Abstract
The overall survival of patients with metastatic Castration-resistant Prostate Cancer (CRPC) is discouraging low (Attar et al., Clin Cancer Res 15:3251–3255, 2009).
CRPC exhibit tremendous heterogeneity and complexity, reflecting the dysregulation of multiple patterns, mutations, and pathways, combined in a different manner in each patient. Of course, the impact of this heterogeneity on outcome and response to therapy is tremendous. It is therefore an urgent need to identify the multiple cellular pathways cooperatively promoting progression of the single cases of CRPC for successfully therapeutically target them. Several molecular pathways have been implicated in prostate cancer progression from localized androgen-sensitive disease to lethal CRPC.
In this article, we will review some of the recent findings on signal transduction studies performed to identify novel targets and alternative chances of therapeutic intervention for advanced prostate cancer.
Keywords
- Prostate Cancer
- Androgen Receptor
- Prostate Cancer Cell
- Prostate Cancer Cell Line
- Androgen Receptor Expression
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Ang JE, Olmos D, de Bono JS (2009) CYP17 blockade by abiraterone: further evidence for frequent continued hormone-dependence in castration-resistant prostate cancer. Br J Cancer 100:671–675
Antonarakis ES, Armstrong AJ (2011) Emerging therapeutic approaches in the management of metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis 14(3):206–18, Epub 2011 May 17. Review
Araujo J, Logothetis C (2009) Targeting Src signaling in metastatic bone disease. Int J Cancer 124:1–6
Araujo J, Mathew P, Armstrong AJ et al (2009) Dasatinib and docetaxel combination treatment for patients with metastatic castration-resistant prostate cancer: analysis of study CA180–086 [abstract 7028]. Eur J Cancer 7:415S
Attar RM, Takimoto CH, Gottardis MM (2009) Castration-resistant prostate cancer: locking up the molecular escape routes. Clin Cancer Res 15:3251–3255
Attard G, Reid AH, Yap TA, Raynaud F, Dowsett M et al (2008) Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol 26:4563–4571
Cairns P, Okami K, Halachmi S et al (1997) Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res 57:4997–5000
Catz SD, Johnson JL (2003) BCL-2 in prostate cancer: a minireview. Apoptosis 8:29–37
Cha E, Fong L (2011) Immunotherapy for prostate cancer: biology and therapeutic approaches. J Clin Oncol 29(27):3677–85
Chang YM, Kung HJ, Evans CP (2007) Nonreceptor tyrosine kinases in prostate cancer. Neoplasia 9:90–100
Chang YM, Bai L, Liu S et al (2008) Src family kinase oncogenic potential and pathways in prostate cancer as revealed by AZD0530. Oncogene 27:6365–6375
Chen CD, Welsbie DS, Tran C, Baek SH, Chen R et al (2004) Molecular determinants of resistance to antiandrogen therapy. Nat Med 10:33–39
Chien Y et al (2011) Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity. Genes Dev 25:2125–2136
Chin KV, Yang WL, Ravatn R, Kita T, Reitman E et al (2002) Reinventing the wheel of cyclic AMP: novel mechanisms of cAMP signaling. Ann N Y Acad Sci 968:49–64
Cho YS, Kim MK, Tan L, Srivastava R, Agrawal S et al (2002) Protein kinase A RIα antisense inhibition of PC3M prostate cancer cell growth: Bcl- 2 hyperphosphorylation, Bax up-regulation, and Bad-hypophosphorylation. Clin Cancer Res 8:607–614
Comstock CE, Knudsen KE (2007) The complex role of AR signaling after cytotoxic insult: implications for cell cycle based chemotherapeutics. Cell Cycle 6:1307–1313
Cunha GR (2008) Mesenchymal-epithelial interactions: past, present, and future. Differentiation 76:578–586
de Vries TJ, Mullender MG, van Duin MA et al (2009) The Src inhibitor AZD0530 reversibly inhibits the formation and activity of human osteoclasts. Mol Cancer Res 7:476–488
Edwards J, Bartlett JM (2005) The androgen receptor and signal-transduction pathways in hormone-refractory prostate cancer. Part 2: androgen-receptor cofactors and bypass pathways. BJU Int 95:1327–35
Evans CP, Bai L, Kung H et al (2011) Effect of the specific Src kinase inhibitor AZD0530 on osteolytic lesions in prostate cancer [abstract 170]. Presented at the 2008 American Society of Clinical Oncology Genitourinary Cancers symposium, San Francisco, 14–16 Feb 2008. Available at: http://www.asco.org/ASCOv2/Meetings/Abstracts. Accessed 8 Feb 2011
Fizazi K (2007) The role of Src in prostate cancer. Ann Oncol 18:1765–1773
Francis SH, Corbin JD (1999) Cyclic nucleotide-dependent protein kinases: intracellular receptors for cAMP and cGMP action. Crit Rev Clin Lab Sci 36:275–328
Gao J, Arnold JT, Isaacs JT (2001) Conversion from a paracrine to an autocrine mechanism of androgen-stimulated growth during malignant transformation of prostatic epithelial cells. Cancer Res 61:5038–5044
Gerritsen WR, Sharma P (2012) Current and emerging treatment options for castration-resistant prostate cancer: a focus on immunotherapy. J Clin Immunol 32(1):25–35
Grossmann ME, Huang H, Tindall DJ (2001) Androgen receptor signaling in androgen-refractory prostate cancer. J Natl Cancer Inst 93:1687–1697
Haag P, Bektic J, Bartsch G, Klocker H, Eder IE (2005) Androgen receptor down regulation by small interference RNA induces cell growth inhibition in androgen sensitive as well as in androgen independent prostate cancer cells. J Steroid Biochem Mol Biol 96:251–258
Holzbeierlein J, Lal P, LaTulippe E, Smith A, Satagopan J et al (2004) Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am J Pathol 164:217–227
Jiao J, Wang S, Qiao R et al (2007) Murine cell lines derived from Pten null prostate cancer show the critical role of PTEN in hormone refractory prostate cancer development. Cancer Res 67:6083–6091
Kantoff PW, Schuetz TJ, Blumenstein BA, Glode LM, Bilhartz DL, Wyand M, Manson K, Panicali DL, Laus R, Schlom J, Dahut WL, Arlen PM, Gulley JL, Godfrey WR (2010) Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol 28(7):1099–105
Kawata H, Ishikura N, Watanabe M, Nishimoto A, Tsunenari T et al (2010) Prolonged treatment with bicalutamide induces androgen receptor overexpression and androgen hypersensitivity. Prostate 70:745–754
Khor LY, Bae K, Al-Saleem T, Hammond EH, Grignon DJ et al (2008) Protein kinase A RI-α predicts for prostate cancer outcome: analysis of radiation therapy oncology group trial 86-10. Int J Radiat Oncol Biol Phys 71:1309–1315
Kumari R (2012) Lighting up cancer studies. Drug Discov Devel 15(1):18
Kung HJ, Evans CP (2009) Oncogenic activation of androgen receptor. Urol Oncol 27:48–52
Li L, Ittmann MM, Ayala G, Tsai MJ, Amato RJ et al (2005) The emerging role of the PI3-K-Akt pathway in prostate cancer progression. Prostate Cancer Prostatic Dis 8:108–118
Linja MJ, Savinainen KJ, Saramäki OR, Tammela TL, Vessella RL et al (2001) Amplification and overexpression of androgen receptor gene in hormonerefractory prostate cancer. Cancer Res 61:3550–3555
Locke JA, Guns ES, Lubik AA, Adomat HH, Hendy SC et al (2008) Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res 68:6407–6415
LoPiccolo J, Blumenthal GM, Bernstein WB et al (2008) Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Updat 11:32–50
Lubaroff DM (2012) Prostate cancer vaccines in clinical trials. Expert Rev Vaccines 11(7):857–868
Malinowska K, Neuwirt H, Cavarretta IT, Bektic J, Steiner H et al (2009) Interleukin-6 stimulation of growth of prostate cancer in vitro and in vivo through activation of the androgen receptor. Endocr Relat Cancer 16:155–169
Mayr B, Montminy M (2001) Transcriptional regulation by the phosphorylationdependent factor CREB. Nat Rev Mol Cell Biol 2:599–609
McMenamin ME, Soung P, Perera S et al (1999) Loss of PTEN expression in paraffin-embedded primary prostate cancer correlates with high Gleason score and advanced stage. Cancer Res 59:4291–4296
Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF et al (2008) Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res 68:4447–4454
Morgan TM, Koreckij TD, Corey E (2009) Targeted therapy for advanced prostate cancer: inhibition of the PI3K/Akt/mTOR pathway. Curr Cancer Drug Targets 9:237–249
Nam S, Kim D, Cheng JQ et al (2005) Action of the Src family kinase inhibitor, dasatinib (BMS-354825), on human prostate cancer cells. Cancer Res 65:9185–9189
Neary CL, Nesterova M, Cho YS, Cheadle C, Becker KG et al (2004) Protein kinase A isozyme switching: eliciting differential cAMP signaling and tumor reversion. Oncogene 23:8847–8856
Nelson EC, Cambio AJ, Yang JC, Ok JH, Lara PN et al (2007) Clinical implications of neuroendocrine differentiation in prostate cancer. Prostate Cancer Prostatic Dis 10:6–14
Sakamoto KM, Frank DA (2009) CREB in the pathophysiology of cancer: implications for targeting transcription factors for cancer therapy. Clin Cancer Res 15:2583–2587
Sands WA, Palmer TM (2008) Regulating gene transcription in response to cyclic AMP elevation. Cell Signal 20:460–466
Sarwar M, Persson JL (2011) The protein kinase A (PKA) intracellular pathway and androgen receptor: a novel mechanism underlying the castration-resistant and metastatic prostate cancer. J Cancer Sci Ther S5:003
Scher HI, Sawyers CL (2005) Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol 23:8253–8261
Schmitz M, Grignard G, Margue C et al (2007) Complete loss of PTEN expression as a possible early prognostic marker for prostate cancer metastasis. Int J Cancer 120:1284–1292
Shen MM, Abate-Shen C (2007) Pten inactivation and the emergence of androgenindependent prostate cancer. Cancer Res 67:6535–6538
Sircar K, Yoshimoto M, Monzon FA et al (2009) PTEN genomic deletion is associated with p-Akt and AR signalling in poorer outcome, hormone refractory prostate cancer. J Pathol 218:505–513
Sun S, Sprenger CC, Vessella RL, Haugk K, Soriano K et al (2010) Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J Clin Invest 120:2715–2730
Taplin ME, Rajeshkumar B, Halabi S, Werner CP, Woda BA, Picus J, Stadler W, Hayes DF, Kantoff PW, Vogelzang NJ, Small EJ, Cancer and Leukemia Group B Study 9663 (2003) Androgen receptor mutations in androgen-independent prostate cancer: Cancer and Leukemia Group B Study 9663. J Clin Oncol 21(14):2673–2678
Urbanucci A, Waltering KK, Suikki HE, Helenius MA, Visakorpi T (2008) Androgen regulation of the androgen receptor coregulators. BMC Cancer 8:219
Vander Griend DJ, D’Antonio J, Gurel B, Antony L, Demarzo AM et al (2010) Cell-autonomous intracellular androgen receptor signaling drives the growth of human prostate cancer initiating cells. Prostate 70:90–99
Vandyke K, Dewar AL, Farrugia AN et al (2009) Therapeutic concentrations of dasatinib inhibit in vitro osteoclastogenesis. Leukemia 23:994–997
Waltering KK, Helenius MA, Sahu B, Manni V, Linja MJ et al (2009) Increased expression of androgen receptor sensitizes prostate cancer cells to low levels of androgens. Cancer Res 69:8141–8149
Wang Q, Li W, Zhang Y, Yuan X, Xu K et al (2009) Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer. Cell 138:245–256
Wu D, Zhau HE, Huang WC, Iqbal S, Habib FK et al (2007) cAMP-responsive element-binding protein regulates vascular endothelial growth factor expression: implication in human prostate cancer bone metastasis. Oncogene 26:5070–5077
Xiao X, Li BX, Mitton B, Ikeda A, Sakamoto KM (2010) Targeting CREB for cancer therapy: friend or foe. Curr Cancer Drug Targets 10:384–391
Yang JC, Ok JH, Busby JE, Borowsky AD, Kung HJ, Evans CP (2009) Aberrant activation of androgen receptor in a new neuropeptide-autocrine model of androgen-insensitive prostate cancer. Cancer Res 69(1):151–60
Yoshimoto M, Cunha IW, Coudry RA et al (2007) FISH analysis of 107 prostate cancers shows that PTEN genomic deletion is associated with poor clinical outcome. Br J Cancer 97:678–685
Yu EY, Wilding G, Posadas E et al (2009) Phase II study of dasatinib in patients with metastatic castration-resistant prostate cancer. Clin Cancer Res 15:7421–7428
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media Dordrecht
About this chapter
Cite this chapter
Staibano, S. (2013). Efficacy of Signal Transduction Inhibition in Advanced Prostate Cancer. In: Staibano, S. (eds) Prostate Cancer: Shifting from Morphology to Biology. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7149-9_15
Download citation
DOI: https://doi.org/10.1007/978-94-007-7149-9_15
Published:
Publisher Name: Springer, Dordrecht
Print ISBN: 978-94-007-7148-2
Online ISBN: 978-94-007-7149-9
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)