K Mahon, Medical Oncology, Sydney Cancer Centre, Camperdown, 2050, Australia.
Chemotherapy remains the major treatment option for castration-resistant prostate cancer and limited cytotoxic options are available. Inherent chemotherapy resistance occurs in half of all patients and inevitably develops even in those who initially respond. Docetaxel has been the mainstay of therapy for six years, providing a small survival benefit at the cost of significant toxicity. Cabazitaxel is a promising second line agent, however, it is no less toxic, while mitoxantrone provides only symptomatic benefit. Multiple cellular pathways involving apoptosis, inflammation, angiogenesis, signalling intermediaries, drug efflux pumps and tubulin are implicated in the development of chemoresistance. A thorough understanding of these pathways is needed to identify biomarkers that predict chemotherapy resistance with the aim to avoid unwarranted toxicities in patients who will not benefit from treatment. Until recently, the search for predictive biomarkers has been disappointing however the recent discovery of MIC1 as a marker of chemoresistance may herald a new era of biomarker discovery in castration-resistant prostate cancer. Understanding the interface between this complex array of chemoresistance pathways rather than their study in isolation will be required to effectively predict response and target the late stages of advanced disease. The preclinical evidence for these resistance pathways and their progress through clinical trials as therapeutic targets is reviewed here.
Written by:
Mahon KL, Henshall SM, Sutherland RL, Horvath LG. Are you the author?
Reference: Endocr Relat Cancer. 2011 May 12. Epub ahead of print.
doi: 10.1530/ERC-10-0343
PubMed Abstract
PMID: 21565970
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