Targeting GPR30 in Abiraterone- and MDV3100 Resistant Prostate Cancer
Technical Report,30 Sep 2014,29 Sep 2017
University of Washington Seattle United States
Pagination or Media Count:
Little information is available on the novel treatment for abiraterone Abi- and MDV3100 MDV-resistant disease. G protein-coupled receptor 30GPR30 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,P0.046 or minimally responsive to Abi and MDV LuCaP 35CR, P0.005. 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 Abiandor 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.
- Medicine and Medical Research