Despite considerable progress in our understanding of prostate cancer (PCa) biology, it remains a significant cause of suffering and the second leading cause of cancer death among men. There is a pressing need for new and better approaches to treatment. PCa arises as an androgen receptor (AR)-driven disease and first line therapy involves AR suppression by androgen deprivation therapy. However, resistance invariably emerges, resulting in a lethal phase termed castration-resistant PCa (CRPC). Even with the profound AR-targeting achieved by new agents, CRPC remains incurable. A major challenge is to address not only the primary target (AR), but also new drivers that emerge in response to therapy and are not addressed by existing FDA approved agents. The remarkably adaptive nature and complexity of PCa progression and the uniform development of resistance underscores the importance of developing a broader range of therapeutic agents and approaches to increase chances of overcoming resistance. Meaningful improvement in anti-tumor efficacy is likely to require strategies that simultaneously co-targeting the principal drivers of the disease as well as the networks on which it depends.

We have identified Sigma1, a unique multi-functional and pharmacologically controllable integral membrane scaffolding protein, as a druggable target that is aberrantly expressed and enriched in prostate tumors. Sigma1 regulates cellular lipid and protein homeostasis to support the increased demand for lipid metabolism and protein synthesis associated with prostate tumor growth and metastasis. Emerging evidence suggests that certain small molecule Sigma1 modulator compounds can alter cancer cell lipid metabolism and may be effective tumor growth and metastasis inhibiting agents. We are investigating the mechanisms underlying these Sigma1 modulator actions and how pharmacological modulation of Sigma1 can be used to disrupt key adaptive mechanisms that emerge in response to standard of care targeted therapies.