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Cell Biology of Prostate Cancer and Molecular Targets

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Drug Management of Prostate Cancer

Abstract

While not appreciated at the time, the Nobel Prize-winning work of Huggins and Hodges in the 1940s illustrated the androgen dependence of prostate cancer and credentialized the first “targeted” (in this case, the androgen receptor) anticancer therapy. Androgen deprivation therapy induces long-term remission in most patients, but development of castration-resistant prostate cancer (CRPC) is inevitable. Most treatments for CRPC have been approved for symptomatic benefit, with only docetaxel shown to improve overall survival. Mechanisms underlying shift to castrate resistance have been attributed to a complex interplay of clonal selection, reactivation of AR axis despite castrate levels of serum T, adaptive upregulation of antiapoptotic and survival gene networks, stress-induced cytoprotective chaperones, and alternative growth factor pathways. CRPC tumors develop compensatory mechanisms during androgen deprivation, tailored to the synthesis of intratumoral androgens, which along with ligand-independent mechanisms involving cofactors or growth factor pathways, cooperatively trigger AR activation and thus disease progression. Over the last few years, numerous gene targets involved with CRPC that regulate apoptosis, proliferation, angiogenesis, cell signaling, and tumor-bone stromal interactions have been identified, and many novel compounds have entered clinical trials either as single agents or in combination with cytotoxic chemotherapy. In this review, several genes and pathways involved in CRPC progression will be reviewed, with particular emphasis on preclinically credentialized genes and pathways that are currently the targets of novel inhibitors in later stages of clinical development. These include the AR axis, molecular chaperones, tumor vasculature, bone stroma, and signal transduction pathways such as those triggered by IGF-1 and IL-6.

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Authors and Affiliations

  1. UBC Department of Urologic Sciences, The Vancouver Prostate Center, Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada

    Martin E. Gleave

  2. The Vancouver Prostate Center, Vancouver General Hospital, Vancouver, BC, Canada

    Martin E. Gleave

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  1. Martin E. Gleave
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  2. Michael E. Cox
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  3. Yuzhuo Wang
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Correspondence to Martin E. Gleave .

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  1. Medical Oncology Branch, NIH National Cancer Institute, Rockville Pike 9000, Bethesda, 20892, Maryland, USA

    William D. Figg

  2. Medical Oncology Branch, NIH National Cancer Institute, Rockville Pike 9000, Bethesda, 20892, Maryland, USA

    Cindy H. Chau

  3. School of Medicine, Dept. Urology, University of California, San Francisco, Divisadero Street 1600, San Francisco, 94115, California, USA

    Eric J. Small

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Gleave, M.E., Cox, M.E., Wang, Y. (2010). Cell Biology of Prostate Cancer and Molecular Targets. In: Figg, W., Chau, C., Small, E. (eds) Drug Management of Prostate Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-60327-829-4_1

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