Therapeutic Targeting of Brain Metastasis-Initiating Cells

Abstract

Brain metastases (BM) have a 90% mortality rate within 4-12 months of diagnosis because they are mainly treated palliatively. The Singh Lab uses patient-derived BM samples in clinically relevant xenograft models of BM that recapitulate BM progression as seen in human patients. The objectives of my thesis were twofold: to understand whether targeting pre-metastatic cells could intercept BM formation, and whether macro-metastatic BM tumors could respond to immunotherapy as an alternative to palliative care. To intercept BM formation, I mined a Connectivity Map analysis on pre-metastatic BM gene expression signatures and identified a key regulator of the pre-metastatic process. Pharmacological and genetic perturbation of this target attenuates BMIC proliferation in vitro and slows down the formation of BM in vivo, highlighting a targetable metabolic vulnerability in BM. This work has inspired a preclinical drug development program focused on creating inhibitors with enhanced brain permeation for clinical translation. To identify whether macro-metastatic tumors respond to immunotherapy, we used a chimeric antigen receptor (CAR) T-cell to target the glycoprotein CD133, whose expression correlates with disease progression, recurrence, chemo- and radio-resistance and overall poor prognosis. We saw significant impediment in tumor progression and significant survival advantage in tumor-bearing mice after a single dose. Together, I propose that prophylaxis should be the focus of BM research moving forward and that immunotherapies should be considered where BM diagnosis precedes the chance for interception. The development of a drug that can eradicate pre-metastatic cells has the potential to prevent BM in at-risk cancer patients, while the development of a CD133-targetting immunotherapy can dramatically improve the prognosis of patients who would otherwise be limited to palliative care.