INTERCEPTING BRAIN METASTASES THROUGH METABOLIC VULNERABILITIES

BTFC travel award recipient Patients with brain metastases (BM) face a 90% mortality rate within one year of diagnosis because the current standard of care is mainly palliative. Our patient-derived xenograft models have successfully recapitulated all the stages of the metastatic cascade and captured a “premetastatic” population of BM cells that have just seeded the brains of mice before forming mature, clinically detectable tumors. We applied RNA sequencing of premetastatic BM cells to reveal a unique deregulated transcriptomic profile that is specific to premetastatic cells despite the tumor of origin. Subsequent Connectivity Map analysis led us to identify a tool compound that exhibits anti-BM activity in vitro, while remaining ineffective against normal brain cell controls. Follow up preclinical studies showed that treatment with this tool compound reduces the tumor burden of mice compared to placebo, while providing a significant survival advantage. Mass spectrometry-based metabolomics and CRISPR knock-out studies directly validated our tool compound’s target as a targetable therapeutic vulnerability in BM, where pharmacological and genetic perturbation of the target attenuates BM cell proliferation both in vitro and in vivo. We have now begun a large-scale medicinal chemistry campaign to develop novel, brain penetrant inhibitors of this target with drug-like pre-clinical profiles validated by our in vivo experimental models for later stage preclinical development and subsequent clinical development. This potential first-in-class anti-metastatic therapy may provide an alternative treatment strategy for at-risk patients that are otherwise limited to palliation and could open the gate to future development of other anti-metastatic therapies.