Platinum Priority – Collaborative Review – Prostate CancerEditorial by Joaquim Bellmunt, Jonathan E. Rosenberg and Toni K. Choueiri on pp. 606–608 of this issueCastration-resistant Prostate Cancer: From New Pathophysiology to New Treatment Targets
Introduction
Prostate cancer (PCa) remains a significant medical burden in developed countries and a major cause of morbidity and mortality. In men, it is the most commonly diagnosed noncutaneous cancer and the second to third most common cause of cancer death in the western world [1]. Many patients with localised disease have an excellent long-term survival and high cure rates with standard approaches [2]. However, patients with high-risk, locally advanced, and metastatic disease have a poor prognosis; and although hormone therapy (HT) in the form of medical or surgical castration can induce significant long-term remissions, development of castration-resistant disease is inevitable. Castration-resistant prostate cancer (CRPC) has been used synonymously with androgen-independent PCa and hormone-refractory PCa but is the preferred term, as we now know that many men with CRPC respond to additional manipulations that ablate or block PCa growth stimulation by androgens. CRPC is clinically detected by a rise in prostate-specific antigen (PSA), typically defined as three consecutive rises over nadir in the context of castrate levels of serum testosterone and after antiandrogen withdrawal for at least 4 wk and despite secondary hormonal manipulations and/or radiologic progression [3], [4].
Systemic therapy for metastatic CRPC is remarkable for the relatively few options that have been developed. After failure of HT, treatments have been approved primarily for symptomatic benefit, such as mitoxantrone chemotherapy [5], radioactive isotopes [6], and the bisphosphonate zoledronic acid [7]. Despite multiple trials of cytotoxic chemotherapy in patients with metastatic CRPC, only docetaxel has been shown to improve overall survival (OS) [8], [9], with a median improvement in OS of 2.4 mo over mitoxantrone. In addition, an improvement in patient-reported pain and quality of life scores were also superior in docetaxel-treated patients and has now become a standard of care. Gains in this late-stage patient population may translate to greater benefits when applied to earlier states of PCa in the future to prevent or delay metastases and increase cure rates and OS. Indeed, a recent update of a study randomising patients with castration-sensitive disease to receive either the oral bisphosphonate clodronate or placebo has suggested that the secondary endpoint of OS was improved in those patients who received clodronate [10]. To this end, trials are ongoing with zoledronic acid in patients with metastatic castration-sensitive and high-risk localised disease (Table 1). Trials evaluating docetaxel given in an adjuvant or neoadjuvant fashion to patients with high-risk, clinically localised disease undergoing surgery or radiation therapy (RT) are also underway. Additionally, randomised studies testing the benefit of docetaxel in patients with PSA-recurrent or castration-naïve metastatic disease are ongoing (Table 1).
Over the past decade, there has been a significant increase in understanding of the biologic basis for PCa progression, fuelled in part from the development of high-throughput genomic, transcriptomic, and proteomic technologies. The mechanisms of androgen independence can be divided into those that are mediated by the androgen receptor (AR)—for example, through a hypersensitive, promiscuous, or amplified AR—and others that bypass it [11], [12]. Mechanisms common to all cancers underlying malignant proliferation, angiogenesis, metastases, and avoidance of immune surveillance are also implicated in PCa progression. From these advances, a large number of potential therapeutic targets have been identified. This article reviews the current concepts behind targeted therapy for CRPC with a focus on novel agents that are currently in late-stage clinical testing for patients with advanced PCa.
Section snippets
Androgen receptor signalling
It has long been recognized that after failure of castration therapy, second-line HTs can often be associated with clinical responses, initially presumed on the basis of extragonadal production of androgens [13]. An additional factor underlying such responses may also reside within PCa tissue itself. Several studies have demonstrated amplification and increased expression of AR in xenografts with hormone resistance and in PCa tissues from patients with CRPC [14], [15], [16]. In vitro and in
Vascular endothelial growth factor and receptor
In order for growth beyond a few millimetres and to be able to metastasize, malignant tumours must be able to recruit new vasculature in a process referred to as angiogenesis. Several mediators of angiogenesis have been identified, including vascular endothelial growth factor (VEGF), which signals through VEGF receptors (VEGFR) 1 and 2 to promote angiogenesis. Elevated VEGFR—notably VEGFR-2—has been associated with progression of PCa in the transgenic adenocarcinoma of mouse prostate (TRAMP)
Immunotherapy
The harnessing of the body’s immune system to illicit an antitumour effect and overcome immunologic tolerance of malignancies has been a long-sought-after oncologic therapeutic strategy. Active specific immunotherapy seeks to induce an immune-mediated antitumour effect by immunisation of a patient with tumour-specific antigens. Antigen-presenting cells such as dendritic cells are integral in the processing and presentation of antigens, via major histocompatibility complex (MHC) class I and
Apoptosis
Resistance to apoptosis, or programmed cell death, is another mechanism attributed to PCa progression and treatment resistance. The B-cell leukaemia/lymphoma 2 gene (BCL-2) is the prototype of a class of oncogenes that contributes to neoplastic progression by enhancing tumour cell survival through inhibition of apoptosis. Initially identified in follicular lymphoma as a result of the characteristic t14,18 translocation, BCL-2 is a mitochondrial membrane protein that functions to heterodimerize
Chaperone proteins
The heat shock protein-90 (HSP90) molecular chaperone complex is essential for AR stability and maturation and thus has been identified as a potential therapeutic target for CRPC. In addition, HSP90 acts as a chaperone to a number of other client proteins associated with malignant progression, including Akt, Raf-1, Her-2, and hypoxia-inducible factor 1α (HIF-1α) [53]. HSP90 is an ATP-dependent chaperone, and a number of specific inhibitors have been developed against its ATPase activity.
Insulin-like growth factor 1 and receptor
The insulin-like growth factor (IGF) axis is composed of two peptide growth factors (IGF-1 and IGF-2), two transmembrane receptors (IGF-IR and IGF-IIR), six IGF binding proteins (IGFBP-1 to IGFBP-6), and IGFBP proteases. IGFs are synthesized primarily in the liver and have effects on protein and carbohydrate metabolism but also regulate cellular processes of proliferation, differentiation, and apoptosis. These later attributes have resulted in the IGF axis being associated with a critical role
Bone targeting
Given the predilection of PCa to metastasize to bone, therapies directed towards the biologic underpinnings of bone progression are a rational treatment direction. Bisphosphonates, which inhibit bone the bone resorbing activity of osteoclasts by binding to the mineralised bone surface, are already an established treatment for patients with metastatic CRPC, and studies continue to define their use for earlier disease. Additional agents targeting bone metastases–related biologic targets are also
Conclusions
Over the past two decades, there has been an increased understanding of the biologic underpinnings of cancer in general and PCa specifically relating to androgen-independent progression, immune tolerance, factors affecting cell proliferation and survival, and mediators of metastases. Coupled with rational drug design and more sophisticated trial endpoints, a large number of therapeutic agents have entered into clinical trials over the past decade that promise to significantly change our
References (95)
- et al.
EAU guidelines on prostate cancer
Eur Urol
(2008) - et al.
Strontium89 chloride versus palliative local field radiotherapy in patients with hormonal escaped prostate cancer: a phase III study of the European Organisation for Research and Treatment of Cancer Genitourinary Group
Eur Urol
(2003) - et al.
Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance
Am J Pathol
(2004) - et al.
Neutralizing anti-vascular endothelial growth factor antibody inhibits further growth of established prostate cancer and metastases in a pre-clinical model
J Urol
(1999) - et al.
Synthesis and functional analyses of nuclear clusterin, a cell death protein
J Biol Chem
(2003) - et al.
Clusterin has chaperone-like activity similar to that of small heat shock proteins
J Biol Chem
(1999) - et al.
Clusterin activates survival through the phosphatidylinositol 3-kinase/Akt pathway
J Biol Chem
(2008) - et al.
Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis
Lancet
(2004) - et al.
Safety and efficacy of the specific endothelin-A receptor antagonist ZD4054 in patients with hormone-resistant prostate cancer and bone metastases who were pain free or mildly symptomatic: a double-blind, placebo-controlled, randomised, phase 2 trial
Eur Urol
(2009) The role of Src in prostate cancer
Ann Oncol
(2007)
Cancer statistics, 2008
CA Cancer J Clin
Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer
JAMA
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
J Clin Oncol
Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points
J Clin Oncol
A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma
J Natl Cancer Inst
Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer
N Engl J Med
Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer
N Engl J Med
Mechanisms of androgen-refractory prostate cancer
N Engl J Med
The development of androgen-independent prostate cancer
Nat Rev Cancer
Flutamide versus prednisone in patients with prostate cancer symptomatically progressing after androgen-ablative therapy: a phase III study of the European Organization for Research and Treatment of Cancer Genitourinary Group
J Clin Oncol
Amplification and overexpression of androgen receptor gene in hormone-refractory prostate cancer
Cancer Res
Molecular determinants of resistance to antiandrogen therapy
Nat Med
The androgen axis in recurrent prostate cancer
Clin Cancer Res
In vivo knockdown of the androgen receptor results in growth inhibition and regression of well-established, castration-resistant prostate tumors
Clin Cancer Res
Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer
Clin Cancer Res
Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer
Cancer Res
Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer
Cancer Res
Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer
Cancer Res
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
Anti-tumor activity of abiraterone acetate (AA), a CYP17 inhibitor of androgen synthesis, in chemotherapy naive and docetaxel pre-treated castration resistant prostate cancer (CRPC)
J Clin Oncol
Phase I/II study of MDV3100 in patients (pts) with progressive castration-resistant prostate cancer (CRPC)
J Clin Oncol
Angiogenesis and prostate cancer: identification of a molecular progression switch
Cancer Res
Prognostic significance of plasma vascular endothelial growth factor levels in patients with hormone-refractory prostate cancer treated on Cancer and Leukemia Group B 9480
Clin Cancer Res
Effect of vascular normalization by antiangiogenic therapy on interstitial hypertension, peritumor edema, and lymphatic metastasis: insights from a mathematical model
Cancer Res
A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer
N Engl J Med
The use of bevacizumab (B) with docetaxel (D) and estramustine (E) in hormone refractory prostate cancer (HRPC): initial results of CALGB 90006
Proc Am Soc Clin Oncol
Vascular endothelial growth factor trap blocks tumor growth, metastasis formation, and vascular leakage in an orthotopic murine renal cell cancer model
Clin Cancer Res
A phase I dose escalation and pharmacokinetic (PK) study of intravenous aflibercept (VEGF Trap) plus docetaxel (D) in patients (pts) with advanced solid tumors: Preliminary results
J Clin Oncol
Sunitinib versus interferon alfa in metastatic renal-cell carcinoma
N Engl J of Med
Sunitinib malate for metastatic castration resistant prostate cancer following docetaxel-based chemotherapy
J Clin Oncol
Immunotherapy of hormone-refractory prostate cancer with antigen-loaded dendritic cells
J Clin Oncol
Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer
J Clin Oncol
Phase 1/2 dose-escalation study of a GM-CSF-secreting, allogeneic, cellular immunotherapy for metastatic hormone-refractory prostate cancer
Cancer
Anti-cytotoxic T-lymphocyte antigen-4 antibody: the first in an emerging class of immunomodulatory antibodies for cancer treatment
J Clin Oncol
Enhancement of antitumor immunity by CTLA-4 blockade
Science
A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer
Clin Cancer Res
Cited by (138)
miRNAs and androgen deprivation therapy for prostate cancer
2021, Biochimica et Biophysica Acta - Reviews on CancerAntiandrogen abiraterone and docetaxel treatments affect Notch1, Jagged1 and Hes1 expressions in metastatic prostate cancer cells
2021, Experimental and Molecular PathologyExosomes Derived from miR-143-Overexpressing MSCs Inhibit Cell Migration and Invasion in Human Prostate Cancer by Downregulating TFF3
2019, Molecular Therapy Nucleic AcidsTrkA promotes MDM2-mediated AGPS ubiquitination and degradation to trigger prostate cancer progression
2024, Journal of Experimental and Clinical Cancer ResearchNew Drug Approvals in Prostate Cancer and Their Effect on the Treatment Landscape
2023, Clinical Advances in Hematology and Oncology