DMA repair is a fundamental process central to the survival and homeostasis of an organism. The developing nervous system is particularly susceptible to DNA damage and brain tumors can result from defective DNA repair. Brain tumors are the most common solid malignancy in children under 16 years of age and constitute about 20% of all pediatric cancer. Of these, medulloblastoma is the most common malignant brain tumor. During the previous funding cycle we generated novel mouse models of medulloblastoma that resulted from defective DNA repair. Molecular and cytogenetic analyses of the medulloblastomas revealed a remarkable uniformity in the genetic lesions that are present, many of which are also features of the human disease. These data highlight the utility of the mouse models for understanding the molecular basis of human medulloblastoma. In the current application we will expand these studies to investigate the importance of the DNA damage response as a barrier to medulloblastoma formation in Ptch1*'~ mice. We have also developed additional DNA repair deficient mice that target specific DNA strand-break repair pathways, which we will utilize to generate novel brain tumor models. These new tumor models will be important for further delineating the defining molecular events that occur during tumorigenesis in the nervous system. Finally, we will determine the utility of manipulating the DNA damage response as a means to enhance brain tumor therapy. Together, these experiments will expand our understanding of genotoxic stress responses and neural homeostasis, and will have significance for establishing the etiology of brain tumors. Furthermore, this work will also be important for providing a rational basis for designing novel therapeutic approaches for the treatment of these tumors. The successful completion of these goals will result from integration of our research efforts with those of the other members of this program.
Brain tumors are the most common solid malignancy in children under 16 years of age and constitute about 20% of all pediatric cancer. A main goal of this proposal is to understand how the process of responding to DNA damage in the nervous system actively prevents brain tumors. We will also determine the utility of inhibiting the response to DNA damage in brain tumors as an improved method for the treatment of brain tumors.
|Dumitrache, Lavinia C; McKinnon, Peter J (2017) Polynucleotide kinase-phosphatase (PNKP) mutations and neurologic disease. Mech Ageing Dev 161:121-129|
|Hoch, Nicolas C; Hanzlikova, Hana; Rulten, Stuart L et al. (2017) XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia. Nature 541:87-91|
|Vo, BaoHan T; Li, Chunliang; Morgan, Marc A et al. (2017) Inactivation of Ezh2 Upregulates Gfi1 and Drives Aggressive Myc-Driven Group 3 Medulloblastoma. Cell Rep 18:2907-2917|
|Wei, Lei; Murphy, Brian L; Wu, Gang et al. (2017) Exome sequencing analysis of murine medulloblastoma models identifies WDR11 as a potential tumor suppressor in Group 3 tumors. Oncotarget 8:64685-64697|
|Illuzzi, Jennifer L; McNeill, Daniel R; Bastian, Paul et al. (2017) Tumor-associated APE1 variant exhibits reduced complementation efficiency but does not promote cancer cell phenotypes. Environ Mol Mutagen 58:84-98|
|Genthe, Jamie R; Min, Jaeki; Farmer, Dana M et al. (2017) Ventromorphins: A New Class of Small Molecule Activators of the Canonical BMP Signaling Pathway. ACS Chem Biol 12:2436-2447|
|Pajtler, Kristian W; Mack, Stephen C; Ramaswamy, Vijay et al. (2017) The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants. Acta Neuropathol 133:5-12|
|Fukuda, Yu; Wang, Yao; Lian, Shangli et al. (2017) Upregulated heme biosynthesis, an exploitable vulnerability in MYCN-driven leukemogenesis. JCI Insight 2:|
|Nakanishi, Takeo; Ohno, Yasuhiro; Aotani, Rika et al. (2017) A novel role for OATP2A1/SLCO2A1 in a murine model of colon cancer. Sci Rep 7:16567|
|Enriquez-Rios, Vanessa; Dumitrache, Lavinia C; Downing, Susanna M et al. (2017) DNA-PKcs, ATM, and ATR Interplay Maintains Genome Integrity during Neurogenesis. J Neurosci 37:893-905|
Showing the most recent 10 out of 186 publications