Leap Therapeutics Collaborator Dr. David Wise
Recognized with the 2018 John & Daria Barry
Foundation–PCF Valor Young Investigator Award
Proposal Title: Overcoming Immune Evasion in Androgen
Receptor-Independent Prostate Cancer through Targeting
Androgen receptor (AR)-targeted therapy can be highly effective for the treatment of prostate cancer. Unfortunately, most patients will eventually develop resistance and progress to castration resistant prostate cancer (CRPC), an incurable form of the disease. Identifying the mechanisms of treatment resistance will reveal new strategies to prevent or overcome AR-therapy resistance.
David Wise is studying the role of DKK1 as a driver of some forms of CRPC.
Wise previously found that DKK1 is unregulated in a subset of metastatic CRPC with low or no expression of AR and that do not have features of neuroendocrine or small cell prostate cancer. DKK1 is a secreted protein that is known to inhibit the WNT signaling pathway and can also inhibit the development of anti-tumor immune responses.
To determine if DKK1 drives the progression of AR-independent CRPC through promotion of an immunosuppressive microenvironment, immune cell subsets in DKK1-expressing versus DKK1-negative prostate cancer will be characterized.
Whether DKK1 is a required for creating a tumor microenvironment that suppresses immune cell activity will be determined using patient-derived 3D culture models.
The effects of DKK1 blockade on the types and number of immune cells infiltrating tumors will be evaluated in samples from advanced prostate cancer patients on a phase 1/2 clinical trial testing the DKK1-inhibitor DKN01 plus docetaxel.
If successful, this project will determine whether DKK1 drives the development of CRPC by preventing anti-tumor immune responses, and will determine the efficacy of targeting DKK1 for the treatment of advanced prostate cancer.
What this means for patients: Dr. Wise will determine the role of the secreted protein DKK1 in driving the development of CRPC and in preventing anti-tumor immune responses, and will determine the clinical efficacy of targeting DKK1 in advanced prostate cancer patients. This may lead to a new treatment for a subset of patients with CRPC and improve our understanding of immune tolerance in prostate cancer.
David Wise, MD, PhD
New York University