Emerging Therapeutic Approaches in the Management of Metastatic Castration-resistant Prostate Cancer

ES Antonarakis; AJ Armstrong

Disclosures

Prostate Cancer Prostatic Dis. 2011;14(3):206-218. 

In This Article

Abstract and Introduction

Abstract

Although treatment options for men with castration-resistant prostate cancer (CRPC) have improved with the recent and anticipated approvals of novel immunotherapeutic, hormonal, chemotherapeutic and bone-targeted agents, clinical benefit with these systemic therapies is transient and survival times remain unacceptably short. Thus, we devote the second section of this two-part review to discussing emerging therapeutic paradigms and research strategies that are entering phase II and III clinical testing for men with metastatic CRPC. We will discuss a range of emerging hormonal, immunomodulatory, antiangiogenic, epigenetic and cell survival pathway inhibitors in current clinical trials, with an emphasis on how these therapies may complement our existing treatment options.

Introduction

Although we now have four therapies that have been shown to extend survival in patients with metastatic castration-resistant prostate cancer (CRPC) (docetaxel, cabazitaxel, sipuleucel-T and abiraterone acetate), none of these approaches are curative. To this end, annual mortality rates from prostate cancer in the United States remain unacceptably high at ~30 000 deaths per year.[1] For this reason, the discovery of novel treatment strategies for this patient population remains a critical endeavor and the identification of alternative therapeutic targets has never been more actively pursued. Because exploitation of the androgen axis and the antitumor immune response has yielded fruit in recent years, several drug development efforts continue to focus on these avenues. This has resulted in the progression to phase III development of several novel androgen-directed agents (for example, orteronel, MDV3100) and immune-modulating drugs (for example, ipilimumab).

In addition to these strategies, our recently accelerated understanding of other biological and cellular processes driving prostate cancer progression and metastasis has fueled the preclinical and clinical exploration of myriad molecular targets comprising alternative oncogenic pathways (Figure 1). Such cellular processes reflect the basic hallmarks of cancer and include angiogenesis and tumor microenvironment interactions, cell growth and proliferation, apoptosis, cell nutrition, DNA repair and epigenetic regulation.[2] This review is the second article in a series of two papers discussing therapeutic strategies for CRPC. Although the first review focused on Food and Drug Administration approved and available treatment options for these patients, this review will touch upon several novel therapies currently in clinical development that may enter the therapeutic arsenal in the next 5 years. Such therapies include additional androgen-modulating approaches, novel immunotherapies, angiogenesis inhibitors, mammalian target of rapamycin (mTOR) pathway inhibitors, apoptosis-inducing drugs, insulin-like growth factor (IGF) pathway antagonists, epigenetic therapies and poly-ADP ribose polymerase (PARP) inhibitors.

Figure 1.

Promising pathways and targets in metastatic CRPC. A; androgen; AR, androgen receptor; APC, antigen-presenting cell; CRPC, castration-resistant prostate cancer; CoAct, transcriptional coactivators; DNMT, DNA methyltransferase; ERK, extracellular signal-regulated kinase; GM-CSF, granulocyte–macrophage-colony-stimulating factor; HDAC, histone deacetylase; HSP, heat-shock protein; IGF-1R, insulin-like growth factor receptor-1; MEK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; PAP, prostatic acid phosphatase; PARP, poly (ADP-ribose) polymerase; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homologue deleted on chromosome ten; VEGF-R, vascular endothelial growth factor receptor.

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