Login to Access Video or Poster Abstract: MP87-12
Sources of Funding: P01-CA77739, DoD-W81XWH-15-1-0409 and RPCI-CCSG-C416056

Introduction

Prostate Cancer (CaP) growth and survival is dependent on the interaction of androgen receptor (AR) and testicular androgens, testosterone and dihydrotestosterone (DHT). Men that fail potential curative treatment are treated with androgen deprivation therapy (ADT). ADT is palliative and CaP recurs as the lethal phenotype. One mechanism that contributes to CaP recurrence is intratumoral intracrine androgen metabolism, which is the conversion of weak adrenal androgens (androstenedione [ASD] or dehydroepiandrosterone [DHEA]) to T or DHT. Mice lack adrenal androgens and therefore adrenal androgen contribute to CaP xenograft recurrence is overlooked. The hypothesis for these studies is adrenal androgen supplementation will facilitate androgen dependent human CaP CWR22 xenograft resistance to ADT.

Methods

Mice were castrated, implanted with CWR22 and silastic tubes that contained T and empty silastic tubes that contained ASD or DHEA. T silastic tubes were removed after CWR22 tumor volumes reached 0.5 cc to simulate ADT. Digital calipers were used to measure changes in CWR22 tumor volume. Mouse serum, prostate and CWR22 were harvested at designated time points and liquid chromatography tandem-mass spectrometry (LC-MS/MS) was performed to measure androgen levels.

Results

CWR22 xenografts treated with no adrenal androgen regressed and began to grow 120 days after T silastic tube removal. ASD treated CWR22 tumors did not regress; CWR22 tumor growth increased and mice were euthanized because tumors grew beyond veterinary limits. DHEA treated CWR22 did not regress and did not grow like ASD treated CWR22. However, CWR22 xenografts recurred faster than control CWR22 xenografts. Serum PSA levels correlated with tumor volume. CWR22 androgen levels decreased in all treatment groups, but T levels remained sufficient to activate AR in ASD treated CWR22, but not control or DHEA treated CWR22 xenografts.

Conclusions

DHEA and ASD supplementation facilitated CWR22 resistance to ADT. However, CWR22 xenografts responded differently to DHEA and ASD, which suggests that adrenal androgens may play different roles when CaP cells undergo ADT. These studies show that adrenal androgen contributes should be taken into account when in vivo studies are performed to test CaP responses to ADT or therapeutic agents.

Funding

P01-CA77739, DoD-W81XWH-15-1-0409 and RPCI-CCSG-C416056