Defining and interrupting metabolic crosstalk in the glioblastoma microenvironment

University Of Michigan At Ann Arbor, Ann Arbor MI

Investigators

Abstract

Project Summary/Abstract Glioblastoma (GBM) is the most common aggressive primary brain tumor and is uniformly fatal with a median survival of only 1.5 years. Surgical resection and chemoradiation therapy are critical interventions for almost all GBM patients and have repeatedly improved survival in multiple randomized trials. Still, almost all GBMs recur with acquired therapeutic resistance that cannot be overcome with conventional treatments. Thus, there is an urgent need to develop novel strategies to inhibit therapeutic resistance and improve patient outcomes. In my work so far, I have found that metabolite levels in brain tumors inform patient survival outcome. My work in vivo and in human clinical studies demonstrate that GBM tumors upregulate biosynthesis pathways relative to adjacent brain tissue, rewiring cortical glucose metabolism to support pro-tumor processes. I have also shown this metabolic activity responds to genotoxic insult and promotes therapy resistance. Thus, targeting metabolism in GBM is an attractive therapeutic strategy, and we are now performing clinical trials to inhibit this activity in GBM patients at the University of Michigan. The research described in this proposal will build on these findings and define how GBMs acquire nutrients required to grow and resist therapy. My preliminary data suggest GBMs coopt neurometabolic processes including brain-derived production of glutamine and lactate, which are neurotransmitter precursor and metabolic fuel. Importantly, their production (by astrocytes) and uptake (by tumors) can be intracranially blocked by pharmacological agents but has never been tested in GBM or in combination with chemoradiation therapy. Therefore, experiments will define how brain-derived metabolites support GBM through three specific aims. The first aim is mechanistic and will use in vitro models to determine how metabolite exchange between normal brain and cancer cells promotes GBM growth and survival after therapy. The second aim will investigate how tumor metabolism and growth/survival are impacted in mice whose cortical astrocytes fail to supply specific metabolites to GBM. The third aim will assess the therapeutic promise of pharmacologically antagonizing these processes in intracranial GBM models, laying the groundwork for clinical studies targeting glutamine and lactate in patients. The mentored K99 phase of this program will be overseen by Drs. Daniel Wahl and Jack Parent at the University of Michigan. In addition, Drs. Theodore Lawrence (University of Michigan), Maria Castro (University of Michigan), Costas Lyssiotis (University of Michigan), and Nathalie Agar (Harvard Medical School, Brigham and Women’s Hospital) will serve as a postdoctoral advisory committee. Together, the applicant and mentorship team have established a career development plan employing exceptional resources at the University of Michigan focused on neuroscience and tumor microenvironment, collaboration, grantsmanship, presentation, mentorship, and management skills for the applicant to lead a successful and productive independent research program.