Kristoffer C. Valerie, M.S., Ph.D.
Research program member: Developmental Therapeutics
401 College St.
Richmond, VA 23298-0058
Professor, Radiation Oncology, School of Medicine
Professor & Professor, Biochemistry and Molecular Biology, School of Medicine
Professor & Professor, Microbiology and Immunology, School of Medicine
Professor & Professor, Physics, College of Humanities and Sciences
PhD, Royal Institute of Technology, Sweden (1986)
MS, Temple University (1985)
I focus on molecular radiobiology, DNA repair, radiation-induced signaling, glioma biology, animal tumor models, and the development and testing of novel radiosensitizers. We study mechanisms of DNA double-strand break repair in human cells, focusing on the roles of ATM and BRCA1 in DSB repair and the DNA damage response in glioma cell systems. We're testing ATM kinase inhibitors as potential radiosensitizers for malignant glioma using mouse brain tumor models and found that p53 mutant gliomas or dysregulated p53 signaling are particularly responsive to ATMi radiosensitization. ATM inhibitors also negatively impact glioma cell growth and invasion and inhibit the DDR. Pro-survival AKT and ERK signaling was negatively affected by ATM inhibition and inhibiting ERK signaling impaired ATM activation, suggesting a network between tumor growth control and the DDR. We published a report on an orally bioavailable and CNS penetrating ATMi (AZ32) that demonstrated cancer-specific killing of gliomas in mice through a mechanism in line with enhanced mitotic catastrophe in p53 dysregulated cells and large therapeutic ratios determined by cleaved-caspase 3 mediated cell death. A clinical candidate ATMi (AZD1390) showed similar results. We also have translational trials: 1) We generated a nanoconjugate, PEAMOtecan, targeting proliferating brain tumors by the slow release of camptothecin after direct intra-tumoral injection to prolong mice with intracranial tumors. 2) We investigate the relationship between the ATM kinase and protein phosphatase 2, which forms a kinase-phosphatase pair during DDR with numerous targets, including cell cycle checkpoints, apoptosis, and DNA double-strand break repair. In response to radiation, ATM kinase phosphorylates the regulatory PP2A subunit A (PR65) at S401, which inactivates PP2A and keeps the DDR in 'ON' position. As DDR subsides, PP2A regains activity and dephosphorylates ATM kinase targets and the cell returns normal. We have generated genetically matched mouse embryonic fibroblasts expressing PR65-S401A and -S401D, representing S401 unphoshorylatable and phospho-mimetic PR65, to determine the effect on DDR. Both S401A and -D cells have altered response to DNA damage with cell cycle checkpoints abrogated, cell growth, and the quality of DSB repair fundamentally altered.
DNA damage response, ATM, DNA repair, glioma, radiosensitizers