HE3235 inhibits growth of castration-resistant prostate cancer.
Treatments for advanced prostate cancer (CaP) typically involve androgen deprivation therapy. However, most patients eventually develop castration-resistant CaP (CRPC) for which highly effective therapies are limited. We explored the efficacy of a novel agent, HE3235, in inhibiting growth of CRPC in preclinical models. Castrated male mice were implanted subcutaneously with LuCaP35V CaP xenografts in the presence and absence of 5'-androstenediol (AED) and treated with HE3235. To investigate the effect of HE3235 on CaP tumor in the bone, castrated mice were injected intratibially with C4-2B CaP cells and treated with HE3235. Serum prostate-specific antigen (PSA) levels, tumor volume, immunohistochemistry, gene expression, and levels of intratumoral androgens were analyzed. HE3235 significantly prolonged the tumor doubling time of LuCaP35V, decreased androgen receptor expression, and lowered levels of intratumoral testosterone by approximately 89% and dihydrotestosterone by approximately 63% in both the presence and the absence of AED. HE3235 inhibited tumor growth in the bone environment. Weights of tumored tibiae of HE3235-treated animals were lower than those of control (P = .031), and normalized PSA levels were also significantly decreased at the end of study by HE3235 treatment (P = .0076). HE3235 inhibits the growth of subcutaneous CRPC as well as CRPC in the bone environment. Our data show that HE3235 exhibits a wide range of effects, including alteration of androgen receptor signaling and reductions in levels of intratumoral androgens. Our results support ongoing clinical investigations into the effectiveness of HE3235 in the setting of CRPC and warrants further studies into the mechanisms behind the effects of HE3235.
Koreckij
Theodore D
TD
Department of Urology, University of Washington, Seattle, WA 98195, USA.
Trauger
Richard J
RJ
Montgomery
Robert Bruce
RB
Pitts
Tiffany E M
TE
Coleman
Ilsa
I
Nguyen
Holly
H
Reading
Chris L
CL
Nelson
Peter S
PS
Vessella
Robert L
RL
Corey
Eva
E
D000732:Androstanols / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000556:secondary; D002369:Castration; D013196:Dihydrotestosterone / Q000032:analysis / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000188:drug therapy; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013739:Testosterone / Q000032:analysis / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
C540077:17-ethynylandrostane-3,17-diol; D000732:Androstanols; D000970:Antineoplastic Agents; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D013739:Testosterone