Endocrine Abstracts

Castration-resistant prostate cancer (CRPC) develops after androgen deprivation therapy of advanced PC, often with metastatic growth in bone and very poor prognosis. Standard treatment is docetaxel, followed by androgen-synthesis (abiraterone) or androgen receptor inhibition, or treatment with the novel taxane cabazitaxel. Novel drugs are constantly under development and molecular properties of individual tumors will determine treatment effectiveness in individual cases. The aim of this study was to identify possible response and resistance mechanisms towards Abiraterone acetate and Cabazitaxel in the human PC 22Rv1 xenograft. Xenografts were established by subcutaneous inoculation of 22Rv1 PC cells in nude mice and treated with vehicle and/or sham operation (n=23), castration by surgical incision (n=7), abiraterone (n=9), cabazitaxel (n=7), castration plus abiraterone (n=8), or castration plus cabazitaxel (n=11). Therapy response and tumor progression/relapse were monitored by measurement of tumor volume. Animals were followed until tumor progression and sacrificed when tumor size reached ~1000 mm³. Preliminary results showed very little effect of abiraterone in hindering tumor progression while cabazitaxel induced complete tumor regression in 3 animals and tumor regression followed by relapse in 15 animals. Cell lines from xenografts relapsing after cabazitaxel treatment were established. Analysis of mechanisms behind response and resistance is ongoing; analysis of AR, AR-V7, steroidogenic enzymes and whole genome expression patterns. Results are probably related to 22Rv1 cell expression of constitutively active AR variants, including the AR-V7, making tumor cells resistant to androgen-deprivation (castration, abiraterone) but, due to high proliferation rate, sensitive to cabazitaxel.

Presenting Author: Erik Bovinder Ylitalo, Department of Medical Biosciences, Umeå University, By 6M Sjukhusområdet, 901 85, Umeå, Sweden. Email: [email protected]