Targeting GPR30 in Abiraterone- and MDV3100 Resistant Prostate Cancer
Abstract
Little information is available on the novel treatment for abiraterone (Abi)- and MDV3100 (MDV)-resistant disease. G protein-coupled receptor 30(GPR30) is a seven-transmembrane estrogen receptor and activation by its specific agonist G-1 inhibited growth in multiple castration-resistant prostate cancer (CRPC) xenograft models that were resistant to the first-generation androgen deprivation therapy. More importantly, GPR30 is an androgen-repressed target and its expression increased in clinical CRPC when compared to primary prostate cancer. Here, we showed that G-1 significantly inhibited the growth and extended the progression-free survival of patient-derived xenograft models that are sensitive (LuCaP 136CR,P=0.046) or minimally responsive to Abi and MDV (LuCaP 35CR, P=0.005). Interesting, no survival benefit was observed with G-1 when these mice had been pre-treated with Abi or MDV. However, G-1 delayed the development of Abi resistance in the Abi-sensitive LuCaP 136CR, suggesting a defined window for the G-1 therapy. Together with our previous findings, G-1 invariably inhibited 5 models of CRPC, independent oftheir sensitivity to Abi or MDV. No adverse side effect of G-1 was detected in these preclinical studies. Clinically, GPR30 expression was detectedin >90 of CRPC metastases, whereas 80 showed a moderate to high expression level. In rapid autopsy patients who were treated with Abiand/or MDV, GPR30 was highly expressed in both lung and bone metastases. The high level of GPR30 in CRPC receiving Abi and MDV highlights the potential in effective G-1 therapy on CRPC patients either in combination with Abi, or on CRPC that is minimally responsive to Abiand MDV.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2017
- Accession Number
- AD1049938
Entities
People
- Hung-ming Lam
Organizations
- University of Washington