Elsevier

European Urology

Volume 61, Issue 5, May 2012, Pages 950-960
European Urology

Review – Prostate Cancer
Novel Molecular Targets for the Therapy of Castration-Resistant Prostate Cancer

https://doi.org/10.1016/j.eururo.2011.12.028Get rights and content

Abstract

Context

Improved understanding of mechanisms underlying metastatic castration-resistant prostate cancer (mCRPC) progression has led to the recognition of multiple molecular targets and advances in the therapeutic landscape. The addition of abiraterone acetate, sipuleucel-T, cabazitaxel, and denosumab to the therapeutic armamentarium and the impending addition of MDV-3100 and radium-223 underscore the importance of androgen pathway inhibition, immunotherapy, tubulin antagonism, and pathophysiology of bone metastasis.

Objective

Review the next generation of molecular targets in mCRPC.

Evidence acquisition

Medline databases were searched for >100 original articles published as of October 18, 2011, with the search terms metastatic castration-resistant prostate cancer, targeted therapy, biologic agents, and immunotherapy. Proceedings from the last 5 yr of conferences of the American Society of Clinical Oncology, American Urological Association, European Society of Medical Oncology, and the European Association of Urology were also searched. We included novel and promising drugs that have reached clinical trial evaluation.

Evidence synthesis

The major findings were addressed in an evidence-based fashion. Prospective trials and important preclinical data were analyzed.

Conclusions

mCRPC is a disease with multiple molecular drivers. Molecular pathways being targeted in ongoing phase 3 trials are androgen signaling (MDV3100, TAK700), immunoregulatory pathways (ipilimumab, Prostvac-VF-TRICOM), Src (dasatinib), Met (cabozantinib), clusterin (custirsen), and angiogenesis (aflibercept, tasquinimod). The strides made in identifying multiple other novel molecular targets offer potential opportunities for further improving outcomes.

Introduction

Over the past year, multiple new systemic therapy agents have become available to treat men with metastatic castration-resistant prostate cancer (mCRPC) that provide modest but much needed benefits (Table 1). Docetaxel and cabazitaxel chemotherapy provide modest 2.5- to 3-mo extensions of median survival as first- and second-line chemotherapy, respectively [1], [2]. The realization of the importance of androgen-mediated signaling led to the eventual approval of abiraterone acetate, the CYP17 and potent androgen synthesis inhibitor, in the second-line post-docetaxel setting [3]. Despite these advances, the median survival in the first-line setting of mCRPC is approximately 20 mo and in the post-docetaxel setting is about 15 mo. Immunotherapy with the autologous antigen-presenting cell (APC)-based product expressing prostatic acid phosphatase-granulocyte macrophage-colony stimulating factor (PAP-GM-CSF), sipuleucel-T, extended median survival by approximately 4.5 mo in relatively asymptomatic and mostly chemotherapy-naive patients [4]. Finally, denosumab, a monoclonal antibody that targets receptor activator of nuclear factor κB ligand (RANKL), provided a modest incremental benefit, about 18%, over zoledronic acid in preventing skeletal-related events (SREs) in men with bone metastases [5].

Given the incremental benefits conferred by these recently approved agents, novel and tolerable agents are necessary to make further gains. Multiple ongoing trials are combining novel agents with first-line docetaxel-based chemotherapy (Table 2, Table 3). We review some of the most promising and emerging molecular targets in mCRPC and the efforts to develop agents against these targets.

Section snippets

Evidence acquisition

A review of the literature searching Medline and major cancer conferences for prospective trials and major preclinical and retrospective studies from the last 5 yr was performed in October 2011. The search strategy included the terms metastatic castration-resistant prostate cancer, targeted therapy, biologic agents, and immunotherapy.

Biology of castration-resistant prostate cancer

Prostate cancer appears to be androgen-pathway dependent through multiple lines of therapy to varying extents, as suggested by the activity of secondary hormonal manipulations and the activity of abiraterone acetate following docetaxel. Although immunotherapy, tubulin inhibition, and osteoclast inhibition by targeting the RANKL have also yielded broad benefits, all of the hallmarks of cancer may be invoked to drive growth (Fig. 1) [6]. These include sustaining proliferative signaling, evading

Conclusions

Although multiple new drugs have recently been approved for the treatment of mCRPC, improvement in overall survival remains modest at best, with all patients eventually experiencing disease progression and early mortality. In addition to immunotherapy and androgen pathway signaling, multiple other molecular targets promise to provide the next generation of advances. In recent years, the simultaneous development of novel and more potent classes of drugs targeting these pathways has emerged. A

References (71)

  • C.N. Sternberg et al.

    Docetaxel plus oblimersen sodium (Bcl-2 antisense oligonucleotide): an EORTC multicenter, randomized phase II study in patients with castration-resistant prostate cancer

    Ann Oncol

    (2009)
  • S.K. Hong et al.

    The Raf/MEK/extracellular signal-regulated kinase 1/2 pathway can mediate growth inhibitory and differentiation signaling via androgen receptor downregulation in prostate cancer cells

    Exp Cell Res

    (2011)
  • J.C. Brenner et al.

    Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer

    Cancer Cell

    (2011)
  • M.T. Fleming et al.

    Association of rash with outcomes in a randomized Phase II trial evaluating cetuximab in combination with mitoxantrone plus prednisone following docetaxel for metastatic castration-resistant prostate cancer

    Clin Genitourin Cancer

    (2012)
  • I.F. Tannock et al.

    Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer

    N Engl J Med

    (2004)
  • J.S. de Bono et al.

    Abiraterone and increased survival in metastatic prostate cancer

    N Engl J Med

    (2011)
  • P.W. Kantoff et al.

    Sipuleucel-T immunotherapy for castration-resistant prostate cancer

    N Engl J Med

    (2010)
  • K.G. Hermans et al.

    TMPRSS2:ERG fusion by translocation or interstitial deletion is highly relevant in androgen-dependent prostate cancer, but is bypassed in late-stage androgen receptor-negative prostate cancer

    Cancer Res

    (2006)
  • R. Ummanni et al.

    Identification of clinically relevant protein targets in prostate cancer with 2D-DIGE coupled mass spectrometry and systems biology network platform

    PLoS One

    (2011)
  • E.A. Mostaghel et al.

    Resistance to CYP17A1 inhibition with abiraterone in castration-resistant prostate cancer: induction of steroidogenesis and androgen receptor splice variants

    Clin Cancer Res

    (2011)
  • Medivation and Astellas announce positive survival data from interim analysis of phase 3 AFFIRM trial of MDV3100 in men...
  • P. Mendiratta et al.

    Genomic strategy for targeting therapy in castration-resistant prostate cancer

    J Clin Oncol

    (2009)
  • L. Chen et al.

    Chemical ablation of androgen receptor in prostate cancer cells by the histone deacetylase inhibitor LAQ824

    Mol Cancer Ther

    (2005)
  • D. Bradley et al.

    Vorinostat in advanced prostate cancer patients progressing on prior chemotherapy (National Cancer Institute Trial 6862): trial results and interleukin-6 analysis: a study by the Department of Defense Prostate Cancer Clinical Trial Consortium and University of Chicago Phase 2 Consortium

    Cancer

    (2009)
  • A. Hoos et al.

    Improved endpoints for cancer immunotherapy trials

    J Natl Cancer Inst

    (2010)
  • D.B. Solit et al.

    17-Allylamino-17-demethoxygeldanamycin induces the degradation of androgen receptor and HER-2/neu and inhibits the growth of prostate cancer xenografts

    Clin Cancer Res

    (2002)
  • G. Sonpavde et al.

    Results of a phase I/II clinical trial of BPX-101, a novel drug-activated dendritic cell (DC) vaccine for metastatic castration-resistant prostate cancer (mCRPC) [abstract 132]

    J Clin Oncol

    (2011)
  • J.R. Brahmer et al.

    Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates

    J Clin Oncol

    (2010)
  • A.I. Chin et al.

    Toll-like receptor 3-mediated suppression of TRAMP prostate cancer shows the critical role of type I interferons in tumor immune surveillance

    Cancer Res

    (2010)
  • J.A. Tuxhorn et al.

    Inhibition of transforming growth factor-beta activity decreases angiogenesis in a human prostate cancer-reactive stroma xenograft model

    Cancer Res

    (2002)
  • S.T. Tagawa et al.

    Anti-prostate-specific membrane antigen-based radioimmunotherapy for prostate cancer

    Cancer

    (2010)
  • W.K. Kelly et al.

    A randomized, double-blind, placebo-controlled phase III trial comparing docetaxel, prednisone, and placebo with docetaxel, prednisone, and bevacizumab in men with metastatic castration-resistant prostate cancer (mCRPC): Survival results of CALGB 90401 [abstract LBA4511]

    J Clin Oncol

    (2010)
  • M.D. Michaelson et al.

    Randomized, placebo-controlled, phase III trial of sunitinib in combination with prednisone (SU + P) versus prednisone (P) alone in men with progressive metastatic castration-resistant prostate cancer (mCRPC) [abstract 4515]

    J Clin Oncol

    (2011)
  • T.S. Udayakumar et al.

    Pharmacological inhibition of FGF receptor signaling inhibits LNCaP prostate tumor growth, promatrilysin, and PSA expression

    Mol Carcinog

    (2003)
  • R. Pili et al.

    Phase II randomized, double-blind, placebo-controlled study of tasquinimod in men with minimally symptomatic metastatic castrate-resistant prostate cancer

    J Clin Oncol

    (2011)
  • Cited by (59)

    • Engineered microbes for cancer immunotherapy

      2022, Engineering Technologies and Clinical Translation: Volume 3 of Delivery Strategies and Engineering Technologies in Cancer Immunotherapy
    • Nonneoplastic Diseases of the Prostate

      2020, Urologic Surgical Pathology
    • The Emergence of Precision Urologic Oncology: A Collaborative Review on Biomarker-driven Therapeutics

      2017, European Urology
      Citation Excerpt :

      These include further reductions of androgen production by targeting synthetic enzymes such as CYP17, the target of abiraterone acetate (Zytiga), and improved inhibition of the androgen receptor itself (enzalutamide/Xtandi, ARN-509/apalutamide) and downstream effects on transcription, proliferation, and survival of prostate cancer cells. These approaches have been reviewed elsewhere [8,9]. A critical question for these next-generation antiandrogen agents going forward is determining the patients that will most benefit from their use.

    View all citing articles on Scopus

    Please visit www.eu-acme.org/europeanurology to read and answer questions on-line. The EU-ACME credits will then be attributed automatically.

    View full text