Targeting WNT5A-Mediated Therapy Resistance Mechanisms and Tumor Genomic Heterogeneity in Lethal Bone-Metastatic Prostate 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 models e developed form surgical prostate cancer bone metastases and prostate cancer 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 Y2 of this grant we have built on our work showing 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. To study the mechanisms of WNT5A/ROR1 signaling in CRPC we generated CRISPR/Cas9 ROR1 knock out cell lines which we are testing invitro and in vivo for responsiveness to combination therapy of docetaxel plus radiation the standard of care for bone metastatic CRPC. Cirmtuzumab has demonstrated efficacy in our patient derived xenograft tumors in vivo in combination with the taxane chemotherapy, docetaxel. We have performed in vitro and in vivo testing of the anti-ROR1 Cirmtuzumab-based CART cells in NEPC cell lines and in our patient-derived xenograft (PDX) mouse models. Our most important result thus far is that anti-ROR1 Cirmtuzumab-based CART cells can durably eradicate PC3 xenograft tumors in vivo (more than 100 days so far and counting). We obtained an IRB amendment to an existing IRB protocol and have collected archival NEPC specimens for testing ROR1 expression in immunohistochemistry (IHC) assays to detect ROR1.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2021
- Accession Number
- AD1163383
Entities
People
- Christina A. Jamieson
Organizations
- University of California Regents