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Experimental and Molecular Therapeutics

Abstract #1713: HE3235 inhibits growth of castration-resistant prostate cancer xenografts and reduces levels of intratumoral androgens in these tumors

Theodore Koreckij, R Montgomery, Holly Nguyen, Tiffany Pitts, Ilsa Coleman, Robert Vessella and Eva Corey
Theodore Koreckij
Univ. of Washington, Seattle, WA; Fred Hutchinson Cancer Research Center, Seattle, WA
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R Montgomery
Univ. of Washington, Seattle, WA; Fred Hutchinson Cancer Research Center, Seattle, WA
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Holly Nguyen
Univ. of Washington, Seattle, WA; Fred Hutchinson Cancer Research Center, Seattle, WA
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Tiffany Pitts
Univ. of Washington, Seattle, WA; Fred Hutchinson Cancer Research Center, Seattle, WA
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Ilsa Coleman
Univ. of Washington, Seattle, WA; Fred Hutchinson Cancer Research Center, Seattle, WA
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Robert Vessella
Univ. of Washington, Seattle, WA; Fred Hutchinson Cancer Research Center, Seattle, WA
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Eva Corey
Univ. of Washington, Seattle, WA; Fred Hutchinson Cancer Research Center, Seattle, WA
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DOI:  Published May 2009
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AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Abstract

Treatment for advanced prostate cancer (CaP) typically involves androgen deprivation therapy. Despite an initial response, most patients will develop castration-resistant CaP (CRPC) for which additional therapies offer minimal survival benefit. Although the biology behind the development of CRPC is not fully understood, one theory is that adrenal and intratumoral androgens support the growth of CRPC cells. We sought to determine the efficacy of a novel drug, HE3235, in two preclinical models of CRPC and investigate the various mechanisms behind its inhibition of CRPC including its effect on intratumoral androgen levels. Mice were implanted subcutaneously (s.c.) with LuCaP 35V CaP cells and treated with HE3235 with and without androstendiol (AED) supplementation. Tumor volumes, prostate specific antigen (PSA) levels, gene expression arrays, immunohistochemistry (IHC), and intratumoral androgen levels were analyzed. Additionally, C4-2B CaP cells were injected into the tibiae of mice to evaluate the effect of HE3235 on the growth of CaP in bone. Serum PSA levels, tibiae weights, and bone mineral densities were analyzed in these animals. HE3235 significantly inhibited the growth of LuCaP 35V tumors as demonstrated by a 75 % (P=0.0004) increase in tumor volume doubling time in the absence of AED and 33% (P=0.007) increase in the presence of AED supplementation compared to respective control tumors. HE3235 therapy in the non-AED supplemented animals resulted in ~ 2.6 fold increases in the amount of serum PSA per volume of tumor (P<0.0001). However, HE3235 significantly lowered intra-tumoral levels of testosterone (T) by 93% (P=0.006) and dihydrotestosterone (DHT) by 85% (P=0.0005) in non-AED animals vs. control non-AED animals with similar significant reductions in T (85%; P<0.001) and DHT (40%; P=0.015) in AED supplemented animals. cDNA array results showed that treatment with HE3235 resulted in alterations in the expression of genes associated with androgen receptor mediated transcription, apoptosis, and cellular differentiation. IHC analysis confirmed significant reductions in androgen receptor levels in non-AED supplemented animals vs. control (P=0.005) although this was not seen in tumors with AED supplementation. In the intra-tibial model, HE3235 significantly decreased the weight of tumor tibiae vs. control tumored tibiae (P=0.034) and reduced serum PSA levels (P=0.007). HE3235 significantly inhibits the growth of CRPC in both a s.c. tumor model as well as in the bone environment. HE3235 causes wide ranging effects in various cellular processes within tumor cells including a reduction in the synthesis of intratumoral androgens. Further investigations are ongoing to delineate the mechanisms behind this reduction as well as its effect on tumor growth inhibition. These data support the ongoing clinical investigations of HE3235 in the treatment of CRPC.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1713.

Footnotes

  • 100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

  • American Association for Cancer Research
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Cancer Research: 69 (9 Supplement)
May 2009
Volume 69, Issue 9 Supplement
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Abstract #1713: HE3235 inhibits growth of castration-resistant prostate cancer xenografts and reduces levels of intratumoral androgens in these tumors
Theodore Koreckij, R Montgomery, Holly Nguyen, Tiffany Pitts, Ilsa Coleman, Robert Vessella and Eva Corey
Cancer Res May 1 2009 (69) (9 Supplement) 1713;

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Abstract #1713: HE3235 inhibits growth of castration-resistant prostate cancer xenografts and reduces levels of intratumoral androgens in these tumors
Theodore Koreckij, R Montgomery, Holly Nguyen, Tiffany Pitts, Ilsa Coleman, Robert Vessella and Eva Corey
Cancer Res May 1 2009 (69) (9 Supplement) 1713;
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