Mechanisms of resistance in castration-resistant prostate cancer (CRPC)

Despite advances in prostate cancer diagnosis and management, morbidity from prostate cancer remains high. Approximately 20% of men present with advanced or metastatic disease, while 29,000 men continue to die of prostate cancer each year. Androgen deprivation therapy (ADT) has been the standard of care for initial management of advanced or metastatic prostate cancer since Huggins and Hodges first introduced the concept of androgen-dependence in 1972, but progression to castration-resistant prostate cancer (CRPC) occurs within 2-3 years of initiation of ADT. CRPC, previously defined as hormone-refractory prostate cancer, is now understood to still be androgen dependent. Multiple mechanisms of resistance help contribute to the progression to castration resistant disease, and the androgen receptor (AR) remains an important driver in this progression. These mechanisms include AR amplification and hypersensitivity, AR mutations leading to promiscuity, mutations in coactivators/corepressors, androgen-independent AR activation, and intratumoral and alternative androgen production. More recently, identification of AR variants (ARVs) has been established as another mechanism of progression to CRPC. Docetaxel chemotherapy has historically been the first-line treatment for CRPC, but in recent years, newer agents have been introduced that target some of these mechanisms of resistance, thereby providing additional survival benefit. These include AR signaling inhibitors such as enzalutamide (Xtandi, ENZA, MDV-3100) and CYP17A1 inhibitors such as abiraterone acetate (Zytiga). Ultimately, these agents will also fail to suppress CRPC. While some of the mechanisms by which these agents fail are unique, many share similarities to the mechanisms contributing to CRPC progression. Understanding these mechanisms of resistance to ADT and currently approved CRPC treatments will help guide future research into targeted therapies.     

Castration-resistant Prostate Cancer: From New Pathophysiology to New Treatment Targets

Context

Castration-resistant prostate cancer (CRPC) refers to patients who no longer respond to surgical or medical castration. Standard treatment options are limited.

Objective

To review the concepts and rationale behind targeted agents currently in late-stage clinical testing for patients with CRPC.

Evidence acquisition

Novel targeted therapies in clinical trials were identified from registries. The MEDLINE database was searched for all relevant reports published from 1996 to October 2009. Bibliographies of the retrieved articles and major international meeting abstracts were hand-searched to identify additional studies.

Evidence synthesis

Advances in our understanding of the molecular mechanisms underlying prostate cancer (PCa) progression has translated into a variety of treatment approaches. Agents targeting androgen receptor (AR) activation and local steroidogenesis, angiogenesis, immunotherapy, apoptosis, chaperone proteins, the insulin-like growth factor (IGF) pathway, RANK-ligand, endothelin receptors, and the Src family kinases are entering or have recently completed accrual to phase 3 trials for patients with CRPC.

Conclusions

A number of new agents targeting mechanisms of PCa progression with early promising results are in clinical trials and have the potential to provide novel treatment options for CRPC in the near future.     

Androgen receptor targeted therapies in metastatic castration-resistant prostate cancer – The urologists' perspective

Androgen deprivation therapy (ADT), which involves the maximal suppression of circulating testosterone, underpins the treatment approach to metastatic hormone sensitive prostate cancer. Although initial responses are generally favourable, approximately half of cases progress to metastatic castrate resistant prostate cancer (mCRPC), rendering traditional hormonal therapies ineffective. mCRPC is defined by disease progression despite established ADT. New research has improved our understanding of the the molecular mechanisms behind metastatic castration-resistant prostate cancer (mCRPC). This has led to a renewed interest in the androgen receptor as a target for therapy, paving the way for the introduction of novel androgen therapies such as abiraterone acetate and enzalutamide. Recent trials on these treatments have demonstrated their benefit to improving overall survival in the setting of mCRPC. The resultant effect is a new, constantly changing, and complex treatment paradigm for treating clinicians, who are now required to know the mechanism of actions of new medications, side effect profiles, modes of administration, and preferred sequencing of various treatment options. Furthermore, treatments involving new androgen biosynthesis are currently being developed and tested. Therefore, in the context of a highly heterogenous disease with a continuously changing treatment landscape, management of mCRPC can be particularly challenging.The purpose of this review is to provide an overview of the literature on new androgen receptor targeted therapies, and discuss the changing treatment landscape specific to metastatic CRPC.     

Evolving landscape and novel treatments in metastatic castrate-resistant prostate cancer

Treatment options for castrate-resistant prostate cancer (CRPC) have advanced in recent years and significantly improved the outlook for patients with this aggressive and lethal disease. Further understanding of the biology of CRPC has led to several new targeted therapies and continues to emphasize the importance of androgen receptor (AR) directed therapy. The treatment landscape is rapidly changing and further biologically rationale, biomarker-based ongoing clinical trials are needed. We review the recent results of major clinical trials in CRPC. New and investigational agents now in clinical evaluation are reviewed including inhibitors of angiogenesis, microtubules, chaperones, AR and intracellular kinases, as well as immunotherapy, radiopharmaceuticals and bone-targeted agents. The recent improvement in prognosis for CRPC brings continued optimism for further improvements. Thoughtful planning of clinical trials and further understanding of the mechanisms of resistance to therapies will allow for continued progress in patient care.     

Targeting the androgen receptor signalling axis in castration‐resistant prostate cancer (CRPC)

What's known on the subject? and What does the study add? Castration resistance has been appreciated for decades, and several mechanisms theorising on this effect have been proposed. A rich pipeline of novel agents, including abiraterone and MDV3100, have provided proof of principle that novel agents targeting the AR signalling pathway with superior selectivity and activity than predecessors have yielded significant clinical benefit for patients with metastatic castration‐resistant prostate cancer. Our review provides an update in the development of several novel agents targeting the AR signalling pathway now in clinical testing, as well as review novel therapies in development with distinct mechanisms of action showing promising preclinical activity.

• ? Despite undergoing local therapy with curative intent, 20–30% of patients with prostate cancer will ultimately development metastatic disease, leading to morbidity and mortality.
• ? Androgen‐deprivation therapy (ADT) for men with metastatic prostate cancer results in transient clinical benefit, but ultimately, cancers progress despite castrate levels of serum testosterone, a clinical state classically referred to as ‘hormone refractory’ disease.
• ? In this review, we examine mechanisms of resistance to ADT that have redefined our understanding of the more appropriately termed ‘castration resistant’ disease, and have paved the way for a new generation of therapeutics targeting the androgen signalling axis in advanced prostate cancer.

     

去势抵抗性前列腺癌新型内分泌治疗耐药机制研究进展

前列腺癌是男性泌尿生殖系统最常见的恶性肿瘤之一,雄激素在其发生发展中都扮演着重要角色。经去势治疗(ADT)后绝大多数前列腺癌都会进展成为去势抵抗性前列腺癌(CRPC)。肾上腺来源的雄激素和(或)雄激素受体(AR)的改变(包括AR基因扩增)驱动了瘤内雄激素的合成,进而重新雄激素轴信号通路。目前,阿比特龙、恩扎鲁胺等抗雄激素治疗药物都是CRPC患者的一线治疗用药。但是,治疗一段时间后患者仍然会出现耐药和疾病进展。因此,明确CRPC患者抗雄激素治疗耐药机制可以为克服CRPC治疗耐药和改善CRPC患者的预后提供契机。     

CYP17 inhibition as a hormonal strategy for prostate cancer

Androgen receptor (AR) signaling has a key role in the pathogenesis of prostate cancer. AR gene amplification, AR overexpression, and activating mutations in the AR occur more frequently as castration-resistant prostate cancer (CRPC) evolves, with intratumoral androgen levels remaining sufficient for AR activation despite castration. The source of these androgens might be either adrenal or intratumoral. AR signaling, therefore, remains a valid treatment target for patients with CRPC. CYP17 is a key enzyme for androgen biosynthesis. The imidazole antifungal agent ketoconazole weakly and nonspecifically inhibits CYP17, but remains unlicensed for this indication. Chemists at the Cancer Research UK Centre for Cancer Therapeutics have designed a novel, selective, irreversible inhibitor of CYP17 called abiraterone, which is more than 20 times more potent than ketoconazole. Abiraterone acetate, a prodrug, has undergone phase I assessment, and is rapidly progressing from phase II to phase III trials, in view of its high level of antitumor activity. This agent is safe and well tolerated, and activity profiles suggest that approximately 50% of CRPC remains AR-ligand driven. Other CYP17 inhibitors with alternative mechanisms of action, for example VN/124-1, are in preclinical development. The rationale for and implications of CYP17 inhibition and the CYP17-targeting agents in development are discussed in this Review.     

Translating insights of AR signaling from mouse models

Androgen receptor (AR) signaling plays a critical role in the physiology of the prostate and thus the biology of prostate cancer. Agents targeting the AR pathway have been the mainstay of treatment for patients with locally advanced and metastatic prostate cancer. In this review we will cover the role of androgen signaling in prostate cancer mouse models with an emphasis on how tumorigenic molecular alterations impact response to AR pathway inhibition and downstream AR target gene expression. Both of these concepts have meaningful implications for the management of patients with prostate cancer.     

Novel non-AR therapeutic targets in castrate resistant prostate cancer

Castrate resistant prostate cancer (CRPC) remains a disease with significant morbidity and mortality. The recent approval of abiraterone and enzalutamide highlight the improvements which can be made targeting the androgen receptor (AR) axis. Nonetheless, resistance inevitably develops and there is continued interest in targeting alternate pathways which cause disease resistance and progression. Here, we review non-AR targets in CRPC, with an emphasis on novel agents now in development. This includes therapeutics which target the tumour microenvironment, the bone metastatic environment, microtubules, cellular energetics, angiogenesis, the stress response, survival proteins, intracellular signal transduction, DNA damage repair and dendritic cells. Understanding the hallmarks of prostate cancer resistance in CRPC has led to the identification and development of these new targets. We review the molecular rationale, as well at the clinical experience for each of these different classes of agents which are in clinical development.     

Bipolar androgen therapy: The rationale for rapid cycling of supraphysiologic androgen/ablation in men with castration resistant prostate cancer

Androgen ablation is highly effective palliative therapy for metastatic prostate cancer but eventually all men relapse. New findings demonstrating that androgen receptor (AR) expression continues in androgen ablated patients has resulted in the classification “Castration Resistant Prostate Cancer” (CRPC) and has led to the development of new second‐line “anti‐ligand” hormonal agents. In this background is the paradoxical observation that the growth of some AR‐expressing “androgen sensitive” human prostate cancer cells can be inhibited by supraphysiologic levels of androgens. This response may be due to effects of high‐dose androgen on inhibiting re‐licensing of DNA in cells expressing high levels of AR. It may also be due to recently described effects of androgen in inducing double strand DNA breaks. Based on available preclinical data described in this review demonstrating the effects of supraphysiologic levels of testosterone on inhibition of growth of CRPC xenografts, we initiated a clinical trial in men with CRPC testing the effect of monthly treatments with an intramuscular (IM) depot injection of testosterone. This IM formulation achieves supraphysiologic levels of testosterone that cannot be achieved with standard testosterone gel‐based applications. The supraphysiologic testosterone level is followed by a rapid drop to castrate levels of testosterone with each cycle of therapy. This “bipolar androgen therapy” will not allow time for prostate cancer cells to adapt their AR expression in response to environmental conditions. The goal is to determine if a clinical response can be achieved through this non‐adaptive rapid cycling approach in men with CRPC. Prostate 70: 1600–1607, 2010. © 2010 Wiley‐Liss, Inc.     

Epigenetic reprogramming: A key mechanism driving therapeutic resistance

Prostate cancer initiation, development and progression is driven by androgen receptor (AR) signaling. Androgen deprivation therapy is the primary treatment for patients that present with locally advanced or metastatic disease. However, androgen deprivation therapy is not curative, and patients will progress to castrate-resistant disease (CRPC). Although most patient’s progress to CRPC via restoration of AR signaling (CRPC-Ad), approximately a quarter of patients will progress via mechanisms independent of AR signaling. This highly lethal phenotype is termed aggressive variant prostate cancer (AVPC). Data from clinical and preclinical studies demonstrate that AVPC involves combinatorial loss-of-function mutations in key tumor suppressor genes, low to absent AR levels, and re-expression of reprogramming, stem, and neuroendocrine related gene signatures. Further, AVPC is shown to evolve from a CRPC-Ad phenotype. Overall, lineage plasticity underlying progression to AVPC is thought to be provoked by genome-wide chromatin remodeling. Here, we will discuss an emerging focus on key drivers of chromatin remodeling in AVPC, and how their identification could provide noninvasive biomarkers to predict or detect AVPC emergence, and therapeutic targets to prevent or reverse progression to AVPC.     

Finding the optimal treatment sequence in metastatic castration-resistant prostate cancer—a narrative review

Over the last two decades, there has been significant progress in the treatment of metastatic prostate cancer. Multiple treatments with diverse mechanisms of action have improved clinical outcomes for patients with metastatic castration-resistant prostate cancer (mCRPC) including taxane chemotherapy, immunotherapy, potent androgen receptor pathway inhibitors (ARPI), and radiopharmaceuticals (radium-223). As these treatments have entered standard clinical practise, clinicians have been challenged on how to optimally select and sequence them as the landmark studies establishing their efficacy had control arms with placebo or minimally effective therapy and there is a paucity of prospective trials examining treatment sequencing. More recently, the situation has been further complicated as the earlier up-front use of docetaxel and ARPI with standard gonadal testosterone inhibition has been shown to impart substantial improvements in disease control and survival for patients with castration sensitive prostate cancer. As new therapies enter into clinical practise such as the inhibitors of Poly (ADP-Ribose) Polymerase and Prostate Specific Membrane Antigen (PSMA)-targeted therapy, how to optimally select and sequence available treatments will be a continued dilemma in the absence of validated predictive biomarkers. This review will summarize the literature supporting the use of each active agent in mCRPC. We will propose a framework which will guide the selection of appropriate agents based on prior therapies, disease characteristics and biomarkers.     

A phase II study of mifepristone (RU-486) in castration-resistant prostate cancer, with a correlative assessment of androgen-related hormones

OBJECTIVE

To evaluate mifepristone (RU‐486) in patients with castration‐resistant prostate cancer (CRPC), with a correlative assessment of serum androgens and androgen metabolites

PATIENTS AND METHODS

The androgen receptor (AR) is critical in the development and progression of prostate cancer, but available antiandrogens incompletely abrogate AR signalling. Mifepristone is a potent AR antagonist that functions by competing with androgen, preventing AR coactivator binding and by enhancing binding of AR corepressors. Patients with CRPC were treated with mifepristone 200 mg/day oral until disease progression. Testosterone, dihydrotestosterone (DHT), androstenedione, dihydroepiandrosterone sulphate and the testosterone metabolite 3α‐diol G, were measured at baseline and during therapy.

RESULTS

Nineteen patients were enrolled between April and August 2005; they were treated for a median (range) of 85 (31–338) days. The median prostate‐specific antigen (PSA) level at enrolment was 22.0 (3.0–937.2) ng/mL. No patient had a PSA response (>50% reduction in PSA). Six patients had stable disease for a median of 5.5 months. After 1 month, adrenal androgens were increased and testosterone and DHT increased by 91% and 80%, respectively, compared to baseline.

CONCLUSION

Mifepristone had limited activity in patients with CRPC, and stimulated a marked increase in adrenal androgens, testosterone and DHT. We hypothesise that inhibition of glucocorticoid receptor by mifepristone resulted in an increase in adrenocorticotropic hormone and subsequent increase in adrenal androgens, and that their conversion by tumour cells to testosterone and DHT probably limited the efficacy of mifepristone. These data emphasize the continued importance of alternative androgen sources in AR signalling in CRPC.     

Key targets of hormonal treatment of prostate cancer. Part 1: the androgen receptor and steroidogenic pathways

OBJECTIVE

Knowledge of the molecular and cellular changes that occur during the transition of hormone‐naïve to castration‐resistant prostate cancer (CRPC) is increasing rapidly. This might provide a window of opportunity for (future) drug development, and for treating patients with these potential devastating states of disease. The objective of this review is to provide an understanding of the mechanisms that prostate cancer cells use to bypass androgen‐deprived conditions.

METHODS

We searched PubMed for experimental and clinical studies that describe the molecular changes that lead to CRPC.

RESULTS

CRPC remains dependent on a functional androgen receptor (AR), AR‐mediated processes, and on the availability of intraprostatic intracellular androgens. CRPCs might acquire different (molecular) mechanisms that enable them to use intracellular androgens more efficiently (AR amplification, AR protein overexpression, AR hypersensitivity), use alternative splice variants of the AR protein to mediate androgen‐independent AR functioning, and have altered co‐activator and co‐repressor gene and protein expression. Furthermore, CRPCs might have the ability to synthesise androgens de novo from available precursors through a renewed and up‐regulated synthesis of steroid‐hormone converting enzymes. Blocking of enzymes key to de novo androgen synthesis could be an alternative means to treat patients with advanced and/or metastatic disease.

CONCLUSION

In CRPC, prostate cancer cells still rely on intracellular androgens and on an active AR for growth and survival. CRPCs have gained mechanisms that enable them to use steroids from the circulation more efficiently through altered gene expression, and through a renewed and up‐regulated synthesis of steroid hormone‐converting enzymes. Additionally, CRPCs might synthesise AR isoforms that enable AR mediated processes independent from available androgens.     

PI3K-AKT-mTOR signaling in prostate cancer progression and androgen deprivation therapy resistance

Prostate cancer （PCa） is the second most common malignancy among men in the world. Castration-resistant prostate cancer （CRPC） is the lethal form of the disease, which develops upon resistance to first line androgen deprivation therapy （ADT）. Emerging evidence demonstrates a key role for the PI3K-AKT-mTOR signaling axis in the development and maintenance of CRPC. This pathway, which is deregulated in the majority of advanced PCas, serves as a critical nexus for the integration of growth signals with downstream cellular processes such as protein synthesis, proliferation, survival, metabolism and differentiation, thus providing mechanisms for cancer cells to overcome the stress associated with androgen deprivation. Furthermore, preclinical studies have elucidated a direct connection between the PI3K-AKT-mTOR and androgen receptor （AR） signaling axes, revealing a dynamic interplay between these pathways during the development of ADT resistance. Thus, there is a clear rationale for the continued clinical development of a number of novel inhibitors of the PI3K pathway, which offer the potential of blocking CRPC growth and survival. In this review, we will explore the relevance of the PI3K-AKT-mTOR pathway in PCa progression and castration resistance in order to inform the clinical development of specific pathway inhibitors in advanced PCa. In addition, we will highlight current deficiencies in our clinical knowledge, most notably the need for biomarkers that can accurately predict for response to PI3K pathway inhibitors.