4344 in clinical trials, for patients with GC.
Advisors/Committee Members: Ribas Despuig, Gloria (advisor).
Subjects/Keywords: ATR inhibitors;
synthetic lethality;
ATR;
ARID1A;
GW CRISPR screen;
gastric cancer
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
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Manager
APA (6th Edition):
Llorca Cardeñosa, M. J. (2019). Genetic determinants of ATR inhibitor sensitivity and resistance in Gastric Cancer
. (Doctoral Dissertation). Universitat de Valencia. Retrieved from http://hdl.handle.net/10550/70728
Chicago Manual of Style (16th Edition):
Llorca Cardeñosa, Marta Jessica. “Genetic determinants of ATR inhibitor sensitivity and resistance in Gastric Cancer
.” 2019. Doctoral Dissertation, Universitat de Valencia. Accessed April 14, 2021.
http://hdl.handle.net/10550/70728.
MLA Handbook (7th Edition):
Llorca Cardeñosa, Marta Jessica. “Genetic determinants of ATR inhibitor sensitivity and resistance in Gastric Cancer
.” 2019. Web. 14 Apr 2021.
Vancouver:
Llorca Cardeñosa MJ. Genetic determinants of ATR inhibitor sensitivity and resistance in Gastric Cancer
. [Internet] [Doctoral dissertation]. Universitat de Valencia; 2019. [cited 2021 Apr 14].
Available from: http://hdl.handle.net/10550/70728.
Council of Science Editors:
Llorca Cardeñosa MJ. Genetic determinants of ATR inhibitor sensitivity and resistance in Gastric Cancer
. [Doctoral Dissertation]. Universitat de Valencia; 2019. Available from: http://hdl.handle.net/10550/70728
University of Oklahoma
13.
Bhowmik, Bijit Kumar.
Chromosome Organization and Segregation in Pseudomonas Aeruginosa.
Degree: Dr.P.H, 2017, University of Oklahoma
URL: http://hdl.handle.net/11244/52950
► To determine the segregation pattern in the P. aeruginosa strain PAO1, a fluorescent repressor-operator system was used. The data indicate that the PAO1 chromosome is…
(more)
▼ To determine the segregation pattern in the P. aeruginosa strain PAO1, a fluorescent repressor-operator system was used. The data indicate that the PAO1 chromosome is longitudinally organized between the origin of replication site, oriC to the sister chromosome resolution site, dif. In PAO1, both replication and segregation initiate at oriC and progress bidirectionally. Interestingly, chromosome segregation but not replication ends at the dif site. Proteins of the condensin family play a major role in global chromosome organization in both prokaryotes and eukaryotes. In Pseudomonas aeruginosa, two different families of condensins are present: MksBEF and SMC-ScpAB. These two proteins localize on different regions of the chromosome and differentially affect chromosome segregation. Finally, the study uncovered a novel co-ordination between condensin mediated global chromosome organization and ParABS mediated chromosome segregation, where the presence of at least one of them is necessary for cell viability.
Advisors/Committee Members: Rybenkov, Valentin V. (advisor), Zgurskaya, Elena (committee member), Rajan, Rakhi (committee member), Bourne, Christina (committee member), Libault, Marc (committee member).
Subjects/Keywords: Pseudomonas aeruginosa; Two condensins; Asymmetric chromosome; Chromosome segregation; ParB; Synthetic lethality
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Export
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APA (6th Edition):
Bhowmik, B. K. (2017). Chromosome Organization and Segregation in Pseudomonas Aeruginosa. (Doctoral Dissertation). University of Oklahoma. Retrieved from http://hdl.handle.net/11244/52950
Chicago Manual of Style (16th Edition):
Bhowmik, Bijit Kumar. “Chromosome Organization and Segregation in Pseudomonas Aeruginosa.” 2017. Doctoral Dissertation, University of Oklahoma. Accessed April 14, 2021.
http://hdl.handle.net/11244/52950.
MLA Handbook (7th Edition):
Bhowmik, Bijit Kumar. “Chromosome Organization and Segregation in Pseudomonas Aeruginosa.” 2017. Web. 14 Apr 2021.
Vancouver:
Bhowmik BK. Chromosome Organization and Segregation in Pseudomonas Aeruginosa. [Internet] [Doctoral dissertation]. University of Oklahoma; 2017. [cited 2021 Apr 14].
Available from: http://hdl.handle.net/11244/52950.
Council of Science Editors:
Bhowmik BK. Chromosome Organization and Segregation in Pseudomonas Aeruginosa. [Doctoral Dissertation]. University of Oklahoma; 2017. Available from: http://hdl.handle.net/11244/52950
14.
Walason da Silva Abjaude.
Estudo de letalidade sintética em células transformadas por papilomavírus humano (HPV).
Degree: 2016, University of São Paulo
URL: http://www.teses.usp.br/teses/disponiveis/42/42132/tde-15052017-144525/
► Os Papilomavírus Humanos (HPV) são vírus de DNA, não envelopados que infectam as células epiteliais. A infecção persistente por alguns tipos de HPV é o…
(more)
▼ Os Papilomavírus Humanos (HPV) são vírus de DNA, não envelopados que infectam as células epiteliais. A infecção persistente por alguns tipos de HPV é o principal fator de risco para o desenvolvimento do câncer cervical. A maquinaria de reparo de DNA desempenha um papel essencial em várias fases do ciclo de vida do HPV e é crucial para a sobrevivência de células tumorais. Durante a transformação maligna, as oncoproteínas E6 e E7 de HPV são capazes de induzir alterações cromossômicas e numéricas, além de modular a resposta de danos ao DNA. Estas observações sugerem que a maquinaria celular de reparo de dano ao DNA podem desempenhar um papel duplo na biologia do HPV e na sua patogênese. No presente estudo, procurou-se investigar o papel das proteínas de reparo de DNA na biologia das células derivadas de câncer cervical. A fim de alcançar este objetivo, a expressão de 189 genes foi silenciada em células HeLa (HPV 18) e em células SiHa (HPV16), bem como
em queratinócitos humanos primários (QHP), utilizando vetores lentivirais que expressam shRNAs específicos. O efeito do silenciamento gênico foi determinado por ensaios de viabilidade celular, análise de proliferação celular, ensaio clonogênico e de formação de colônias em soft ágar. Observamos que o silenciamento dos genes ATM, BRCA1, CHEK2 e HMGB1 reduziu a taxa de crescimento celular, o potencial de crescimento em colônia e a capacidade de crescimento independente de ancoragem das linhagens celulares derivadas de câncer cervical transformadas por HPV, sem afetar QHP. O tratamento das linhagens celulares com fármacos capazes de inibir a atividade das proteínas ATM e CHEK2 revelou uma maior sensibilidade das células tumorais à inibição destas proteínas quando comparadas a QHP. Além disso, mostramos que QHP que expressavam E6E7 ou somente E6 de HPV16 foram mais sensíveis a estes inibidores, quando comparados ao controle QHP ou QHP expressando apenas E7. Além disso, QHP que
expressavam mutantes de E6 de HPV16, defectivos para a degradação de p53, foram menos sensíveis do que QHP, que expressavam HPV16 E6 selvagem. Desta forma, estes resultados indicam que estes genes são necessários para a sobrevivência de células transformadas por HPV. Além disso, os nossos resultados sugerem que este efeito está relacionado com a expressão oncoproteína de HPV16 E6 e a sua capacidade para degradar p53.
Human Papillomaviruses (HPV) are non-enveloped DNA viruses that infect epithelial cells. Persistent infection with some HPV types is the main risk factor for the development of cervical cancer. DNA repair machinery plays an essential role in several stages of the HPV life cycle and is crucial for tumor cells survival. During malignant transformation, HPV E6 and E7 oncoproteins induce structural and numerical chromosome alterations and modulate DNA damage response. These observations suggest that cellular DNA repair machinery may play a dual role in both HPV biology
and pathogenesis. In the present study, we sought to investigate the role of DNA repair proteins in cervical cancer…
Advisors/Committee Members: Enrique Mario Boccardo Pierulivo, Roger Chammas, Erico Tosoni Costa, Rodrigo da Silva Galhardo, Bryan Eric Strauss.
Subjects/Keywords: HPV; Letalidade sintética; Reparo de DNA; DNA repair; HPV; Synthetic lethality
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APA (6th Edition):
Abjaude, W. d. S. (2016). Estudo de letalidade sintética em células transformadas por papilomavírus humano (HPV). (Doctoral Dissertation). University of São Paulo. Retrieved from http://www.teses.usp.br/teses/disponiveis/42/42132/tde-15052017-144525/
Chicago Manual of Style (16th Edition):
Abjaude, Walason da Silva. “Estudo de letalidade sintética em células transformadas por papilomavírus humano (HPV).” 2016. Doctoral Dissertation, University of São Paulo. Accessed April 14, 2021.
http://www.teses.usp.br/teses/disponiveis/42/42132/tde-15052017-144525/.
MLA Handbook (7th Edition):
Abjaude, Walason da Silva. “Estudo de letalidade sintética em células transformadas por papilomavírus humano (HPV).” 2016. Web. 14 Apr 2021.
Vancouver:
Abjaude WdS. Estudo de letalidade sintética em células transformadas por papilomavírus humano (HPV). [Internet] [Doctoral dissertation]. University of São Paulo; 2016. [cited 2021 Apr 14].
Available from: http://www.teses.usp.br/teses/disponiveis/42/42132/tde-15052017-144525/.
Council of Science Editors:
Abjaude WdS. Estudo de letalidade sintética em células transformadas por papilomavírus humano (HPV). [Doctoral Dissertation]. University of São Paulo; 2016. Available from: http://www.teses.usp.br/teses/disponiveis/42/42132/tde-15052017-144525/
Harvard University
15.
Vallurupalli, Mounica.
Identifying Targetable Liabilities in Ewing Sarcoma.
Degree: Doctor of Medicine, 2014, Harvard University
URL: http://etds.lib.harvard.edu/hms/admin/view/62
;
http://nrs.harvard.edu/urn-3:HUL.InstRepos:12407620
► Background: Despite multi-modality therapy, the majority of patients with metastatic or recurrent Ewing sarcoma (ES), the second most common pediatric bone malignancy, will die of…
(more)
▼ Background: Despite multi-modality therapy, the majority of patients with metastatic or recurrent Ewing sarcoma (ES), the second most common pediatric bone malignancy, will die of their disease. ES tumors express aberrantly activated ETS transcription factors through translocations that fuse the EWS gene to ETS family genes FLI1 or ERG. The aberrant activation of ETS transcription factors promotes malignant transformation and proliferation. While, FLI1 or ERG cannot be readily targeted, there is an opportunity to deploy functional genomics screens, to develop novel therapeutic approaches by identifying targetable liabilities in EWS/FLI1 dependent tumors.
Materials and Methods: We performed a near whole-genome pooled shRNA screen in a panel of five EWS/FLI1 dependent Ewing sarcoma cell lines and one EWS/ERG cell line to identify essential genes. Essential genes were defined as those genes whose loss resulted in reduced viability selectively in ES cells compared to non-Ewing cancer cell lines. Essential hits were subsequently validated with genomic knockdown and chemical inhibition in vitro, followed by validation of the on-target effect of chemical inhibition. Next, we determined the in vivo effects of small-molecule inhibition on survival and tumor growth in NOD scid gamma (NSG) mice with established subcutaneous ES xenografts.
Results: Top hits in our screen that could be readily targeted by small-molecule inhibitors, and thus have potential for rapid clinical validation, were selected for further investigation. These hits included IKBKE, CCND1 and CDK4. IKBKΕ, a non-canonical IKK with an oncogenic role in breast cancer, was one of the top kinase hits in the screen. IKBKΕ shares significant homology to TBK1, another non-canonical IKK that is essential in k-RAS dependent lung cancer. We validated IKBKE through small-molecule inhibition of IKBKE/TBK1 and shRNA based knockdown. Ewing sarcoma cell lines are sensitive to low micromolar concentrations of two IKBKE/TBK1 inhibitors (CYT387 and MRT67307). Additionally, in a panel of ES cell lines, knockdown of IKBKE resulted in decreased growth and impaired colony formation. These observations, paired with impairment of NF-κB nuclear localization following CYT387 treatment suggests that non-canonical IKK mediated signaling may be essential in Ewing sarcoma. We further validated these results through inhibition of IKBKE/TBK1 in in vivo xenograft models treated with 100 mg/kg/day of CYT387. Treatment over the course of twenty-nine days resulted in a significant increase in survival (p-value = 0.0231) and a significant decrease (p-value = 0.036) in tumor size after fifteen days of treatment.
CDK4 and CCND1 are highly expressed in Ewing sarcoma as compared to other tumor types. shRNA mediated knockdown of CDK4 and CCND1 resulted in impaired viability and anchorage independent growth. Furthermore, treatment of Ewing sarcoma cell lines with a highly selective CDK4/6 inhibitor, LEE011, resulted in decreased viability (IC50 range of 0.26-18.06 μM), potent G1 arrest in six of…
Subjects/Keywords: Ewing sarcoma; synthetic lethality; cancer genomics; NF-kB; Cell cycle; chemical biology
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APA (6th Edition):
Vallurupalli, M. (2014). Identifying Targetable Liabilities in Ewing Sarcoma. (Doctoral Dissertation). Harvard University. Retrieved from http://etds.lib.harvard.edu/hms/admin/view/62 ; http://nrs.harvard.edu/urn-3:HUL.InstRepos:12407620
Chicago Manual of Style (16th Edition):
Vallurupalli, Mounica. “Identifying Targetable Liabilities in Ewing Sarcoma.” 2014. Doctoral Dissertation, Harvard University. Accessed April 14, 2021.
http://etds.lib.harvard.edu/hms/admin/view/62 ; http://nrs.harvard.edu/urn-3:HUL.InstRepos:12407620.
MLA Handbook (7th Edition):
Vallurupalli, Mounica. “Identifying Targetable Liabilities in Ewing Sarcoma.” 2014. Web. 14 Apr 2021.
Vancouver:
Vallurupalli M. Identifying Targetable Liabilities in Ewing Sarcoma. [Internet] [Doctoral dissertation]. Harvard University; 2014. [cited 2021 Apr 14].
Available from: http://etds.lib.harvard.edu/hms/admin/view/62 ; http://nrs.harvard.edu/urn-3:HUL.InstRepos:12407620.
Council of Science Editors:
Vallurupalli M. Identifying Targetable Liabilities in Ewing Sarcoma. [Doctoral Dissertation]. Harvard University; 2014. Available from: http://etds.lib.harvard.edu/hms/admin/view/62 ; http://nrs.harvard.edu/urn-3:HUL.InstRepos:12407620
16.
O. An.
ROLE OF SOMATIC COPY NUMBER VARIATIONS IN CANCER.
Degree: 2016, Università degli Studi di Milano
URL: http://hdl.handle.net/2434/361604
► Genetic variation is the main reason of the phenotypic differences among individuals, as well as of many human genetic diseases. Recent advances in the methods…
(more)
▼ Genetic variation is the main reason of the phenotypic differences among individuals, as well as of many human genetic diseases. Recent advances in the methods to study the human genetic variation allow better identification of its different forms, in particular of copy number variations (CNVs). The causative role of germline CNVs in Mendelian diseases and in cancer predisposition is well established. Moreover, the driver role of cancer somatic CNVs is recently emerging, and large-scale quantitative analyses elucidating their functional role in cancer genomes are needed. To achieve this, we have analysed the genomic landscape of somatic CNVs in cancer genomes in comparison to germline CNVs in the genomes of healthy individuals. We observed that somatic CNVs substantially affect the genic portion of the genome, preferentially targeting cancer genes. Moreover, this is independent of genomic features, such as DNA repeating elements and recombination rate. In particular, we confirmed that oncogenes are preferentially amplified and tumour suppressors are preferentially deleted. To investigate their functional impact, we measured the gene expression changes upon copy number variation. We observed that amplification of a gene leads to its higher expression whereas deletion results in decreased gene expression, which suggests that amplifications activate dominant genes and deletions inactivate recessive genes. The two classes of cancer genes are vastly modified consistent with their functional roles as oncogenes and tumour suppressors, with the few exceptions of frequently amplified recessive genes underlying complex epigenetic regulation. The mutational spectrum of the human genes in cancer, together with their systems-level properties, can be exploited to identify novel targets for anti-cancer therapy, in which
synthetic lethality emerges as a promising approach. Based on the working hypothesis that paralogous genes may engage in
synthetic lethal interactions due to the functional redundancy between them, we combined several gene properties to predict
synthetic lethality between paralogous gene pairs. Out of 37 candidate gene pairs, we experimentally validated the
synthetic lethal interaction between two components of the cohesin complex, STAG1 and STAG2. Finally, we present the latest release of Network of Cancer Genes (NCG 5.0), a manually curated database of cancer genes and their systems-level properties. NCG 5.0 collects a list of 1,571 cancer genes mutated in 13,315 cancer samples and 24 primary sites from 175 published papers. NCG has been increasingly appreciated as a central resource for cancer genomics research, facilitating candidate prioritization for hypothesis testing and experimental planning in a wide range of studies.
Advisors/Committee Members: supervisor: F. Ciccarelli, tutor: G. Testa, A. Reymond, Ciccarelli, Francesca.
Subjects/Keywords: somatic CNV; gene expression; synthetic lethality; cancer genes; Settore BIO/11 - Biologia Molecolare
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
An, O. (2016). ROLE OF SOMATIC COPY NUMBER VARIATIONS IN CANCER. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/361604
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
An, O.. “ROLE OF SOMATIC COPY NUMBER VARIATIONS IN CANCER.” 2016. Thesis, Università degli Studi di Milano. Accessed April 14, 2021.
http://hdl.handle.net/2434/361604.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
An, O.. “ROLE OF SOMATIC COPY NUMBER VARIATIONS IN CANCER.” 2016. Web. 14 Apr 2021.
Vancouver:
An O. ROLE OF SOMATIC COPY NUMBER VARIATIONS IN CANCER. [Internet] [Thesis]. Università degli Studi di Milano; 2016. [cited 2021 Apr 14].
Available from: http://hdl.handle.net/2434/361604.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
An O. ROLE OF SOMATIC COPY NUMBER VARIATIONS IN CANCER. [Thesis]. Università degli Studi di Milano; 2016. Available from: http://hdl.handle.net/2434/361604
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Cambridge
17.
Thompson, Nicola Anne.
Identification of novel synthetic lethal interactions using multiplexed CRISPR-Cas9 screening.
Degree: PhD, 2019, University of Cambridge
URL: https://www.repository.cam.ac.uk/handle/1810/291485https://www.repository.cam.ac.uk/bitstream/1810/291485/1/1.1%20Multiplex%20library%20content.xlsx
;
https://www.repository.cam.ac.uk/bitstream/1810/291485/2/1.2%20Oligonucleotides.xlsx
;
https://www.repository.cam.ac.uk/bitstream/1810/291485/3/1.3%20Gene%20pair%20output%20of%20the%20paired%20library.xlsx
;
https://www.repository.cam.ac.uk/bitstream/1810/291485/4/1.4%20Single%20gene%20output%20of%20the%20paired%20library.xlsx
;
https://www.repository.cam.ac.uk/bitstream/1810/291485/5/1.5%20Genomics%20of%20the%20cell%20lines%20used.xlsx
;
https://www.repository.cam.ac.uk/bitstream/1810/291485/6/1.6%20Mass%20spectrometry%20data.xlsx
;
https://www.repository.cam.ac.uk/bitstream/1810/291485/7/1.7%20Differential%20expression%20analysis.xlsx
;
https://www.repository.cam.ac.uk/bitstream/1810/291485/8/1.8%20RNA%20splicing%20analysis.xlsx
► Abstract As our understanding of the cancer genome has progressed, traditional chemotherapeutic agents are being replaced, in part, by targeted therapies. Development of these therapies…
(more)
▼ Abstract As our understanding of the cancer genome has progressed, traditional chemotherapeutic agents are being replaced, in part, by targeted therapies. Development of these therapies is driven by our understanding of genetic vulnerabilities harboured by tumours.
The aim of this project is to identify novel synthetic lethal interactions within melanoma. Synthetic lethality describes a relationship between two genes, where loss of either of the pair is compatible with cellular viability, but simultaneous loss of both genes induces cell death. This approach can therefore exploit somatically acquired mutations to specifically kill tumour cells and to define new therapeutic targets.
Abstract In order to do this, we selected a panel of putative synthetic lethal interactions and built a bespoke multiplex CRISPR-Cas9 library to interrogate 1192 gene-pair interactions. We deployed this library on a panel of melanoma cell lines and a retinal pigment epithelial cell line as a normal comparator. We went on to develop a bioinformatic pipeline with which to analyse the paired screen output and using this pipeline we have identified a number of novel synthetic lethal relationships. Using low throughput assays we validated a number of the interactions found by our screen. Finally, using human tumour expression data, we identified a candidate pair with potential therapeutic relevance. Using external datasets and isogenic knockout models we have further validated this relationship and performed mechanistic experiments to explore the role of these genes within the cell and generate a hypothesis to explain why loss of these two genes results in cell death.
Subjects/Keywords: CRISPR screen; synthetic lethality; paralog; FAM50A; FAM50B; paired screening; melanoma; cancer genetics; target discovery; paralogue
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Thompson, N. A. (2019). Identification of novel synthetic lethal interactions using multiplexed CRISPR-Cas9 screening. (Doctoral Dissertation). University of Cambridge. Retrieved from https://www.repository.cam.ac.uk/handle/1810/291485https://www.repository.cam.ac.uk/bitstream/1810/291485/1/1.1%20Multiplex%20library%20content.xlsx ; https://www.repository.cam.ac.uk/bitstream/1810/291485/2/1.2%20Oligonucleotides.xlsx ; https://www.repository.cam.ac.uk/bitstream/1810/291485/3/1.3%20Gene%20pair%20output%20of%20the%20paired%20library.xlsx ; https://www.repository.cam.ac.uk/bitstream/1810/291485/4/1.4%20Single%20gene%20output%20of%20the%20paired%20library.xlsx ; https://www.repository.cam.ac.uk/bitstream/1810/291485/5/1.5%20Genomics%20of%20the%20cell%20lines%20used.xlsx ; https://www.repository.cam.ac.uk/bitstream/1810/291485/6/1.6%20Mass%20spectrometry%20data.xlsx ; https://www.repository.cam.ac.uk/bitstream/1810/291485/7/1.7%20Differential%20expression%20analysis.xlsx ; https://www.repository.cam.ac.uk/bitstream/1810/291485/8/1.8%20RNA%20splicing%20analysis.xlsx
Chicago Manual of Style (16th Edition):
Thompson, Nicola Anne. “Identification of novel synthetic lethal interactions using multiplexed CRISPR-Cas9 screening.” 2019. Doctoral Dissertation, University of Cambridge. Accessed April 14, 2021.
https://www.repository.cam.ac.uk/handle/1810/291485https://www.repository.cam.ac.uk/bitstream/1810/291485/1/1.1%20Multiplex%20library%20content.xlsx ; https://www.repository.cam.ac.uk/bitstream/1810/291485/2/1.2%20Oligonucleotides.xlsx ; https://www.repository.cam.ac.uk/bitstream/1810/291485/3/1.3%20Gene%20pair%20output%20of%20the%20paired%20library.xlsx ; https://www.repository.cam.ac.uk/bitstream/1810/291485/4/1.4%20Single%20gene%20output%20of%20the%20paired%20library.xlsx ; https://www.repository.cam.ac.uk/bitstream/1810/291485/5/1.5%20Genomics%20of%20the%20cell%20lines%20used.xlsx ; https://www.repository.cam.ac.uk/bitstream/1810/291485/6/1.6%20Mass%20spectrometry%20data.xlsx ; https://www.repository.cam.ac.uk/bitstream/1810/291485/7/1.7%20Differential%20expression%20analysis.xlsx ; https://www.repository.cam.ac.uk/bitstream/1810/291485/8/1.8%20RNA%20splicing%20analysis.xlsx.
MLA Handbook (7th Edition):
Thompson, Nicola Anne. “Identification of novel synthetic lethal interactions using multiplexed CRISPR-Cas9 screening.” 2019. Web. 14 Apr 2021.
Vancouver:
Thompson NA. Identification of novel synthetic lethal interactions using multiplexed CRISPR-Cas9 screening. [Internet] [Doctoral dissertation]. University of Cambridge; 2019. [cited 2021 Apr 14].
Available from: https://www.repository.cam.ac.uk/handle/1810/291485https://www.repository.cam.ac.uk/bitstream/1810/291485/1/1.1%20Multiplex%20library%20content.xlsx ; https://www.repository.cam.ac.uk/bitstream/1810/291485/2/1.2%20Oligonucleotides.xlsx ; https://www.repository.cam.ac.uk/bitstream/1810/291485/3/1.3%20Gene%20pair%20output%20of%20the%20paired%20library.xlsx ; https://www.repository.cam.ac.uk/bitstream/1810/291485/4/1.4%20Single%20gene%20output%20of%20the%20paired%20library.xlsx ; https://www.repository.cam.ac.uk/bitstream/1810/291485/5/1.5%20Genomics%20of%20the%20cell%20lines%20used.xlsx ; https://www.repository.cam.ac.uk/bitstream/1810/291485/6/1.6%20Mass%20spectrometry%20data.xlsx ; https://www.repository.cam.ac.uk/bitstream/1810/291485/7/1.7%20Differential%20expression%20analysis.xlsx ; https://www.repository.cam.ac.uk/bitstream/1810/291485/8/1.8%20RNA%20splicing%20analysis.xlsx.
Council of Science Editors:
Thompson NA. Identification of novel synthetic lethal interactions using multiplexed CRISPR-Cas9 screening. [Doctoral Dissertation]. University of Cambridge; 2019. Available from: https://www.repository.cam.ac.uk/handle/1810/291485https://www.repository.cam.ac.uk/bitstream/1810/291485/1/1.1%20Multiplex%20library%20content.xlsx ; https://www.repository.cam.ac.uk/bitstream/1810/291485/2/1.2%20Oligonucleotides.xlsx ; https://www.repository.cam.ac.uk/bitstream/1810/291485/3/1.3%20Gene%20pair%20output%20of%20the%20paired%20library.xlsx ; https://www.repository.cam.ac.uk/bitstream/1810/291485/4/1.4%20Single%20gene%20output%20of%20the%20paired%20library.xlsx ; https://www.repository.cam.ac.uk/bitstream/1810/291485/5/1.5%20Genomics%20of%20the%20cell%20lines%20used.xlsx ; https://www.repository.cam.ac.uk/bitstream/1810/291485/6/1.6%20Mass%20spectrometry%20data.xlsx ; https://www.repository.cam.ac.uk/bitstream/1810/291485/7/1.7%20Differential%20expression%20analysis.xlsx ; https://www.repository.cam.ac.uk/bitstream/1810/291485/8/1.8%20RNA%20splicing%20analysis.xlsx
University of California – San Francisco
18.
Ku, Angel Alejandro.
Systems Biology Approaches for Identifying Synthetic Lethal Targets in Cancer.
Degree: Pharmaceutical Sciences and Pharmacogenomics, 2019, University of California – San Francisco
URL: http://www.escholarship.org/uc/item/0gj863n2
► The development of therapeutic agent against cancer is based on targeting key signaling proteins that cancer highjacks and uses to survive. Although progress has been…
(more)
▼ The development of therapeutic agent against cancer is based on targeting key signaling proteins that cancer highjacks and uses to survive. Although progress has been made to define cancer’s vulnerabilities, a subset of cancer drivers remain undruggable. To address this problem the field has attempted to identify drug targets that would selectively kill cancer cells and spare wild type tissue, a concept known as synthetic lethality. The work outlined here seeks to address major challenges in identifying synthetic lethal targets. First, I provide an overview of the platforms for synthetic lethal screening and highlight the advantages and caveats of each approach. Chapter three is focused on a case study where we developed a network-based integration method for published KRAS synthetic lethal studies and derived principles for synthetic lethal screening. The major findings of this study highlight principles of synthetic lethal screening and identify a subset of genes, which may offer new therapeutic targets in the context of oncogenic KRAS. Chapter four explores the use of PARP inhibitors in non-small cell lung cancer cell lines and derive molecular signatures associated with response and resistance to PARP inhibitor. Chapter 5 reports the results of a KRAS 4a/4b drug screen which highlight isoform specific vulnerabilities that may inform therapeutic strategies for KRAS mutant cancers.
Subjects/Keywords: Biology; Cellular biology; Bioinformatics; Cancer Biology; DNA Repair; Functional Genomics; KRAS; Synthetic Lethality; Systems Biology
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Ku, A. A. (2019). Systems Biology Approaches for Identifying Synthetic Lethal Targets in Cancer. (Thesis). University of California – San Francisco. Retrieved from http://www.escholarship.org/uc/item/0gj863n2
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Ku, Angel Alejandro. “Systems Biology Approaches for Identifying Synthetic Lethal Targets in Cancer.” 2019. Thesis, University of California – San Francisco. Accessed April 14, 2021.
http://www.escholarship.org/uc/item/0gj863n2.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Ku, Angel Alejandro. “Systems Biology Approaches for Identifying Synthetic Lethal Targets in Cancer.” 2019. Web. 14 Apr 2021.
Vancouver:
Ku AA. Systems Biology Approaches for Identifying Synthetic Lethal Targets in Cancer. [Internet] [Thesis]. University of California – San Francisco; 2019. [cited 2021 Apr 14].
Available from: http://www.escholarship.org/uc/item/0gj863n2.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Ku AA. Systems Biology Approaches for Identifying Synthetic Lethal Targets in Cancer. [Thesis]. University of California – San Francisco; 2019. Available from: http://www.escholarship.org/uc/item/0gj863n2
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Florida
19.
Srinivasan, Gayathri.
MicroRNA Regulation of DNA Repair.
Degree: PhD, Medical Sciences - Genetics (IDP), 2017, University of Florida
URL: https://ufdc.ufl.edu/UFE0051684
Subjects/Keywords: damage; dna; lethality; microrna; repair; synthetic
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Srinivasan, G. (2017). MicroRNA Regulation of DNA Repair. (Doctoral Dissertation). University of Florida. Retrieved from https://ufdc.ufl.edu/UFE0051684
Chicago Manual of Style (16th Edition):
Srinivasan, Gayathri. “MicroRNA Regulation of DNA Repair.” 2017. Doctoral Dissertation, University of Florida. Accessed April 14, 2021.
https://ufdc.ufl.edu/UFE0051684.
MLA Handbook (7th Edition):
Srinivasan, Gayathri. “MicroRNA Regulation of DNA Repair.” 2017. Web. 14 Apr 2021.
Vancouver:
Srinivasan G. MicroRNA Regulation of DNA Repair. [Internet] [Doctoral dissertation]. University of Florida; 2017. [cited 2021 Apr 14].
Available from: https://ufdc.ufl.edu/UFE0051684.
Council of Science Editors:
Srinivasan G. MicroRNA Regulation of DNA Repair. [Doctoral Dissertation]. University of Florida; 2017. Available from: https://ufdc.ufl.edu/UFE0051684
20.
Albrecht, Delphine.
Etude des mutants synthétiques létaux avec l'AICAR chez la levure et conservation chez l'Homme : Chemo-genetic interactions between histone modification and the antiproliferation drug aicar are conserved in yeast and humans.
Degree: Docteur es, Génétique, 2016, Bordeaux
URL: http://www.theses.fr/2016BORD0134
► L’identification d’interactions synthétiques létales (SL) apparait aujourd’hui comme une approche prometteuse, qui permet de cibler directement les cellules cancéreuses. Dans cette étude, nous avons utilisé…
(more)
▼ L’identification d’interactions synthétiques létales (SL) apparait aujourd’hui comme une approche prometteuse, qui permet de cibler directement les cellules cancéreuses. Dans cette étude, nous avons utilisé la levure Saccharomyces cerevisiae en tant qu’organisme modèle simple pour cribler des mutations SL avec une drogue, l’AICAR (5-Amino-4-Imidazole CArboxamide Ribonucleoside). L’AICAR est une molécule connue pour inhiber spécifiquement la prolifération de multiples lignées cancéreuses. Ici, nous montrons que la perte d’ubiquitination de l’histone H2B ou de méthylation de l’histone H3K4 est SL avec l’AICAR. Nos résultats pointent sur l’AICAR causant une accumulation de cellules en G1 due à ses effets sur la localisation subcellulaire de la cycline Cln3, tandis que la perte d’ubiquitination d’H2B ou de méthylation de H3K4 affectent l’expression des deux autres cyclines deG1, CLN1 et CLN2. Ainsi, l’AICAR et la perte d’ubiquitination de l’histone H2B ou de méthylation del’histone H3K4 affectent les trois cyclines simultanément, conduisant à une condition connue pourêtre SL. De plus, cette interaction chemo-genetique s’est révélée être conservée chez les cellules humaines HCT116. En effet, le knock down de RNF40, ASH2L ou MLL2 conduit à une sensibilité àl’AICAR exacerbée. Or, on sait que MLL2 est muté dans de nombreux cancers, ce qui rend cette interaction SL très intéressante dans le cadre d’une approche thérapeutique.
Identifying synthetic lethal interactions has emerged as a promising new therapeutic approach that aims to directly target the cancer cells. Here, we used the yeast Saccharomyces cerevisiae as a simple eukaryotic model to screen for mutations resulting in a synthetic lethality with 5-Amino-4-ImidazoleCArboxamide Ribonucleoside (AICAR) treatment. Indeed, AICAR has been reported to specifically inhibit the proliferation of multiple cancer cell lines. Here, we found that loss of two several histone modifying enzymes, including Bre1 (histone H2B ubiquitination) and Set1 (histone H3 lysine 4methylation), greatly enhanced AICAR inhibitory effects on growth. Our results point to AICAR causing a significant accumulation of G1 cells due to its impact on Cln3 subcellular localization, whilebre1 or set1 deletion impacts on the two other G1 cyclins, by affecting CLN1 and CLN2 expression .As a consequence, AICAR and bre1/set1 deletions jointly affect all three G1 cyclins, leading to a condition that is known to result in synthetic lethality. Most importantly, these chemo-genetic synthetic interactions were conserved in human HCT116 cells. Knock-down of RNF40, ASH2L orKMT2D induced a highly significant increased sensitivity to AICAR. As KMT2D is mutated at high frequency in a variety of cancers, this synthetic lethal interaction has an interesting therapeutic potential.
Advisors/Committee Members: Daignan-Fornier, Bertrand (thesis director).
Subjects/Keywords: Levure; Génétique; Modification d’histones; Cancer; Létalité synthétique; Yeast; Histone Modifications; Cancer; Synthetic Lethality; Genetics
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Albrecht, D. (2016). Etude des mutants synthétiques létaux avec l'AICAR chez la levure et conservation chez l'Homme : Chemo-genetic interactions between histone modification and the antiproliferation drug aicar are conserved in yeast and humans. (Doctoral Dissertation). Bordeaux. Retrieved from http://www.theses.fr/2016BORD0134
Chicago Manual of Style (16th Edition):
Albrecht, Delphine. “Etude des mutants synthétiques létaux avec l'AICAR chez la levure et conservation chez l'Homme : Chemo-genetic interactions between histone modification and the antiproliferation drug aicar are conserved in yeast and humans.” 2016. Doctoral Dissertation, Bordeaux. Accessed April 14, 2021.
http://www.theses.fr/2016BORD0134.
MLA Handbook (7th Edition):
Albrecht, Delphine. “Etude des mutants synthétiques létaux avec l'AICAR chez la levure et conservation chez l'Homme : Chemo-genetic interactions between histone modification and the antiproliferation drug aicar are conserved in yeast and humans.” 2016. Web. 14 Apr 2021.
Vancouver:
Albrecht D. Etude des mutants synthétiques létaux avec l'AICAR chez la levure et conservation chez l'Homme : Chemo-genetic interactions between histone modification and the antiproliferation drug aicar are conserved in yeast and humans. [Internet] [Doctoral dissertation]. Bordeaux; 2016. [cited 2021 Apr 14].
Available from: http://www.theses.fr/2016BORD0134.
Council of Science Editors:
Albrecht D. Etude des mutants synthétiques létaux avec l'AICAR chez la levure et conservation chez l'Homme : Chemo-genetic interactions between histone modification and the antiproliferation drug aicar are conserved in yeast and humans. [Doctoral Dissertation]. Bordeaux; 2016. Available from: http://www.theses.fr/2016BORD0134
University of Cambridge
21.
Thompson, Nicola Anne.
Identification of novel synthetic lethal interactions using multiplexed CRISPR-Cas9 screening.
Degree: PhD, 2019, University of Cambridge
URL: https://doi.org/10.17863/CAM.38647
;
https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.774707
► As our understanding of the cancer genome has progressed, traditional chemotherapeutic agents are being replaced, in part, by targeted therapies. Development of these therapies is…
(more)
▼ As our understanding of the cancer genome has progressed, traditional chemotherapeutic agents are being replaced, in part, by targeted therapies. Development of these therapies is driven by our understanding of genetic vulnerabilities harboured by tumours. The aim of this project is to identify novel synthetic lethal interactions within melanoma. Synthetic lethality describes a relationship between two genes, where loss of either of the pair is compatible with cellular viability, but simultaneous loss of both genes induces cell death. This approach can therefore exploit somatically acquired mutations to specifically kill tumour cells and to define new therapeutic targets. Abstract In order to do this, we selected a panel of putative synthetic lethal interactions and built a bespoke multiplex CRISPR-Cas9 library to interrogate 1192 gene-pair interactions. We deployed this library on a panel of melanoma cell lines and a retinal pigment epithelial cell line as a normal comparator. We went on to develop a bioinformatic pipeline with which to analyse the paired screen output and using this pipeline we have identified a number of novel synthetic lethal relationships. Using low throughput assays we validated a number of the interactions found by our screen. Finally, using human tumour expression data, we identified a candidate pair with potential therapeutic relevance. Using external datasets and isogenic knockout models we have further validated this relationship and performed mechanistic experiments to explore the role of these genes within the cell and generate a hypothesis to explain why loss of these two genes results in cell death.
Subjects/Keywords: CRISPR screen; synthetic lethality; paralog; FAM50A; FAM50B; paired screening; melanoma; cancer genetics; target discovery; paralogue
Record Details
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Record Details
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Thompson, N. A. (2019). Identification of novel synthetic lethal interactions using multiplexed CRISPR-Cas9 screening. (Doctoral Dissertation). University of Cambridge. Retrieved from https://doi.org/10.17863/CAM.38647 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.774707
Chicago Manual of Style (16th Edition):
Thompson, Nicola Anne. “Identification of novel synthetic lethal interactions using multiplexed CRISPR-Cas9 screening.” 2019. Doctoral Dissertation, University of Cambridge. Accessed April 14, 2021.
https://doi.org/10.17863/CAM.38647 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.774707.
MLA Handbook (7th Edition):
Thompson, Nicola Anne. “Identification of novel synthetic lethal interactions using multiplexed CRISPR-Cas9 screening.” 2019. Web. 14 Apr 2021.
Vancouver:
Thompson NA. Identification of novel synthetic lethal interactions using multiplexed CRISPR-Cas9 screening. [Internet] [Doctoral dissertation]. University of Cambridge; 2019. [cited 2021 Apr 14].
Available from: https://doi.org/10.17863/CAM.38647 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.774707.
Council of Science Editors:
Thompson NA. Identification of novel synthetic lethal interactions using multiplexed CRISPR-Cas9 screening. [Doctoral Dissertation]. University of Cambridge; 2019. Available from: https://doi.org/10.17863/CAM.38647 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.774707
University of Cincinnati
22.
Michel, Daniel R.
Cytoskeletal Architecture and Cell Motility Remain
Unperturbed in Mouse Embryonic Fibroblasts from
<i>Plk3</i> Knockout Mice.
Degree: PhD, Medicine: Molecular Genetics, Biochemistry, and
Microbiology, 2015, University of Cincinnati
URL: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1446546516
► Polo-like kinase 3 (Plk3) is a member of a conserved family of serine/threonine kinases that primarily regulate cell cycle progression and mitotic events. In response…
(more)
▼ Polo-like kinase 3 (Plk3) is a member of a conserved
family of serine/threonine kinases that primarily regulate cell
cycle progression and mitotic events. In response to ionizing
radiation, Plk3 facilitates the activation of G1/S checkpoint
arrest. Further, published data from our lab suggested that Plk3
may be capable of activating G1/S checkpoint arrest independent of
p53 signaling. The tumor suppressor protein p53 is the central hub
of DNA damage response signaling and the most frequently deleted or
mutated gene in cancers. A Plk3-dependent, p53-independent
mechanism for G1/S checkpoint arrest could partially compensate for
the loss of p53 function. Therefore, in our first project, we
investigated the hypothesis that the combined loss of p53 and Plk3
would be
synthetic lethal with cell death resulting from the
abolishment of the G1/S checkpoint and the accumulation of
unrepaired DNA damage. However, our experimental results did not
support our hypothesis and we decided to shift to a new project.
The Plk literature also suggests that Plk3 may have additional
roles associated with normal cell function. Here, mouse embryonic
fibroblasts generated from Plk3 knockout or wildtype mice were
compared, to identify alternative functions for Plk3 in addition to
its canonical role. Specifically, Plk3 has been reported to
associate with key proteins involved in cytoskeletal organization;
co-localizing with f-actin and directly phosphorylating ß-tubulin.
These and other data suggested a role for Plk3 in regulation of the
cytoskeleton and cell morphology. To this end, given the importance
of dynamic cytoskeletal rearrangement to cell motility, we analyzed
whether Plk3 is involved in cell migration, attachment and/or
invasion using <i>Plk3</i> knockout mouse embryonic
fibroblasts.
Advisors/Committee Members: Stambrook, Peter (Committee Chair).
Subjects/Keywords: Molecular Biology; Polo-like kinase 3; Synthetic lethality; Plk3; Cell motility; Cytoskeleton; Polo-like kinases
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APA (6th Edition):
Michel, D. R. (2015). Cytoskeletal Architecture and Cell Motility Remain
Unperturbed in Mouse Embryonic Fibroblasts from
<i>Plk3</i> Knockout Mice. (Doctoral Dissertation). University of Cincinnati. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=ucin1446546516
Chicago Manual of Style (16th Edition):
Michel, Daniel R. “Cytoskeletal Architecture and Cell Motility Remain
Unperturbed in Mouse Embryonic Fibroblasts from
<i>Plk3</i> Knockout Mice.” 2015. Doctoral Dissertation, University of Cincinnati. Accessed April 14, 2021.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1446546516.
MLA Handbook (7th Edition):
Michel, Daniel R. “Cytoskeletal Architecture and Cell Motility Remain
Unperturbed in Mouse Embryonic Fibroblasts from
<i>Plk3</i> Knockout Mice.” 2015. Web. 14 Apr 2021.
Vancouver:
Michel DR. Cytoskeletal Architecture and Cell Motility Remain
Unperturbed in Mouse Embryonic Fibroblasts from
<i>Plk3</i> Knockout Mice. [Internet] [Doctoral dissertation]. University of Cincinnati; 2015. [cited 2021 Apr 14].
Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1446546516.
Council of Science Editors:
Michel DR. Cytoskeletal Architecture and Cell Motility Remain
Unperturbed in Mouse Embryonic Fibroblasts from
<i>Plk3</i> Knockout Mice. [Doctoral Dissertation]. University of Cincinnati; 2015. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1446546516
University of Cambridge
23.
Mulhearn, Darcie Sinead.
Exploring genetic interactions with G-quadruplex structures.
Degree: PhD, 2019, University of Cambridge
URL: https://doi.org/10.17863/CAM.35269
;
https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.763883
► G-quadruplexes are non-canonical nucleic acid secondary structures of increasing biological and medicinal interest due to their proposed physiological functions in transcription, replication, translation and telomere…
(more)
▼ G-quadruplexes are non-canonical nucleic acid secondary structures of increasing biological and medicinal interest due to their proposed physiological functions in transcription, replication, translation and telomere biology. Aberrant G4 formation and stabilisation have been linked to genome instability, cancer and other diseases. However, the specific genes and pathways involved are largely unknown, and the work within this thesis aims to investigate this. Stabilisation of G4s by small molecules can perturb G4-mediated processes and initial studies suggest that this approach has chemotherapeutic potential. I therefore also aimed to identify cell genotypes sensitive to G4-ligand treatment that may offer further therapeutic opportunities. To address these aims, I present the first unbiased genome-wide genetic screen in cells where genes were silenced via short-hairpin RNAs (shRNAs) whilst being treated with either PDS or PhenDC3, two independent G4-stabilising small molecules. I explored gene deficiencies that enhance cell death (sensitisation) or provide a growth advantage (resistance) in the presence of these G4-ligands. Additionally, I present a validation screen, comprising hits uncovered via genome-wide screening, and also the use of this in another cell line of different origin. Sensitivities were enriched in DNA replication, cell cycle, DNA damage repair, splicing and ubiquitin-mediated proteolysis proteins and pathways. Ultimately, I uncovered four synthetic lethalities BRCA1, TOP1, DDX42, GAR1, independent of cell line and ligand. These were validated with three G4-stabilising ligands (PDS, PhenDC3 and CX-5461) using an independent siRNA approach. The latter siRNA methodology was used to screen 12 PDS derivatives with improved medicinal chemistry properties and ultimately identified SA-100-128, as a lead compound. The mechanism behind synthetic lethality with G4-stabilising ligands was explored further for DDX42, which I show has in vitro affinity for both RNA- and DNA-G4s and may represent a previously unknown G4-helicase. Also within this thesis, gene deficiencies that provided a growth advantage to PDS and/or PhenDC3 as uncovered by genome-wide and focused screening were explored. These showed enrichment in transcription, chromatin and lysosome-associated genes. The resistance phenotype of three gene deficiencies, TAF1, DDX39A and ZNF217 was further supported by additional siRNA experiments. Overall, I satisfied the primary aims and established many novel synthetic lethal and resistance interactions that may represent new therapeutic possibilities. Additionally, the results expand our knowledge of G4-biology by identifying genes, functions and subcellular locations previously not known to involve or regulate G4s.
Subjects/Keywords: 572.8; synthetic lethality; G-quadruplex; secondary structures; shRNA screening; screening; RNAi; genomic instability; small molecule
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APA (6th Edition):
Mulhearn, D. S. (2019). Exploring genetic interactions with G-quadruplex structures. (Doctoral Dissertation). University of Cambridge. Retrieved from https://doi.org/10.17863/CAM.35269 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.763883
Chicago Manual of Style (16th Edition):
Mulhearn, Darcie Sinead. “Exploring genetic interactions with G-quadruplex structures.” 2019. Doctoral Dissertation, University of Cambridge. Accessed April 14, 2021.
https://doi.org/10.17863/CAM.35269 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.763883.
MLA Handbook (7th Edition):
Mulhearn, Darcie Sinead. “Exploring genetic interactions with G-quadruplex structures.” 2019. Web. 14 Apr 2021.
Vancouver:
Mulhearn DS. Exploring genetic interactions with G-quadruplex structures. [Internet] [Doctoral dissertation]. University of Cambridge; 2019. [cited 2021 Apr 14].
Available from: https://doi.org/10.17863/CAM.35269 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.763883.
Council of Science Editors:
Mulhearn DS. Exploring genetic interactions with G-quadruplex structures. [Doctoral Dissertation]. University of Cambridge; 2019. Available from: https://doi.org/10.17863/CAM.35269 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.763883
24.
Kirzinger, Morgan 1988-.
Humanized yeast genetic interaction mapping predicts synthetic lethal interactions of FBXW7 in breast cancer.
Degree: 2018, University of Saskatchewan
URL: http://hdl.handle.net/10388/11057
► A Synthetic lethal (SL) interaction involves a pair of genes (geneA and geneB) where inhibition of either geneA or geneB individually has no effect on…
(more)
▼ A
Synthetic lethal (SL) interaction involves a pair of genes (geneA and geneB) where inhibition of either geneA or geneB individually has no effect on cell viability, but the inhibition of both geneA and geneB causes cell death. SL interactions that occur between gene pairs can be exploited for cancer therapeutics. Studies in the model eukaryote yeast have identified approximately 550,000 negative genetic interactions that have been extensively applied to characterize novel pathways and gene functions. In the context of this thesis, a negative genetic interaction is the equivalent of a SL interaction. Harnessing the vast available knowledge of yeast genetics, we generated a Humanized Yeast Genetic Interaction Network (HYGIN) for 1,009 human genes with yeast orthologs and 10,419 interactions. Through the addition of patient-data from The Cancer Genome Atlas (TCGA), we generated a breast cancer specific subnetwork. Specifically, by comparing 1,009 genes in HYGIN to genes that were down-regulated in breast cancer, we identified 15 breast cancer genes with 130 potential SL interactions. Interestingly, 32 of the 130 predicted SL interactions occurred with FBXW7, a well-known tumor suppressor that functions as a substrate-recognition protein within the SKP/CUL1/F-Box ubiquitin ligase complex for degradation through the proteasome. Validation of these SL interactions using chemical genetic data indicate that patients with loss of FBXW7 may respond to treatment with drugs like Selumitinib or Cabozantinib. Taken together, our patient-data driven interpretation of HYGIN represents a novel strategy to uncover therapeutically relevant drug targets.
Advisors/Committee Members: Kusalik, Anthony, Vizeacoumar, Franco, Harkness, Troy, McQuillan, Ian, Lee, Jeremy, Bonham, Keith.
Subjects/Keywords: Breast Cancer; Synthetic Lethality; Genetic Interactions
…Diagram of Synthetic Lethality and Synthetic Dosage Lethality . . . . . . .
Diagram of the… …Mechanisms of Synthetic Lethality . . . . . . . . . . . . . . .
10
13
14
4.1
Steps in the… …palindromic repeats
data mining synthetic lethality
database of genomic variation and phenotype in… …lethality
short hairpin RNA
small interfering RNA
S-phase kinase associated protein 1
synthetic… …lethality
survival of the fittest
synthetic lethal database
T-cell acute lymphoblastic leukaemia…
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APA ·
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APA (6th Edition):
Kirzinger, M. 1. (2018). Humanized yeast genetic interaction mapping predicts synthetic lethal interactions of FBXW7 in breast cancer. (Thesis). University of Saskatchewan. Retrieved from http://hdl.handle.net/10388/11057
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Kirzinger, Morgan 1988-. “Humanized yeast genetic interaction mapping predicts synthetic lethal interactions of FBXW7 in breast cancer.” 2018. Thesis, University of Saskatchewan. Accessed April 14, 2021.
http://hdl.handle.net/10388/11057.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Kirzinger, Morgan 1988-. “Humanized yeast genetic interaction mapping predicts synthetic lethal interactions of FBXW7 in breast cancer.” 2018. Web. 14 Apr 2021.
Vancouver:
Kirzinger M1. Humanized yeast genetic interaction mapping predicts synthetic lethal interactions of FBXW7 in breast cancer. [Internet] [Thesis]. University of Saskatchewan; 2018. [cited 2021 Apr 14].
Available from: http://hdl.handle.net/10388/11057.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Kirzinger M1. Humanized yeast genetic interaction mapping predicts synthetic lethal interactions of FBXW7 in breast cancer. [Thesis]. University of Saskatchewan; 2018. Available from: http://hdl.handle.net/10388/11057
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Otago
25.
Chin, Chue Vin.
Identification of synthetic lethal compounds targeting cancers with cohesin mutations
.
Degree: University of Otago
URL: http://hdl.handle.net/10523/9832
► The cohesin complex, comprising four core subunits, RAD21, SMC3, SMC1A, and STAG1/2, is important for the regulation of many biological processes, including sister chromatid cohesion,…
(more)
▼ The cohesin complex, comprising four core subunits, RAD21, SMC3, SMC1A, and STAG1/2, is important for the regulation of many biological processes, including sister chromatid cohesion, regulation of gene expression, chromatin architecture, DNA damage repair, and ribosome biogenesis. Germline mutations of the cohesin complex and its regulators cause developmental disorders, including Roberts syndrome (RBS) and Cornelia de Lange syndrome (CdLS). Whole-genome sequencing identified somatic mutations in cohesin genes in a wide range of human cancers, including acute myeloid leukemia (AML). Low expression of mutant cohesin transcsripts and protein are correlated with poor survival in AML patients. Despite this correlation, currently, there is no targeted strategy for cancer patients with cohesin mutations.
Synthetic lethality has emerged as a promising approach for targeted therapy. While
synthetic lethal interactions of cohesin subunit, STAG2 have been demonstrated with its paralog, STAG1, and with drugs targeting the DNA damage repair pathway,
synthetic lethal effects of other pathways via chemical perturbations have not been explored. In this project, I aim to identify
synthetic lethal drugs that preferentially inhibit cells with cohesin deficiency.
Using CRISPR-Cas9, I generated three isogenic cohesin-deficient MCF10A cell lines, RAD21+/-, SMC3+/-, and STAG2-/-. Functional characterization of these cell lines showed that they are similar to the MCF10A parental line concerning growth rate, morphology, and chromosome stability. Analysis of nucleolar morphology of cohesin-deficient MCF10A cells using nucleolar markers, fibrillarin, and nucleolin, showed altered nucleolar phenotypes, resembling the nucleolar alterations seen in Roberts Syndrome. In support of this observation, RNA-sequencing analysis revealed downregulation of genes involved in RNA transcription and processing, in addition to dysregulation of cell cycle, DNA damage repair, signaling pathways, chromosome organization, and development.
Using MCF10A parental cells and isogenic cohesin-deficient MCF10A cell lines, we performed a high-throughput drug screen with compound libraries of FDA-approved drugs, kinase, and epigenetics inhibitors.
Synthetic lethal hits were ranked based on the differential area over the curve between MCF10A parental and cohesin-deficient MCF10A cells. Selected hits were then re-screened in a secondary screen to confirm their
synthetic lethal effects in cohesin-deficient MCF10A. Inhibitors targeting PI3K/AKT/mTOR, Wnt signaling pathway, and epigenetic regulators are among the top hits identified in our
synthetic lethal screen, demonstrating that cohesin deficiency creates druggable vulnerabilities in cancer cells. In summary, we have identified potential
synthetic lethal compounds that may provide a new strategy for targeted therapies of cancers with cohesin deficiency or mutations.
Advisors/Committee Members: Horsfield, Julia (advisor).
Subjects/Keywords: cohesin;
synthetic lethality;
high throughput screening;
MCF10A
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APA ·
Chicago ·
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Export
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Manager
APA (6th Edition):
Chin, C. V. (n.d.). Identification of synthetic lethal compounds targeting cancers with cohesin mutations
. (Doctoral Dissertation). University of Otago. Retrieved from http://hdl.handle.net/10523/9832
Note: this citation may be lacking information needed for this citation format:
No year of publication.
Chicago Manual of Style (16th Edition):
Chin, Chue Vin. “Identification of synthetic lethal compounds targeting cancers with cohesin mutations
.” Doctoral Dissertation, University of Otago. Accessed April 14, 2021.
http://hdl.handle.net/10523/9832.
Note: this citation may be lacking information needed for this citation format:
No year of publication.
MLA Handbook (7th Edition):
Chin, Chue Vin. “Identification of synthetic lethal compounds targeting cancers with cohesin mutations
.” Web. 14 Apr 2021.
Note: this citation may be lacking information needed for this citation format:
No year of publication.
Vancouver:
Chin CV. Identification of synthetic lethal compounds targeting cancers with cohesin mutations
. [Internet] [Doctoral dissertation]. University of Otago; [cited 2021 Apr 14].
Available from: http://hdl.handle.net/10523/9832.
Note: this citation may be lacking information needed for this citation format:
No year of publication.
Council of Science Editors:
Chin CV. Identification of synthetic lethal compounds targeting cancers with cohesin mutations
. [Doctoral Dissertation]. University of Otago; Available from: http://hdl.handle.net/10523/9832
Note: this citation may be lacking information needed for this citation format:
No year of publication.
University of Queensland
26.
Bokhari, Fawzi Faisal A.
siRNA screening of the kinome identified Aurora A kinase as a therapeutic target gene in cervical cancer.
Degree: UQ Diamantina Institute, 2014, University of Queensland
URL: http://espace.library.uq.edu.au/view/UQ:341649
► HPV oncogenes disable a number of tumour suppressor pathways, including p53 and Rb, contributing to the transformed phenotype. Loss of these critical host cell functions…
(more)
▼ HPV oncogenes disable a number of tumour suppressor pathways, including p53 and Rb, contributing to the transformed phenotype. Loss of these critical host cell functions may also provide an opportunity to selectively target the destruction of HPV-transformed cells. We have performed an siRNA screen using the kinome (779 genes) library to identify genes that when depleted are synthetically lethal with HPV transformation. The primary and validations screens have confirmed Aurora A kinase (AURKA) as a potential synthetic lethal target selective for HPV transformed cells. AURKA has been further investigated using the selective small molecule inhibitor MLN8237. We found that MLN8237 was significantly more potent towards the HPV transformed cells. The effect was not a consequence of targeting mitosis as two other mitotic inhibitors, PLK1 inhibitor (BI2536) and taxol, demonstrated no selectivity. Analysis of the nuclear structure and DNA content showed that Aurora A inhibition promoted a high level of polyploidy in non-HPV treated cells whilst this same degree of polyploidy was associate with apoptosis in the HPV-transformed cell lines. Whereas Bcl-2 over expression in HeLa cells had no effect on sensitivity to MLN8237, Mcl-1 overexpressing HeLa cells were less sensitive to the MLN8237 in comparison to the parental cell line, which may suggests the involvement of Noxa or Puma pro-apoptotic proteins in the induction of the apoptosis in the HPV-transformed cells. The transfection of the non-HPV C33A cervical cancer and SCC25 squamous cell carcinoma cell lines with the HPV16 oncogenic E7 increased sensitivity to MLN8237 between 3 >10 fold suggesting that the sensitivity to MLN8237-dependent killing was a direct consequence of HPV E7 expression. Xenograft experiments with cervical cancer cell lines in immunodeficient mice showed MLN8237 inhibited growth of HPV and non-HPV xenografts during treatment with 30mg/kg MLN8237 once a day for 10 consecutive days. However, outgrowth of tumour was noticed from the second day post-treatment in the non-HPV tumour group whereas the HPV-induced tumour group did not show cancer recurrence for 50 days post-treatment. These findings suggest that MLN8237 represent a promising novel therapeutic targeted agent against HPV-transformed cervical cancer.
Subjects/Keywords: siRNA; AURKA; AURKB; Haspin; GSG2; cervical cancer; HPV; synthetic lethality; 0601 Biochemistry and Cell Biology; 0604 Genetics; 1112 Oncology and Carcinogenesis
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APA (6th Edition):
Bokhari, F. F. A. (2014). siRNA screening of the kinome identified Aurora A kinase as a therapeutic target gene in cervical cancer. (Thesis). University of Queensland. Retrieved from http://espace.library.uq.edu.au/view/UQ:341649
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Bokhari, Fawzi Faisal A. “siRNA screening of the kinome identified Aurora A kinase as a therapeutic target gene in cervical cancer.” 2014. Thesis, University of Queensland. Accessed April 14, 2021.
http://espace.library.uq.edu.au/view/UQ:341649.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Bokhari, Fawzi Faisal A. “siRNA screening of the kinome identified Aurora A kinase as a therapeutic target gene in cervical cancer.” 2014. Web. 14 Apr 2021.
Vancouver:
Bokhari FFA. siRNA screening of the kinome identified Aurora A kinase as a therapeutic target gene in cervical cancer. [Internet] [Thesis]. University of Queensland; 2014. [cited 2021 Apr 14].
Available from: http://espace.library.uq.edu.au/view/UQ:341649.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Bokhari FFA. siRNA screening of the kinome identified Aurora A kinase as a therapeutic target gene in cervical cancer. [Thesis]. University of Queensland; 2014. Available from: http://espace.library.uq.edu.au/view/UQ:341649
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
27.
Blomen, Vincent A.
Studying disease-linked phenotypes using haploid genetics.
Degree: 2017, University Utrecht
URL: http://dspace.library.uu.nl/handle/1874/355941
;
URN:NBN:NL:UI:10-1874-355941
;
urn:isbn:978-94-6295-782-4
;
URN:NBN:NL:UI:10-1874-355941
;
http://dspace.library.uu.nl/handle/1874/355941
► Although genes are unequivocally important for the development of both common and rare human diseases, the connection between the genotype (an individual’s genetic makeup) and…
(more)
▼ Although genes are unequivocally important for the development of both common and rare human diseases, the connection between the genotype (an individual’s genetic makeup) and phenotype (an individual’s observable traits) is often ill-defined. Even genetic disorders caused by a defect in only a single gene often manifest themselves differently in affected patients, indicating that the precise consequence of genetic mutations is often difficult to predict. This phenotype-genotype conundrum is a result of genes not functioning in isolation, but in complex genetic networks where gene function can be modulated by the action of other genes or the environment. A powerful approach to understand the genetic contribution to a phenotype is to generate mutations in model organisms. Large-scale mutation studies in yeast have illuminated some of the complex genetic architecture, but owing to technical constraints mutagenesis of human cells has long been unachievable. Central to this work is the application of haploid human mutant cells to study gene-environment and gene-gene interactions and their contribution to disease-relevant phenotypes. We describe a method for mapping mutations in pools of mutant cells following a phenotypic selection; typically mutants that survive exposure to otherwise noxious stimuli. This is applied to study the interactions between genes and the environment, focusing on a number of bacterial toxins that exploit the function of human genes in order to enter and cause damage to cells. In addition, the mechanism of resistance to multiple clinically-used drugs is examined. This same method is applied to identify host factors required by Rift Valley Fever Virus for infecting human cells. Further optimizations to this approach have made it possible not only to identify mutants which are favored under particular conditions, but also those which are under negative selection. We have applied this to define a set of around 2.000 genes required for cultured human cells to grow. This includes a number of genes which were uncharacterized, despite their essential function in basic cellular processes. The ability to identify essential genes furthermore enables examining gene essentiality specific to particular genetic backgrounds, referred to as genetic interactions. Mapping the essential genes in cell lines deficient for different genes uncovered a
synthetic lethality network focused on the human secretory pathway. Comparable to yeast, human genes frequently engage in genetic interactions, which implies that many non-essential genes will become essential in the absence of other genes. The ability to efficiently map mutations in populations of fixed haploid cells is further leveraged to examine the genetic regulators of intracellular phenotypes. For a dozen of diverse biological traits, such as oncogenic pathway activation or organelle size, we have identified hundreds of genes that impact the measured phenotype. Based on this, we construct a preview of a phenotypic map of a human cell, and observe that pleiotropy is…
Advisors/Committee Members: Brummelkamp, Thijn.
Subjects/Keywords: Haploid genetics; Genetic Interactions; Mutagenesis; Synthetic lethality; Genetic suppressors
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APA (6th Edition):
Blomen, V. A. (2017). Studying disease-linked phenotypes using haploid genetics. (Doctoral Dissertation). University Utrecht. Retrieved from http://dspace.library.uu.nl/handle/1874/355941 ; URN:NBN:NL:UI:10-1874-355941 ; urn:isbn:978-94-6295-782-4 ; URN:NBN:NL:UI:10-1874-355941 ; http://dspace.library.uu.nl/handle/1874/355941
Chicago Manual of Style (16th Edition):
Blomen, Vincent A. “Studying disease-linked phenotypes using haploid genetics.” 2017. Doctoral Dissertation, University Utrecht. Accessed April 14, 2021.
http://dspace.library.uu.nl/handle/1874/355941 ; URN:NBN:NL:UI:10-1874-355941 ; urn:isbn:978-94-6295-782-4 ; URN:NBN:NL:UI:10-1874-355941 ; http://dspace.library.uu.nl/handle/1874/355941.
MLA Handbook (7th Edition):
Blomen, Vincent A. “Studying disease-linked phenotypes using haploid genetics.” 2017. Web. 14 Apr 2021.
Vancouver:
Blomen VA. Studying disease-linked phenotypes using haploid genetics. [Internet] [Doctoral dissertation]. University Utrecht; 2017. [cited 2021 Apr 14].
Available from: http://dspace.library.uu.nl/handle/1874/355941 ; URN:NBN:NL:UI:10-1874-355941 ; urn:isbn:978-94-6295-782-4 ; URN:NBN:NL:UI:10-1874-355941 ; http://dspace.library.uu.nl/handle/1874/355941.
Council of Science Editors:
Blomen VA. Studying disease-linked phenotypes using haploid genetics. [Doctoral Dissertation]. University Utrecht; 2017. Available from: http://dspace.library.uu.nl/handle/1874/355941 ; URN:NBN:NL:UI:10-1874-355941 ; urn:isbn:978-94-6295-782-4 ; URN:NBN:NL:UI:10-1874-355941 ; http://dspace.library.uu.nl/handle/1874/355941
Universitat Pompeu Fabra
28.
Serrat Farran, Xènia, 1993-.
Unraveling the functional roles of sftb-1/SF3B1 and prpf-4/PRPF4B in Caenorhabditis elegans splicing and human disease.
Degree: Departament de Ciències Experimentals i de la Salut, 2019, Universitat Pompeu Fabra
URL: http://hdl.handle.net/10803/668152
► El nematode Caenorhabditis elegans és un sistema experimental que pot ajudar a resoldre qüestions fonamentals en recerca biomèdica, incloses les conseqüències d’alteracions en el processament…
(more)
▼ El nematode Caenorhabditis elegans és un sistema experimental que pot ajudar a resoldre qüestions fonamentals en recerca biomèdica, incloses les conseqüències d’alteracions en el processament de pre-ARN missatgers o splicing. En aquest treball, hem aplicat les tècniques de CRISPR i seqüenciació d’ARN per a investigar les funcions de dues proteïnes involucrades en splicing, les quals s’han conservat al llarg de l’evolució i s’han associat a diverses malalties de formes diferents.
Hem observat que mutacions en el gen sftb-1 relacionades amb càncer alteren el procés de splicing en C. elegans. Mitjançant l’ús de diferents al·lels, hem descobert noves interaccions de letalitat sintètica entre mutacions en el gen sftb-1 i alteracions addicionals en el complex U2 snRNP. El sistema té el potencial de ser utilitzat per a identificar altres interaccions amb diferents processos biològics. A més, hem humanitzat un domini de la proteïna SFTB-1 per sensibilitzar els cucs als fàrmacs pladienolide B i herboxidiene, que actuen com a moduladors de l’splicing.
Finalment, hem iniciat la caracterització funcional de la quinasa reguladora del procés de splicing prpf-4 en aquest nematode mitjançant l’estudi de la seva localització subcel·lular dinàmica i del requeriment de la seva activitat quinasa durant el desenvolupament de C. elegans.
Advisors/Committee Members: [email protected] (authoremail), true (authoremailshow), Cerón Madrigal, Julián (director).
Subjects/Keywords: Synthetic lethality; Splicing inhibitors; Spliceosome; SF3B1; RNA sequencing; RNA interference; PRP4 kinase; Pre-mRNA splicing; CRISPR; Caenorhabditis elegans; 577
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APA (6th Edition):
Serrat Farran, Xènia, 1. (2019). Unraveling the functional roles of sftb-1/SF3B1 and prpf-4/PRPF4B in Caenorhabditis elegans splicing and human disease. (Thesis). Universitat Pompeu Fabra. Retrieved from http://hdl.handle.net/10803/668152
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Serrat Farran, Xènia, 1993-. “Unraveling the functional roles of sftb-1/SF3B1 and prpf-4/PRPF4B in Caenorhabditis elegans splicing and human disease.” 2019. Thesis, Universitat Pompeu Fabra. Accessed April 14, 2021.
http://hdl.handle.net/10803/668152.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Serrat Farran, Xènia, 1993-. “Unraveling the functional roles of sftb-1/SF3B1 and prpf-4/PRPF4B in Caenorhabditis elegans splicing and human disease.” 2019. Web. 14 Apr 2021.
Vancouver:
Serrat Farran, Xènia 1. Unraveling the functional roles of sftb-1/SF3B1 and prpf-4/PRPF4B in Caenorhabditis elegans splicing and human disease. [Internet] [Thesis]. Universitat Pompeu Fabra; 2019. [cited 2021 Apr 14].
Available from: http://hdl.handle.net/10803/668152.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Serrat Farran, Xènia 1. Unraveling the functional roles of sftb-1/SF3B1 and prpf-4/PRPF4B in Caenorhabditis elegans splicing and human disease. [Thesis]. Universitat Pompeu Fabra; 2019. Available from: http://hdl.handle.net/10803/668152
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
29.
Blomen, Vincent A.
Studying disease-linked phenotypes using haploid genetics.
Degree: 2017, University Utrecht
URL: https://dspace.library.uu.nl/handle/1874/355941
;
URN:NBN:NL:UI:10-1874-355941
;
urn:isbn:978-94-6295-782-4
;
URN:NBN:NL:UI:10-1874-355941
;
https://dspace.library.uu.nl/handle/1874/355941
► Although genes are unequivocally important for the development of both common and rare human diseases, the connection between the genotype (an individual’s genetic makeup) and…
(more)
▼ Although genes are unequivocally important for the development of both common and rare human diseases, the connection between the genotype (an individual’s genetic makeup) and phenotype (an individual’s observable traits) is often ill-defined. Even genetic disorders caused by a defect in only a single gene often manifest themselves differently in affected patients, indicating that the precise consequence of genetic mutations is often difficult to predict. This phenotype-genotype conundrum is a result of genes not functioning in isolation, but in complex genetic networks where gene function can be modulated by the action of other genes or the environment. A powerful approach to understand the genetic contribution to a phenotype is to generate mutations in model organisms. Large-scale mutation studies in yeast have illuminated some of the complex genetic architecture, but owing to technical constraints mutagenesis of human cells has long been unachievable. Central to this work is the application of haploid human mutant cells to study gene-environment and gene-gene interactions and their contribution to disease-relevant phenotypes. We describe a method for mapping mutations in pools of mutant cells following a phenotypic selection; typically mutants that survive exposure to otherwise noxious stimuli. This is applied to study the interactions between genes and the environment, focusing on a number of bacterial toxins that exploit the function of human genes in order to enter and cause damage to cells. In addition, the mechanism of resistance to multiple clinically-used drugs is examined. This same method is applied to identify host factors required by Rift Valley Fever Virus for infecting human cells. Further optimizations to this approach have made it possible not only to identify mutants which are favored under particular conditions, but also those which are under negative selection. We have applied this to define a set of around 2.000 genes required for cultured human cells to grow. This includes a number of genes which were uncharacterized, despite their essential function in basic cellular processes. The ability to identify essential genes furthermore enables examining gene essentiality specific to particular genetic backgrounds, referred to as genetic interactions. Mapping the essential genes in cell lines deficient for different genes uncovered a
synthetic lethality network focused on the human secretory pathway. Comparable to yeast, human genes frequently engage in genetic interactions, which implies that many non-essential genes will become essential in the absence of other genes. The ability to efficiently map mutations in populations of fixed haploid cells is further leveraged to examine the genetic regulators of intracellular phenotypes. For a dozen of diverse biological traits, such as oncogenic pathway activation or organelle size, we have identified hundreds of genes that impact the measured phenotype. Based on this, we construct a preview of a phenotypic map of a human cell, and observe that pleiotropy is…
Advisors/Committee Members: Brummelkamp, Thijn.
Subjects/Keywords: Haploid genetics; Genetic Interactions; Mutagenesis; Synthetic lethality; Genetic suppressors
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APA (6th Edition):
Blomen, V. A. (2017). Studying disease-linked phenotypes using haploid genetics. (Doctoral Dissertation). University Utrecht. Retrieved from https://dspace.library.uu.nl/handle/1874/355941 ; URN:NBN:NL:UI:10-1874-355941 ; urn:isbn:978-94-6295-782-4 ; URN:NBN:NL:UI:10-1874-355941 ; https://dspace.library.uu.nl/handle/1874/355941
Chicago Manual of Style (16th Edition):
Blomen, Vincent A. “Studying disease-linked phenotypes using haploid genetics.” 2017. Doctoral Dissertation, University Utrecht. Accessed April 14, 2021.
https://dspace.library.uu.nl/handle/1874/355941 ; URN:NBN:NL:UI:10-1874-355941 ; urn:isbn:978-94-6295-782-4 ; URN:NBN:NL:UI:10-1874-355941 ; https://dspace.library.uu.nl/handle/1874/355941.
MLA Handbook (7th Edition):
Blomen, Vincent A. “Studying disease-linked phenotypes using haploid genetics.” 2017. Web. 14 Apr 2021.
Vancouver:
Blomen VA. Studying disease-linked phenotypes using haploid genetics. [Internet] [Doctoral dissertation]. University Utrecht; 2017. [cited 2021 Apr 14].
Available from: https://dspace.library.uu.nl/handle/1874/355941 ; URN:NBN:NL:UI:10-1874-355941 ; urn:isbn:978-94-6295-782-4 ; URN:NBN:NL:UI:10-1874-355941 ; https://dspace.library.uu.nl/handle/1874/355941.
Council of Science Editors:
Blomen VA. Studying disease-linked phenotypes using haploid genetics. [Doctoral Dissertation]. University Utrecht; 2017. Available from: https://dspace.library.uu.nl/handle/1874/355941 ; URN:NBN:NL:UI:10-1874-355941 ; urn:isbn:978-94-6295-782-4 ; URN:NBN:NL:UI:10-1874-355941 ; https://dspace.library.uu.nl/handle/1874/355941
30.
Silva Evangelista, Cláudia.
Molecular Characterization of Pediatric Brainstem Gliomas (DIPG) and Identification of New Therapeutic Targets : Caractérisation moléculaire des gliomes malins pédiatriques du tronc cérébral (DIPG) et identification de nouvelles stratégies thérapeutiques.
Degree: Docteur es, Aspects moléculaires et cellulaires de la biologie, 2018, Université Paris-Saclay (ComUE)
URL: http://www.theses.fr/2018SACLS269
► Les DIPG représentent les tumeurs cérébrales pédiatriques les plus sévères. Aucun progrès dans leur prise en charge n’a été accompli au cours des 50 dernières…
(more)
▼ Les DIPG représentent les tumeurs cérébrales pédiatriques les plus sévères. Aucun progrès dans leur prise en charge n’a été accompli au cours des 50 dernières années et la radiothérapie ne demeure que transitoirement efficace. Récemment, une mutation somatique de l’histone H3 (K27M) spécifique des DIPG a été trouvée chez environ 95% des patients. Elle est aujourd’hui considérée comme l'événement oncogénique initiateur de ces tumeurs. Deux sous-groupes majeurs de patients présentant des programmes oncogéniques et une réponse à la radiothérapie distincts peuvent être définis en fonction du gène dans lequel l’altération survient, codant les variantes protéiques H3.1 ou H3.3. Nous avons réalisé deux cribles de létalité synthétique par ARN interférence ciblant le kinome humain afin d'identifier d’une part les gènes nécessaires à la survie des DIPG et d’autre part les gènes dont l’inhibition sensibilise ces tumeurs à la radiothérapie. Le double objectif de ce projet était de mieux comprendre la biologie sous-jacente à l’oncogenèse des DIPG et de découvrir de nouvelles cibles thérapeutiques.Nous avons mis en évidence 41 gènes requis pour la survie des DIPG sans effet délétère majeur sur des cellules contrôles normales. Parmi eux, nous avons identifié VRK3 codant une serine thréonine kinase dont les fonctions restent peu décrites à ce jour et qui n'avait jamais été associée préalablement à l'oncogenèse de DIPG. Nous avons pu confirmer par la suite que son inhibition conduit à un arrêt total de la prolifération des cellules de DIPG associé à d’importants changements morphologiques, plus particulièrement dans les tumeurs mutées pour H3.3-K27M. VRK3 constitue par conséquent une nouvelle cible thérapeutique prometteuse dans cette pathologie à l’issue fatale pour la totalité des patients.En parallèle, un crible de survie similaire a été réalisé en conjonction avec l’irradiation des cellules. Très peu d’ARN interférents ont permis de sensibiliser les cellules H3.3-K27M à la radiothérapie contrairement aux cellules H3.1-K27M. Ce travail nous a permis de mettre en évidence une différence significative de radiosensibilité des modèles vitro de DMG en fonction du sous-groupe de tumeurs considéré, H3.1- ou H3.3-K27M muté, conformément à la survie des patients observée suite à la radiothérapie. Ces résultats inédits laissent entrevoir des perspectives d’amélioration du traitement de référence des patients atteints de DIPG actuellement identique quelle que soit leur génotype.
DIPG is one of the most severe paediatric brain tumours. No progress has been made in their management over the past 50 years and radiotherapy remains only transiently effective. Recently, a specific somatic mutation in the histone H3 (K27M) has been found in approximately 95% of DIPG patients and can be considered as the oncogenic driver of these tumours. Two major subgroup of patients with distinct oncogenic program and response to radiotherapy can be defined according to the gene in which the alteration occurs, encoding the H3.1 or H3.3 protein variants. We…
Advisors/Committee Members: Debily, Marie-Anne (thesis director).
Subjects/Keywords: Dipg; Crible d’ARN interférence; Létalité synthétique; Histone H3-K27M; Radioresistance; Dipg; RNA interference screening; Synthetic lethality; H3-K27M Histone; Radioresistance
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Silva Evangelista, C. (2018). Molecular Characterization of Pediatric Brainstem Gliomas (DIPG) and Identification of New Therapeutic Targets : Caractérisation moléculaire des gliomes malins pédiatriques du tronc cérébral (DIPG) et identification de nouvelles stratégies thérapeutiques. (Doctoral Dissertation). Université Paris-Saclay (ComUE). Retrieved from http://www.theses.fr/2018SACLS269
Chicago Manual of Style (16th Edition):
Silva Evangelista, Cláudia. “Molecular Characterization of Pediatric Brainstem Gliomas (DIPG) and Identification of New Therapeutic Targets : Caractérisation moléculaire des gliomes malins pédiatriques du tronc cérébral (DIPG) et identification de nouvelles stratégies thérapeutiques.” 2018. Doctoral Dissertation, Université Paris-Saclay (ComUE). Accessed April 14, 2021.
http://www.theses.fr/2018SACLS269.
MLA Handbook (7th Edition):
Silva Evangelista, Cláudia. “Molecular Characterization of Pediatric Brainstem Gliomas (DIPG) and Identification of New Therapeutic Targets : Caractérisation moléculaire des gliomes malins pédiatriques du tronc cérébral (DIPG) et identification de nouvelles stratégies thérapeutiques.” 2018. Web. 14 Apr 2021.
Vancouver:
Silva Evangelista C. Molecular Characterization of Pediatric Brainstem Gliomas (DIPG) and Identification of New Therapeutic Targets : Caractérisation moléculaire des gliomes malins pédiatriques du tronc cérébral (DIPG) et identification de nouvelles stratégies thérapeutiques. [Internet] [Doctoral dissertation]. Université Paris-Saclay (ComUE); 2018. [cited 2021 Apr 14].
Available from: http://www.theses.fr/2018SACLS269.
Council of Science Editors:
Silva Evangelista C. Molecular Characterization of Pediatric Brainstem Gliomas (DIPG) and Identification of New Therapeutic Targets : Caractérisation moléculaire des gliomes malins pédiatriques du tronc cérébral (DIPG) et identification de nouvelles stratégies thérapeutiques. [Doctoral Dissertation]. Université Paris-Saclay (ComUE); 2018. Available from: http://www.theses.fr/2018SACLS269
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Open Access Theses and Dissertations
