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Title Investigating novel therapies for brain tumors - the roles of MCT4, cellular senescence, and arsenic trioxide treatment
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University/Publisher Johns Hopkins University
Abstract My studies focused on characterizing signaling and metabolic pathways involved in the pathobiology of brain tumors in order to develop improved therapies. One project was centered on investigating oncogenic KIAA1549-BRAF fusion induced senescence as a growth suppressive mechanism in pilocytic astrocytoma. We found that loss of expression of tumor suppressor p16 lead to significantly decreased survival in pilocytic astrocytoma patients. Another major focus was on metabolic targeting in glioblastoma cells. We found that the lactate exporter MCT4 was specifically upregulated under hypoxic conditions in glioblastoma cells, and its overexpression was significantly linked to survival. Silencing MCT4 in glioblastoma neurospheres led to decreased growth in vitro and in vivo, inhibition of clonogenic capacity, and reductions in CD133-positive stem-like tumor cells. This was partially due to an induction of apoptosis. Interestingly, we found that this apoptotic induction and growth inhibition was not due to lack of lactate export, but instead, due to an inhibition of the HIF response, highlighting the importance of aberrant metabolic regulation in cancer. Finally, we investigated the possibility of targeting Notch and Hedgehog signaling simultaneously in glioblastoma neurospheres using arsenic trioxide. We found that aberrant Notch and Hedgehog pathway signaling was decreased following arsenic trioxide treatment, and this decrease was accompanied by decreased neurosphere growth and proliferation, decreased clonogenic capacity, decreased CD133-positive cells, and increased apoptosis. These studies thus identify mechanisms by which several hallmarks of cancer are altered in brain tumors, and our preclinical data suggest some potential therapeutic applications. However, it is important to note that targeting only one or two hallmark changes in cancer often leads to therapeutic resistance, and multimodal therapies will likely be necessary if we are to cure aggressive brain tumors.
Subjects/Keywords Brain tumors; pilocytic astrocytoma; glioblastoma
Contributors Semenza, Gregg (advisor)
Country of Publication us
Format application/pdf
Record ID oai:jscholarship.library.jhu.edu:1774.2/36976
Repository jhu
Date Retrieved
Date Indexed 2016-10-05
Issued Date 2014-03-10 00:00:00

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…2.3.2 BRAF V600E expression promotes senescence in human cortical neurospheres .24 INK4a 2.3.3 Lack of expression of the senescence marker p16 in pilocytic astrocytoma is associated with shorter survival…

…28 2.3.4 Primary cultures of KIAA1549:BRAF fusion containing pilocytic astrocytoma express markers of senescence ...................................................................................... 30 2.3.5 Induction of senescence is associated with…

…44 3.2.1 Pilocytic Astrocytoma (WHO Grade I) ............................................................... 44 3.2.2 Pilomyxoid Astrocytoma (WHO Grade II) ......................................................... 46 3.2.3…

…in Our Knowledge of Pilocytic Astrocytoma Biology ..................... 126 6.2 Advances in our knowledge of metabolic targeting in glioblastomas .............. 127 6.3 Advances in stem-cell targeting in glioblastoma…

…134 x LIST OF FIGURES Figure 1-1. Schematic showing different growth characteristics of pilocytic astrocytoma cells with or without p16INK4a .................................................................................................. 5 Figure…

…cells upregulate senescence markers and show decreased proliferation after several passages...................................................................... 26 Figure 2-3: Pilocytic astrocytoma cells express markers of senescence in vivo and in…

astrocytoma tumors, other MAPK pathway activating mutations in BRAF and RAS had also been identified in pilocytic astrocytomas, including BRAF V600E. It is thus believed that MAPK pathway hyperactivation might be important in pilocytic astrocytoma pathogenesis…

…Interestingly, pilocytic astrocytoma tumors can be very indolent and sometimes even spontaneously regress(Sakai, Miyahara et al. ; Gunny, Hayward et al. 2005). This led us to draw parallels between pilocytic astrocytoma that have the oncogenic MAPK…

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