Sigma1, cancer, lipid metabolism, metabolic plasticity, metabolic rewiring, pharmacology, drug discovery, protein homeostasis, tumor microenvironment, immune modulation, extracellular vesicles, exosomes

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.

Key ongoing projects in the lab:

I.  Define the role of the Sigma1 system in tumor biology. This component of our research program comprises two principle projects focused on: (1) Metabolism. Define the role of Sigma1 in cancer cell lipid metabolism and metabolic rewiring that enables tumor adaptation and development of resistance. (2) Tumor microenvironment (TME). Here, we investigate the role of Sigma1 in the regulation of immune checkpoint molecules, secretion of immune modulatory cytokine, and production and composition of exosomes and other extracellular vesicles (EVs).

II.   Evaluate the molecular mechanisms of Sigma1 modulator actions. Here, we use in vitro, ex vivo, and in vivo experimental models to define how small molecule Sigma1 modulators regulate Sigma1 activity in prostate cancer cells. (1) The first project is pharmacological mechanism of action focused and aims to define at the molecular, biochemical, and cellular level how drugs that target Sigma1 work to suppress tumor growth, proliferation, and survival. (2) The second project aims to confirm on target mechanism of action in vivo using mouse models of cancer, including standard tumor xenograft and cancer patient derived tumor xenograft models.

III.  Discover novel Sigma1 targeting therapeutic agents and biomarker driven strategies to treat prostate cancer. Our translational cancer research program includes a drug discovery platform which has produced a novel drug-like small molecule Sigma1 modulator series. An emerging paradigm in precision medicine is the co-development of cancer drugs with predictive biomarkers that can optimize treatment efficacy in selected patient populations. Biomarker-guided therapy can also inform synergistic drug combinations that bypass or delay treatment resistance. We are exploring biomarkers to serve as companion diagnostic tools for precision treatment approaches that will enable the identification of patients most likely to benefit from this new class of cancer drugs.