2023 J.C. Kennedy Foundation, GTSN-PCF Challenge Award

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 Investigators: Fan Zhang, PhD (Duke University), Yutian Feng, PhD (Duke University)

Description:

  • Lineage-plastic and neuroendocrine prostate cancer (NEPC) are highly aggressive subtypes of metastatic castration-resistant prostate cancer (mCRPC) that develop as mechanisms of resistance to androgen receptor (AR)-targeted therapies. Approximately 1/3 of patients with lethal prostate cancer have lineage-plastic and/or NEPC phenotypes. New treatments for these subtypes are urgently needed.
  • Drs. Andrew Armstrong and Jiaoti Huang and team have identified the chemokine receptor CXCR2 as a critical regulator of NEPC and lineage plasticity, and others have identified CXCR2 as important for immune evasion in prostate cancer, suggesting it may have potential as a therapeutic target.
  • Preclinical studies suggest that co-targeting AR and CXCR2 may have synergistic efficacy for the treatment of mCRPC. A phase 2 clinical trial (SYNERGY-201) testing the combination of the AR inhibitor enzalutamide and the CXCR1/2 inhibitor SX-682 (Syntrix) is underway and will be conducted through the US Department of Defense Prostate Cancer Clinical Trials Consortium (DOD PCCTC).
  • In this project, Dr. Armstrong and team will use samples from this trial to identify and validate tumor and immune biomarkers that predict which patients with mCRPC are most likely to benefit from treatment with enzalutamide plus SX-682.
  • The team has also identified the GPC3 protein as a promising new cell surface therapeutic target on NEPC cells and has developed a new GPC3-targeted alpha particle radioligand therapy. In this project, the team will perform preclinical studies to evaluate the efficacy of combining AR and GPC3 targeted therapies in CRPC to provide data to support a first-in-human phase 1 trial of this therapy.
  • If successful, this team will develop two new treatment strategies for patients with 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 in significant 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.

The
Grauer Family
Support

The Grauer Family’s support of PCF’s Young Investigator Award Program bolstered Dr. Cho’s success in developing a new PET radiotracer molecule specific for PSMA to detect prostate tumors safely and reliably.

Dr. Cho’s PSMA PET tracer is a new gateway into the world of precision medicine, providing early and increased treatment options for patients and families confronting advanced prostate cancer.