Targeting WNT5A-Mediated Therapy Resistance Mechanisms and Tumor Genomic Heterogeneity in Lethal Bone Metastatic Prostrate Cancer
Abstract
Advanced prostate cancer is usually treated with Androgen deprivation therapy (ADT) which can help maintain remission in patients, however, growth and metastatic spread often recur. Treatments with new mechanisms of action are urgently needed. We are using patient-derived xenograft and PCa cell line models to test mechanism of action of a new therapeutic target: the WNT5A/ROR1 signaling pathway in prostate cancer for which a therapeutic ROR1 inhibitor antibody, Cirmtuzumab, has been developed and clinically tested in CLL and metastatic breast cancer patients. In Y1 of this grant we have shown that ROR1 is expressed at high levels on castration resistant small cell PCa and neuroendocrine PCa (NEPC) models; two of the most lethal forms of prostate cancer for which there are no curative treatments in PCa cell lines and PDX models. Cirmtuzumab has demonstrated efficacy in our patient derived xenograft organoid cultures. We are now performing in vitro and in vivo testing in NEPC cell lines and in our patient-derived xenograft (PDX) mouse models. We have developed immunohistochemistry (IHC) assays to detect ROR1 in patient biopsy samples which will allow us to define the prostate cancer patient population that expressed ROR1 and to be able to evaluate the treatment in patients for a future clinical trial. These studies are will inform us about the appropriate patient populations for treatment and clinical trials. These pre-clinical studies being performed in this grant will support the pending Phase 1B clinical trial (not part of this grant).
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2020
- Accession Number
- AD1124973
Entities
People
- Christina A. Jamieson
Organizations
- University of California, San Diego