This is the competing renewal of a SPORE initiative on glioma at Dana-Farber/Harvard Cancer Center. Our objective is to improve the standard of care for children, young adults, and adults with these tumors through the use of targeted therapies. Towards this end, basic scientists from Harvard Medical School and the Broad Institute join with clinical/translational investigators from Boston Children?s Hospital, Brigham and Women?s Hospital, Dana-Farber Cancer Institute and Massachusetts General Hospital. There are four projects: Project One targets pediatric low-grade astrocytomas (PLGAs). Nearly 75% of PLGAs are driven by activating mutations in the BRAF protein kinase. Clinician/scientists Daphne Haas-Kogan, M.D. and Karen Wright, M.D. together with structural biologist Michael Eck, M.D., Ph.D. will develop and test brain-penetrant targeted therapeutics for BRAF-mutant PLGAs. Project Two targets IDH-mutant gliomas which present typically in young adults. IDH-mutant gliomas produce extraordinarily high levels of the ?oncometabolite? R-2- hydroxyglutarate (2-HG). However, therapeutic exploitation of the differential 2-HG content between normal and malignant brain tissue has yet to be realized. Neurosurgeon Daniel Cahill, M.D., Ph.D. and cancer biologist William Kaelin, M.D. will address this therapeutic lacuna. Project Three targets adult gliomas. Recent studies by basic scientist Jean Zhao, Ph.D. show that in addition to suppressing cell cycle progression, CDK4/6 antagonists promote anti-tumor immunity and synergistically enhance the response to checkpoint inhibitors. Going forward, Dr. Zhao together with neuro-oncologist Patrick Wen, M.D. will test the hypothesis that brain penetrant CDK4/6 inhibitors can augment immunotherapeutic approaches to GBM. Project Four targets the neuronal microenvironment of adult and pediatric gliomas. Neuro-oncologist and developmental neurobiologist Michelle Monje, M.D., Ph.D. has shown that neurons promote glioma growth through activity- regulated secretion of neuroligin-3 (NLGN3) into the tumor microenvironment. Basic scientist Mario Suva, M.D, Ph.D. has refined methods for single cell sequencing of the multiple cell types within the microenvironment of freshly resected human gliomas. Working together, Monje and Suva will define the molecular mechanisms whereby microenvironmental NLGN3 modulates formation and progression of gliomas and explore a novel therapeutic opportunity embedded within the NLGN3 requirement. Rigor and reproducibility of work conducted in the four projects will be fostered by cores for Pathology and for Biostatistics and Computational Biology. An Administration core will enable and manage the multiple consortium agreements and collaborative interactions between Harvard Medical School, the four participating Harvard teaching hospitals and facilitate clinical trials and imaging studies. Intellectual vigor within the program is sustained and refreshed by annual Career Enhancement Awards to young investigators and by annual Developmental Project Awards.
Primary cancers of the brain have surpassed leukemias as the number one cause of cancer-related death in children and low-grade astrocytomas are the most common brain tumor of childhood. Pediatric low-grade astrocytomas (PLGAs) are survivable with current standard of care. However, the quality of life for long-term PLGA survivors and their capacity for independent living is compromised to a significant degree. Targeted therapeutics for PLGA are urgently needed. The work proposed for Project One has the potential to deliver brain-penetrant targeted therapies for these tumors. Primary brain tumors, including high-grade gliomas are the third most common cause of cancer-related death in persons ages 15-39 years (http://www.CBTRUS.org). In the fullness of time, the work proposed for Projects Two and Three could change the standard of care and improve patient outcomes for these tumors via highly selective ?synthetic lethal? therapeutic modalities (Project Two) or small molecule adjuvants to immunotherapy (Project Three). Project Four addresses a unique feature in the biology of high-grade gliomas. These tumors occur within the context of the brain microenvironment. Preliminary studies have shown that neuronal activity within the glioma microenvironment secrete a factor (NLGN3) that promotes the growth of these tumors in adults and also in children. The study plan for this project will explore a novel therapeutic opportunity embedded within the NLGN3 requirement.
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