05 Brain Cancer

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PROJECT SUMMARY/ABSTRACT The Brain Cancer Program (BCP), a multidisciplinary basic, translational, and clinical research program, includes 86 members (36 primary and 50 associate). Leadership is provided by physician-scientists: Amy Heimberger and Frederick Lang, both neurosurgeons; Juan Fueyo-Margareto, a laboratory-based investigator; and John de Groot, a neuro-oncologist. The overall goal of the BCP is to identify the genetic and molecular determinants of primary and metastatic brain tumor formation and progression and to use this knowledge to improve the survival and quality of life of patients through specifically targeted biological and small-molecule therapies. The program has 3 specific aims. Aim 1: To develop effective viral and immunotherapeutic treatment strategies that exploit glioblastoma heterogeneity. Aim 2: To determine how to optimize targeted approaches for central nervous system tumors. Aim 3: To define factors that promote the development of central nervous system metastases, devise strategies to prevent their formation, develop early detection or identify at-risk patients, and prioritize optimal therapeutic approaches. The BCP's annual direct peer-reviewed funding is $5.7M, including a Brain Cancer SPORE. Of the total peer-reviewed funding, $2.1M (37%) is from NCI grants, and $3.6M is from other peer-reviewed sources. BCP members have authored 703 publications in peer-reviewed journals over the past 6 years, of which 362 (51%) were intra-programmatic, 170 (24%) were inter-programmatic, and 485 (69%) involved external collaborations. Forty-one percent of publications have appeared in journals with IF >5, and 13% have appeared in journals with IF >10, including Nature, Cancer Cell, Mol Cell, Lancet Oncol, J Clin Oncol, J Natl Cancer Inst, J Clin Invest, and Nat Genet. Accomplishments include major contributions to The Cancer Genome Atlas and key leadership roles in the international glioblastoma Adaptive Global Innovative Learning Environment Bayesian Clinical Trial. During the last grant period, members of the BCP made important contributions in evaluating transcriptome plasticity and radiation resistance in glioblastoma stem cells (GSCs) (Bhat et al, Cancer Cell, 2013) and the roles of Quaking in self-renewal and preventing terminal differentiation of GSCs (Hu J et al, Proc Natl Acad Sci USA, 2013; Shingu et al, Nat Genet, 2017), WNT5a in driving GSC differentiation into endothelial-like cells that support invasive glioblastoma cells (Hu B et al, Cell, 2016), and PKM2 in altering cell metabolism and cell-cycle progression with the Cancer Biology and Metastasis Program (Yang et al, Mol Cell, 2012; Yang et al, Cell, 2012; Jiang Y et al, Mol Cell, 2014; Jiang Y et al, Nat Commun, 2014). Another important advance by BCP members is the use of stereotactic radiosurgery after brain metastasis resection as an alternative to whole-brain radiotherapy, which has influenced the standard of care for these patients nationally (Mahajan A et al, Lancet Oncol, 2017). We have seen a 50% decrease in the use of whole- brain irradiation at The University of Texas MD Anderson Cancer Center.