Dr. Monika A. Davare – Emerging Research Grant
Oregon Health and Sciences University
Brain tumors are the leading cause of cancer-related mortality in children. Medulloblastoma is the most common malignant pediatric brain tumor; children with high-risk medulloblastoma have poor outcomes and frequently succumb to their disease even after intensive cytotoxic treatments. Further, survivors of pediatric brain cancer are frequently left with lifelong health consequences due to the intensive treatments including chemotherapy and cranio-spinal radiation that diminishes their full potential and quality of life. Therefore settling for improvements in long-term survival is increasingly an incomplete goal. Dr. Monika Davare’s research program is built on the foundational hypothesis that cancer therapy targeted to the causative genetic or signaling pathway abnormality will improve long-term outcomes and quality of life for patients. Accordingly, the Davare laboratory’s specific research goals are directed at dissecting the driving cell biology of pediatric brain tumors in order to identify molecularly targeted drugs to selectively inhibit these pathways and shut down tumor growth and spread.
In the last decade, the wide-spread application of next-generation DNA sequencing technology has allowed the research community to molecularly characterize medulloblastoma tumors. Despite this large amount of genomic data that has been generated, the development of new treatment strategies in high-risk medulloblastoma remains stalled. Notably, several medulloblastoma tumors harbor somatic mutations in actionable genes that can be targeted with existing FDA approved drugs, including new brain permeable kinase inhibitors that are in the clinical pipeline for treating adult cancers. Examples of mutations in actionable kinase genes that are found in some medulloblastoma tumors include, ABL1, AKT1, ALK, FGFR1, FLT3, FLT4, INSR, MAPK isoforms & PDGFRB. However, the functional characterization of these gene mutations in this context is incomplete. Dr. Davare aims to conduct research that will help eliminate this bottleneck.
The experiments supported by the PCRF funding will include complementary approaches that will permit functional sorting of which of these mutations in kinase genes act as cancer drivers versus the ones that are just passenger events. Ultimately, Dr. Davare’s goal is to produce stringent experimental evidence that opens up new avenue(s) for potentially integrating targeted kinase inhibitor therapy, either alone or in combination with other treatments, for children bearing the unimaginable burden of high-risk medulloblastoma.