Collections > Electronic Theses and Dissertations > ATR is a Novel Therapeutic Target for Medulloblastoma Identified by its Role in Cerebellar Development
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Microcephaly and brain tumors can both arise as a consequence of dysregulated expansion of neural progenitor cells. Inadequate progenitor proliferation, premature cell cycle exit, and inappropriate cell death can all result in neurodevelopmental disorders characterized by microcephaly. In contrast, brain tumors may form in response to overactive progenitor proliferation, failed cell cycle exit, and/or escape from cell death. This dissertation focuses on the role of the DNA damage response protein ATR (Ataxia-telangiectasia and Rad3-related) in the survival of cerebellar granule neuron progenitors (CGNPs) and CGNP-derived medulloblastoma, a cerebellar tumor that is the most common brain cancer of childhood. Chapter 1 provides background information on medulloblastoma, cerebellar development, CGNP biology, the ATR-mutated microcephalic disorder Seckel syndrome, ATR’s mechanism of action, and the apoptotic pathway. Chapter 2 is written in the form of a review article on how insights from primary microcephalic disorders in general can inform the development of novel brain cancer therapeutics. Chapter 3 is a published article that explores the function of ATR in CGNPs during neonatal cerebellar development. Specifically, we show that Atr deletion in CGNPs leads to widespread, p53-mediated, BAX/BAK-dependent apoptosis in the early postnatal period due to the accumulation of severe chromosomal abnormalities. This chapter also provides initial data suggesting the therapeutic value of targeting ATR using a novel nanoparticle formulation of the small molecule ATR inhibitor VE-822, pVE-822, for treating medulloblastoma. Chapter 4 presents ongoing work in the form of two research-in-brief articles in progress. The first section further investigates the possibility of treating CGNP-derived medulloblastoma with pVE-822, showing that pVE-822 has an anti-tumor effect in mice with established, spontaneous medulloblastoma. In the second section, data are presented demonstrating that in vivo inhibition of the mitotically-limited, microtubule-associated motor protein KIF11/EG5 potently arrests CGNPs in mitosis without producing DNA damage or apoptosis. Finally, Chapter 5 provides a discussion on how, if at all, ATR performs a special and unique function in CGNPs compared to other brain cells and whether ATR inhibition for the treatment of medulloblastoma should be further pursued.