Old Issues And New Perspectives On Prostate Cancer Hormonal Therapy: The Molecular Substratum

Secondary hormonal therapy is a treatment option in patients with castration-resistant prostate cancer (CRPC); however, it is underutilized and is room for optimization and improvement. In this context, androgen receptor (AR) is the Achilles' heel, being critically important and various mechanisms ranging from receptor mutations to secondary signaling pathways are responsible for some of the biological heterogeneity, demanding a multimodal approach. A comprehensive review of the peerreviewed literature is performed on the topic of molecular mechanisms supporting secondary hormonal therapies, including expanded alternative hormonal therapies for CRPC. Essential concepts in clinical treatment of patients with progression on primary hormonal therapy are maintaining the castrate state, accounting for the intermittency phenomenon and sequentially using oral antiandrogens and adrenolytics heading to androgen depletion microenvironment. Survival prolongation, pain relief or measurable improvement in tumor-related symptoms should be persecuted and are considered to be a tangible benefit of obvious worth to the patient. Understanding the underlying molecular substratum is of paramount importance to hormonal therapy optimization in this context once current androgen-depletion strategies are incomplete, and residual androgens as well as alternative routes contribute to sustained AR activity and disease progression to a lethal phenotype. One or many mechanisms may be playing a role, even within the same patient and lastly are potential targets for treatment. Five fundamental mechanisms mediated through the AR to promote tumor growth (three of which depend on ligand signaling) added to the stem cell pathway must be recognized in CRPC. They are persistence of intratumoral androgens as a result of in situ steroidogenesis or adrenal source; AR mutations that allow promiscuous activation by otherwise nonsignaling ligands; wild-type AR gene amplification; alterations in AR coactivator-to- corepressor ratio that impact transcription; outlaw AR pathways that bypass the need for androgens by signaling through crosstalk with other ligand-bound receptors, cytokines, or transactivation of activated tyrosine kinase receptors in the cytosol. © Springer Science+Business Media, LLC 2011.29319481955Huggins, C., Hodges, C.V., Studies of prostate cancer I. The effect of castration, of oestrogen and of androgen injection on serum phosphatases in metastatic carcinoma f the prostate (1941) Cancer Res, 1, pp. 293-301Scher, H.I., Steineck, G., Kelly, W.K., Hormone-refractory (D3) prostate cancer: Refining the concept (1995) Urology, 46, pp. 142-8Petrylak, D.P., Tangen, C.M., Mha, H., Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer (2004) N Engl J Med, 351, pp. 1513-20Tannock, I.F., De Wit, R., Berry, W.R., Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer (2004) N Engl J Med, 351, pp. 1502-12Fleming, M.T., Morris, M.J., Heller, G., Post-therapy changes in PSA as an outcome measure in prostate cancer clinical trials (2006) Nat Clin Pract Oncol, 3, pp. 658-67Scher, H.I., Halabi, S., Tannock, I., Morris, M., Sternberg, C.N., Carducci, M.A., Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: Recommendations of the Prostate Cancer Clinical Trials Working Group (2008) J Clin Oncol, 26, pp. 1148-59Reis, L.O., Sasse, A.D., Matheus, W.E., Denardi, F., Stopiglia, R.M., Da Silva, M.M., Ferreira, U., Prostate cancer: Evidence based clinical practice (2009) Actas Urol Esp, 33, pp. 344-50Claessens, F., Denayer, S., Van Tilborgh, N., Kerkhofs, S., Helsen, C., Haelens, A., Diverse roles of androgen receptor (AR) domains in AR-mediated signaling (2008) Nucl Recept Signal, 6, pp. e008Denmeade, S.R., Lin, X.S., Isaacs, J.T., Role of programmed (apoptotic) cell death during the progression and therapy for prostate cancer (1996) Prostate, 28, pp. 251-65Chmelar, R., Buchanan, G., Need, E.F., Androgen receptor coregulators and their involvement in the development and progression of prostate cancer (2007) Int J Cancer, 120, pp. 719-33Hsieh, A.C., Small, E.J., Ryan, C.J., Androgen-response elements in hormone refractory prostate cancer: Implications for treatment development (2007) Lancet Oncol, 8, pp. 933-9Hellerstedt, B., Hormonal therapy options for patients with a rising prostate specific antigen level after primary treatment for prostate cancer (2003) Urology, 62, pp. 79-86Culig, Z., Stober, J., Gast, A., Activation of two mutant androgen receptors from human prostatic carcinoma by adrenal androgens and metabolic derivatives of testosterone (1996) Cancer Detect Prev, 20, pp. 68-75Tan, J., Sharief, Y., Hamil, K.G., Dehydroepiandrosterone activates mutant androgen receptors expressed in the androgendependent human prostate cancer xenograft CWR22 and LNCaP cells (1997) Mol Endocrinol, 11, pp. 450-9Serrate, C., Loriot, Y., De La-Motte-Rouge, T., Diethylstilbestrol (DES) retains activity, is a reasonable option in patients previously treated with docetaxel for castration-resistant prostate cancer (2009) Ann Oncol, 20, p. 965Cleffi, S., Neto, A.S., Reis, L.O., Maia, P., Fonseca, F., Wroclawski, M.L., Neves, M., Tobias-Machado, M., Androgen deprivation therapy and morbid obesity: Do they share cardiovascular risk through metabolic syndrome? (2011) Actas Urol Esp, 35 (5), pp. 259-65Mellado, B., Codony, J., Ribal, M.J., Visa, L., Gascon, P., Molecular biology of androgen-independent prostate cancer: The role of the androgen receptor pathway (2009) Clin Trans Oncol, 11, pp. 5-10Freeman, M.R., Cinar, B., Lu, M.L., Membrane rafts as potential sites of nongenomic hormonal signaling in prostate cancer (2005) Trends Endocrinol Metab, 16, pp. 273-9Scher, H.I., Sawyers, C.L., Biology of progressive, castration-resistant prostate cancer: Directed therapies targeting the androgenreceptor signaling axis (2005) J Clin Oncol, 23, pp. 8253-61Eder, I.E., Culig, Z., Putz, T., Nessler-Menardi, C., Bartsch, G., Klocker, H., Molecular biology of the androgen receptor: From molecular understanding to the clinic (2001) Eur Urol, 40, pp. 241-51Feldman, B.J., Feldman, D., The development of androgen-independent prostate cancer (2001) Nat Rev Cancer, 1, pp. 34-45Buchanan, G., Yang, M., Cheong, A., Harris, J.M., Irvine, R.A., Lambert, P.F., Structural and functional consequences of glutamine tract variation in the androgen receptor (2004) Hum Mol Genet, 13, pp. 1677-92Veldscholte, J., Risstalpers, C., Kuiper, G., Jenster, G., Berrevoets, C., Claassen, E., A mutation in the ligand-binding domain of the androgen receptor of human Lncap cells affects steroid binding characteristics and response to anti-androgens (1990) Biochem Biophys Res Commu, 173, pp. 534-40Taplin, M.E., Bubley, G.J., Shuster, T.D., Mutations of the androgen-receptor gene in metastatic androgen independent prostate cancer (1995) N Engl J Med, 332, pp. 1393-8Dehm, S.M., Schmidt, L.J., Heemers, H.V., Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance (2008) Cancer Res, 68, pp. 5469-77Chen, C.D., Welsbie, D.S., Tran, C., Baek, S.H., Chen, R., Vessella, R., Molecular determinants of resistance to antiandrogen therapy (2004) Nat Med, 10, pp. 33-9Dehm, S.M., Tindall, D.J., Androgen receptor structural and functional elements: Role and regulation in prostate cancer (2007) Mol Endocrinol, 21, pp. 2855-63Holzbeierlein, J., Lal, P., Latulippe, E., Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance (2004) Am J Pathol, 164, pp. 217-27Cohen, B.L., Gomez, P., Omori, Y., Duncan, R.C., Civantos, F., Soloway, M.S., Lokeshwar, V.B., Lokeshwar, B.L., Cyclooxygenase-2 (cox-2) expression is an independent predictor of prostate cancer recurrence (2006) Int J Cancer, 119, pp. 1082-7Quinn, D.I., Henshall, S.M., Sutherland, R.L., Molecular markers of prostate cancer outcome (2005) Eur J Cancer, 41, pp. 858-87Need, E.F., Scher, H.I., Peters, A.A., Moore, N.L., Cheong, A., Ryan, C.J., A Novel androgen receptor amino terminal region reveals two classes of amino/carboxyl interaction-deficient variants with divergent capacity to activate responsive sites in chromatin (2009) Endocrinology, 150, pp. 2674-82Chen, C.D., Welsbie, D.S., Tran, C., Baek, S.H., Chen, R., Vessella, R., Rosenfeld, M.G., Sawyers, C.L., Molecular determinants of resistance to anti-androgen therapy (2004) Nature Med, 10, pp. 33-9Baron, S., Manin, M., Beaudoin, C., Leotoing, L., Communal, Y., Veyssiere, G., Androgen receptor mediates non-genomic activation of phosphatidylinositol 3-oh kinase in androgen-sensitive epithelial cells (2004) J Biol Chem, 279, pp. 14579-86Migliaccio, A., Castoria, G., Di Domenico, M., De Falco, A., Bilancio, A., Lombardi, M., Steroid-induced androgen receptor-oestradiol receptor beta-src complex triggers prostate cancer cell proliferation (2000) EMBO J, 19, pp. 5406-17Peterziel, H., Mink, S., Schonert, A., Becker, M., Klocker, H., Cato, A.C.B., Rapid signalling by androgen receptor in prostate cancer cells (1999) Oncogene, 18, pp. 6322-9Malinowska, K., Neuwirt, H., Cavarretta, I.T., Bektic, J., Steiner, H., Dietrich, H., Interleukin-6 stimulation of growth of prostate cancer in vitro and in vivo through activation of the androgen receptor (2009) Endocr Relat Cancer, 16, pp. 155-69Robinson, D.R., Zylstra, C.R., Williams, B.O., Wnt signaling and prostate cancer (2008) Curr Drug Targets, 9, pp. 571-80Seaton, A., Scullin, P., Maxwell, P.J., Wilson, C., Pettigrew, J., Gallagher, R., Interleukin-8 signaling promotes androgen-independent proliferation of prostate cancer cells via induction of androgen receptor expression and activation (2008) Carcinogenesis, 29, pp. 1148-56Dagvadorj, A., Collins, S., Jomain, J.B., Abdulghani, J., Karras, J., Zellweger, T., Li, H., Nevalainen, M.T., Autocrine prolactin promotes prostate cancer cell growth via Janus kinase-2-signal transducer and activator of transcription-5a/b signaling pathway (2007) Endocrinology, 148, pp. 3089-101Montgomery, R.B., Mostaghel, E.A., Vessella, R., Hess, D.L., Kalhorn, T.F., Higano, C.S., True, L.D., Nelson, P.S., Maintenance of intratumoral androgens in metastatic prostate cancer: A mechanism for castration-resistant tumor growth (2008) Cancer Res, 68, pp. 4447-54Geller, J., Albert, J., Nachtsheim, D., Loza, D., Lippman, S., Steroid levels in cancer of the prostate-markers of tumor differentiation and adequacy of antiandrogen therapy (1979) Prog Clin Biol Res, 33, pp. 103-11Geller, J., De La Vega, D.J., Albert, J.D., Nachtsheim, D.A., Tissue dihydrotestosterone levels and clinical response to hormonal therapy in patients with advanced prostate cancer (1984) J Clin Endocrinol Metab, 58, pp. 36-40Mohler, J.L., Gregory, C.W., Ford III, O.H., Kim, D., Weaver, C.M., Petrusz, P., Wilson, E.M., French, F.S., The androgen axis in recurrent prostate cancer (2004) Clin Cancer Res, 10, pp. 440-8Mostaghel, E.A., Page, S.T., Lin, D.W., Fazli, L., Coleman, I.M., True, L.D., Knudsen, B., Matsumoto, A.M., Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: Therapeutic implications for castration-resistant prostate cancer (2007) Cancer Res, 67, pp. 5033-41Nishiyama, T., Hashimoto, Y., Takahashi, K., The influence of androgen deprivation therapy on dihydrotestosterone levels in the prostatic tissue of patients with prostate cancer (2004) Clin Cancer Res, 10, pp. 7121-6Labrie, F., Belanger, A., Dupont, A., Luu-The, V., Simard, J., Labrie, C., Science behind total androgen blockade: From gene to combination therapy (1993) Clin Invest Med, 16, pp. 475-92Palapattu, G.S., Wu, C., Silvers, C.R., Martin, H.B., Williams, K., Salamone, L., Bushnell, T., Huang, J., Selective expression of CD44, a putative prostate cancer stem cell marker, in neuroendocrine tumor cells of human prostate cancer (2009) Prostate, 69, pp. 787-98Reis, L.O., Vieira, L.F., Zani, E.L., Denardi, F., De Oliveira, L.C., Ferreira, U., Assessment of serum chromogranin-A as prognostic factor in high-risk prostate cancer (2010) J Investig Med, 58, pp. 957-60Gugliotta, A., Ferreira, U., Reis, L.O., Matheus, W.E., Denardi, F., Mamprim Stopiglia, R., Piccolotto-Naccarato, A.M., Satisfaction analysis in men presenting with localized prostate cancer treated with radical prostatectomy or radiotherapy: Psychological and social aspects (2008) Actas Urol Esp, 32, pp. 411-6Andriole, G.L., Humphrey, P., Ray, P., Effect of the dual 5alpha-reductase inhibitor dutasteride on markers of tumor regression in prostate cancer (2004) J Urol, 172, pp. 915-9Reis, L.O., Pereira, T.C., Lopes-Cendes, I., Ferreira, U., MicroRNAs: A new paradigm on molecular urological oncology (2010) Urology, 76, pp. 521-