Targeting Neuroendocrine Cells in Prostate Cancer with Small Molecule and Targeted Radionuclide Therapies

Principal Investigators: Andrew Armstrong, MD (Duke University), Jiaoti Huang, MD (Duke University)

Co-Investigators: Michael Zalutsky, PhD (Duke University), Susan Halabi, PhD (Duke University), Kent Weinhold, PhD (Duke University)

Young Investigator: Fan Zhang, PhD (Duke University), Yutian Feng, PhD (Duke University)

Description:

• Lineage-plastic and neuroendocrine prostate cancer (NEPC) are highlyaggressive subtypes of metastatic castration-resistant prostate cancer(mCRPC) that develop as mechanisms of resistance toandrogenreceptor (AR)-targeted therapies. Approximately 1/3 of patients with lethal prostate cancerhave lineage-plastic and/or NEPC phenotypes. New treatments for thesesubtypes are urgently needed
• Drs. Andrew Armstrong and Jiaoti Huang and team have identified thechemokine receptor CXCR2 as a critical regulator of NEPC and lineageplasticity, and others have identified CXCR2 as important for immune evasionin prostate cancer, suggesting it may have potential as a therapeutic target.
• Preclinical studies suggest that co-targeting AR and CXCR2 may havesynergistic efficacy for the treatment of mCRPC. A phase 2 clinical trial(SYNERGY-201) testing the combination of the AR inhibitor enzalutamide andthe CXCR1/2 inhibitor SX-682 (Syntrix) is underway and will be conductedthrough the US Department of Defense Prostate Cancer Clinical TrialsConsortium (DOD PCCTC).
• In this project, Dr. Armstrong and team will use samples from this trial toidentify and validatetumorand immune biomarkers that predict whichpatients with mCRPC are most likely to benefit from treatment withenzalutamide plus SX-682.
• The team has also identified the GPC3 protein as a promising new cell surfacetherapeutic target on NEPC cells and has developed a new GPC3-targetedalpha particle radioligand therapy. In this project, the team willperformpreclinical studies to evaluate the efficacy of combining AR and GPC3 targetedtherapies in CRPC to provide data to support a first-in-human phase 1 trial ofthis therapy.
• If successful, this team will develop two new treatment strategies forpatientswith the most aggressive and lethal forms of prostate cancer.

What this means to patients: New treatments are urgently needed for patients with lineage-plastic and neuroendocrine prostate cancer (NEPC), which are highly aggressive forms of CRPC with no effective therapies available. Drs. Armstrong and Huang and team are studying the efficacy and developing biomarkers for two new treatment approaches for NEPC, which target CXCR2 and GPC3, and may have synergy with AR-targeted therapy in patients with mCRPC. These studies may result insignificant clinical benefit for patients with mCRPC who have progressed on AR blockade, addressing a major unmet need encompassing precision immunotherapy and reversing the lethal treatment-resistant, lineage-plastic phenotype of aggressive prostate cancer.