Maintenance of Intratumoral Androgens in Metastatic Prostate Cancer: A Mechanism for Castration-Resistant Tumor Growth
R. Bruce Montgomery,Elahe A. Mostaghel,Robert L. Vessella,David L. Hess,Thomas F. Kalhorn,Celestia S. Higano,Lawrence D. True,Peter S. Nelson,Peter S. Nelson +8 more
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TLDR
Maximal therapeutic efficacy in the treatment of castration-resistant prostate cancer will require novel agents capable of inhibiting intracrine steroidogenic pathways within the prostate tumor microenvironment.Abstract:
Therapy for advanced prostate cancer centers on suppressing systemic androgens and blocking activation of the androgen receptor (AR). Despite anorchid serum androgen levels, nearly all patients develop castration-resistant disease. We hypothesized that ongoing steroidogenesis within prostate tumors and the maintenance of intratumoral androgens may contribute to castration-resistant growth. Using mass spectrometry and quantitative reverse transcription-PCR, we evaluated androgen levels and transcripts encoding steroidogenic enzymes in benign prostate tissue, untreated primary prostate cancer, metastases from patients with castration-resistant prostate cancer, and xenografts derived from castration-resistant metastases. Testosterone levels within metastases from anorchid men [0.74 ng/g; 95% confidence interval (95% CI), 0.59-0.89] were significantly higher than levels within primary prostate cancers from untreated eugonadal men (0.23 ng/g; 95% CI, 0.03-0.44; P < 0.0001). Compared with primary prostate tumors, castration-resistant metastases displayed alterations in genes encoding steroidogenic enzymes, including up-regulated expression of FASN, CYP17A1, HSD3B1, HSD17B3, CYP19A1, and UGT2B17 and down-regulated expression of SRD5A2 (P < 0.001 for all). Prostate cancer xenografts derived from castration-resistant tumors maintained similar intratumoral androgen levels when passaged in castrate compared with eugonadal animals. Metastatic prostate cancers from anorchid men express transcripts encoding androgen-synthesizing enzymes and maintain intratumoral androgens at concentrations capable of activating AR target genes and maintaining tumor cell survival. We conclude that intracrine steroidogenesis may permit tumors to circumvent low levels of circulating androgens. Maximal therapeutic efficacy in the treatment of castration-resistant prostate cancer will require novel agents capable of inhibiting intracrine steroidogenic pathways within the prostate tumor microenvironment.read more
Citations
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Journal ArticleDOI
Abiraterone and Increased Survival in Metastatic Prostate Cancer
Johann S. de Bono,Christopher J. Logothetis,Arturo Molina,Karim Fizazi,Scott North,Luis Chu,Kim N. Chi,Robert Jones,Oscar B. Goodman,Fred Saad,John Staffurth,Paul N. Mainwaring,S. J. Harland,Thomas W. Flaig,Thomas E. Hutson,Tina Cheng,Helen Patterson,John D. Hainsworth,Charles J. Ryan,Cora N. Sternberg,Susan Ellard,Aude Flechon,Mansoor N. Saleh,Mark C. Scholz,Eleni Efstathiou,Andrea Zivi,Diletta Bianchini,Yohann Loriot,Nicole Chieffo,Thian Kheoh,Christopher M. Haqq,Howard I. Scher +31 more
TL;DR: The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy.
Journal ArticleDOI
Enzalutamide in Metastatic Prostate Cancer before Chemotherapy
Tomasz M. Beer,Andrew J. Armstrong,Dana E. Rathkopf,Yohann Loriot,Cora N. Sternberg,Celestia S. Higano,Peter Iversen,Suman Bhattacharya,Joan Carles,Simon Chowdhury,Ian D. Davis,Johann S. de Bono,Christopher P. Evans,Karim Fizazi,Anthony M. Joshua,Choung-Soo Kim,Go Kimura,Paul N. Mainwaring,Harry H. Mansbach,Kurt Miller,Sarah B. Noonberg,Frank Perabo,De Phung,Fred Saad,Howard I. Scher,Mary-Ellen Taplin,Peter Venner,Bertrand Tombal +27 more
TL;DR: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer.
Journal ArticleDOI
Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy
Charles J. Ryan,Matthew R. Smith,Johann S. de Bono,Arturo Molina,Christopher J. Logothetis,Paul de Souza,Karim Fizazi,Paul N. Mainwaring,Josep M. Piulats,Siobhan Ng,Joan Carles,Peter F.A. Mulders,Ethan Basch,Eric J. Small,Fred Saad,D. Schrijvers,Hendrik Van Poppel,Som D. Mukherjee,Henrik Suttmann,Winald R. Gerritsen,Thomas W. Flaig,Daniel J. George,Evan Y. Yu,Eleni Efstathiou,Allan J. Pantuck,Eric Winquist,Celestia S. Higano,Mary-Ellen Taplin,Youn C. Park,Thian Kheoh,Thomas W. Griffin,Howard I. Scher,Dana E. Rathkopf +32 more
TL;DR: Abiraterone improved radiographic progression-free survival, showed a trend toward improved overall survival, and significantly delayed clinical decline and initiation of chemotherapy in patients with metastatic castration-resistant prostate cancer.
Commentary on: Abiraterone in Metastatic Prostate Cancer Without Previous Chemotherapy
TL;DR: Abiraterone inhibits CYP-17, a crucial enzyme in androgen biosynthesis in the testes, adrenal glands, and in prostate cancer cells as discussed by the authors, and showed a strong trend toward improved survival.
Journal ArticleDOI
Ligand-Independent Androgen Receptor Variants Derived from Splicing of Cryptic Exons Signify Hormone-Refractory Prostate Cancer
Rong Hu,Thomas A. Dunn,Shuanzeng Wei,Sumit Isharwal,Robert W. Veltri,Elizabeth B. Humphreys,Misop Han,Alan W. Partin,Robert L. Vessella,William B. Isaacs,G. Steven Bova,Jun Luo +11 more
TL;DR: Novel forms of AR alteration that are prevalent in HRPC are reported, suggesting a novel mechanism for the development of HRPC that warrants further investigation and may be explored as potential biomarkers and therapeutic targets for advanced PCa.
References
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Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate
TL;DR: Gutman et al. as mentioned in this paper showed that the acid phosphatase of serum is reduced in metastatic carcinoma of the prostate by decreasing the activity of androgens through castration or estrogenic injections and that this enzyme is increased by injecting androgens.
Journal ArticleDOI
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Brian J. Feldman,David Feldman +1 more
TL;DR: It is predicted that understanding the pathways that lead to the development of androgen-independent prostate cancer will pave the way to effective therapies for these, at present, untreatable cancers.
Journal ArticleDOI
Molecular determinants of resistance to antiandrogen therapy
Charlie D. Chen,Derek S. Welsbie,Chris Tran,Sung Hee Baek,Randy Chen,Robert L. Vessella,Michael G. Rosenfeld,Charles L. Sawyers +7 more
TL;DR: Using microarray-based profiling of isogenic prostate cancer xenograft models, it is found that a modest increase in androgen receptor mRNA was the only change consistently associated with the development of resistance to antiandrogen therapy.
Journal ArticleDOI
In vivo amplification of the androgen receptor gene and progression of human prostate cancer.
Tapio Visakorpi,E. Hyytinen,Pasi A. Koivisto,Minna Tanner,Riitta Keinänen,C. Palmberg,Aarno Palotie,Teuvo L.J. Tammela,Jorma Isola,Olli-P. Kallioniemi +9 more
TL;DR: This work has identified a similar molecular mechanism in vivo for endocrine treatment failure in human prostate cancer which involves amplification of the androgen receptor (AR) gene.
Journal ArticleDOI
Increased Expression of Genes Converting Adrenal Androgens to Testosterone in Androgen-Independent Prostate Cancer
Michael Stanbrough,Glenn J. Bubley,Kenneth N. Ross,Todd R. Golub,Mark A. Rubin,Trevor M. Penning,Phillip G. Febbo,Steven P. Balk +7 more
TL;DR: Enhanced intracellular conversion of adrenal androgens to testosterone and dihydrotestosterone is a mechanism by which prostate cancer cells adapt to androgen deprivation and suggest new therapeutic targets.
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