Targeted Therapies in Metastatic Castration-Resistant Prostate Cancer: Beyond the Androgen Receptor

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Introduction

Prostate Cancer (PCa) is the most common cancer in North America and the second leading cause of cancer-related death in men. Despite improved outcomes through early detection and treatment of localized PCa, many men still die of metastatic disease. Although androgen ablation remains the most effective management option for patients with advanced disease, most progress to castration-resistant prostate cancer (CRPC) within 2 years of treatment initiation.1, 2, 3, 4 CRPC progression is a complex process by which cells acquire the ability to survive and proliferate in the absence of testicular androgens. Many mechanisms have been postulated to account for androgen receptor (AR) activation in CRPC tumors, including (1) activation of AR by nonsteroids such as growth factors and cytokines via deregulated multiple signaling pathways; (2) genetic mutation(s) or amplification(s) of AR that render the receptor hyperactive, which sensitizes cells toward low levels of androgen; (3) altered expression of activity of AR coactivators or chaperone proteins; (4) expression of AR splice variants that lack the ligand-binding domain (LBD) and are constitutively active in a ligand-independent manner; and (5) intratumoral steroidogenesis. These proposed mechanisms are not mutually exclusive and they likely work in concert to drive CRPC. Despite the failure of maximal androgen blockade trials using first-generation nonsteroidal AR inhibitors like flutamide or bicalutamide, CRPC tumors are not uniformly hormone refractory and remain sensitive to therapies directed against the AR axis.5 Hence, several new classes of AR-targeting agents are now in clinical development, including inhibitors of steroidogenesis (abiraterone)6 and more potent AR antagonists (MDV3100).7 Although enthusiasm for this approach remains high, prostate tumor heterogeneity and adaptive responses that support development of resistance via alternative mechanisms create a critical need for other strategies to kill prostate cancer cells.

Improved understanding of prostate cancer biology is facilitating the identification of many pathways, aside from the AR, that drive CRPC progression by promoting invasion and metastasis, or by activating cell survival signaling. This article highlights the implications for practice, and focuses on those mediating cell survival, cell invasion, and cell proliferation (Fig. 1).8

Section snippets

Preclinical data

Microtubules consist of tubulin heterodimers and radiate from the centrosome in the cytoplasm of interphase cells. They are involved in many cellular functions including cell motility, cell division, and intracellular transport. During the mitosis, microtubule networks ensure the correct attachment and segregation of chromosomes during cell division, making them attractive targets for anticancer drugs.9 Docetaxel is a taxane that binds to β-tubulin of microtubules during the G2-M phase of the

Targeting survival pathways

Defects in the ability to appropriately regulate apoptotic processes are one of the fundamental properties underlying cancer.8 Bcl-2 was the first identified member of a family of apoptotic regulators sharing at least 1 Bcl-2 homology domain. Bcl-2 family members include antiapoptotic proteins (eg, Bcl-2, Bcl-XL, and Mcl-1), multidomain proapoptotic proteins (eg, Bax and Bak), and BH3-only proapoptotic proteins (eg, Bim, Bid, Noxa, and Puma).9 Interactions between, and relative ratios of,

Targeting Met Kinase

Metastasis is one of the hallmarks of cancer. Growth and motility factor hepatocyte growth factor(HGF)/scatter factor (SF) and its receptor, the tyrosine kinase MET and Src, have been reported to play important roles in metastasis, thus providing a strong rationale for targeting these molecules in cancer. Hence, understanding the structure and function of HGF/SF, MET, and Src as well as associated signaling components has led to the successful development of blocking antibodies and a large

Summary

Many pathways involved in cell survival or bone metastases, in addition to the AR pathway, are currently being targeted in late-stage clinical trials supported by strong a biologic rationale and preclinical data. In the coming years, the interactions between basic and clinical researchers will be critical for designing new combinations for improving maximum inhibition of CRPC progression.

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