Prostate cancer, notoriously resistant to immunotherapy due to its immunologically cool nature, is made “hot” by the addition of SX-682, researchers at The University of Texas MD Anderson Cancer Center and Syntrix report in Nature.
The researchers used a mouse model of human metastatic castrate-resistant prostate cancer (mCRPC). Mice that were engineered to develop prostate-specific deletions in the three tumor suppressor genes Pten, p53 and Smad4, spontaneously developed prostate cancer that efficiently metastasized to the lungs. After treatment with enzalutamide (XTANDI®) for 3 weeks, primary and metastatic tumors in the animals were made castrate-resistant.
Consistent with the human disease, immune checkpoint blockade (ICB) with anti-PD1 and anti-CTLA4 immunotherapies had no effect on the mouse tumors. However, the addition of SX-682 made previously “cold” ICB “hot”, with significant reduction in the average tumor mass. SX-682 significantly reduced tumor size even as a single agent. Remarkably, the combined effect of ICB with SX-682 completely eliminated lung metastasis.
John Zebala, M.D., Ph.D., CEO of Syntrix, said that “We’ve known that prostate cancer is immunologically cold, or quiet, with very little penetration of the tumors or their surrounding microenvironment by immune cells. These results with SX-682 show that blockade of CXCR1/2 reverses this cold, or quiet state, and makes tumors vulnerable to attack by the patient’s own immune system. It’s exciting data that provide a clear rationale for a clinical trial of SX-682 with anti-PD1 and/or anti-CTLA4 immunotherapies.”
ABOUT SX-682: SX-682 is a clinical-stage oral allosteric small-molecule inhibitor of CXCR1 and CXCR2 (CXCR1/2). Inhibiting both human isoforms is believed essential. CXCR1/2 are a combined “master switch” of the tumor microenvironment, where they control tumor cell metastasis, the epithelial to mesenchymal transition, the influx of immunosuppressive MDSCs and neutrophils and angiogenesis. Clinical studies in melanoma, breast, ovarian, prostate and colon cancer have shown a direct correlation between serum levels of CXCR1/2 ligands and disease progression. SX-682 has been validated in all major solid tumor models, where it exhibits mono-agent anti-tumor activity, blocks metastasis, depletes immunosuppressive myeloid cells, activates tumor killing by effector cells, reverses chemo-resistance, and potently synergizes with anti-CTLA-4 and anti-PD1.
ABOUT SYNTRIX: Syntrix is a pharmaceutical company committed to discovering and delivering innovative therapies by doing things differently. We innovate in discovery and clinical trials, engineer risk prospectively, integrate IP strategy creatively, and leverage non-dilutive capital to solve the most difficult clinical problems. Convergent Science & Strategy. Breakthrough Medicines.
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