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Abstract
Resistance to cancer treatment can arise through multiple mechanisms and negatively impacts on progression rates and survival times. New therapies targeting pathways underlying resistance would improve treatment outcomes and be of particular value in the treatment of prostate cancer, many of whom develop tumors refractory to radiation, hormonal therapy and chemotherapy regimens. The improved understanding of metastatic castration resistant prostate cancer progression mechanisms has broadened the therapeutic window by unveiling multiple molecular targets. Several approaches are being investigated to overcome resistance in prostate cancer, including the use of novel taxanes and tubulin inhibitors, and the inhibition of cell survival pathways. This review focuses on clusterin, a small heat-shock-like protein that is overexpressed in many types of solid tumors; we summarize the preclinical and clinical evidence supporting the rationale for targeting clusterin as a means to resensitize prostate tumors to radiation and chemotherapy agents.
Financial & competing interests disclosure
F Saad has received research grants from OncoGenex and Teva. K Munn from Anthemis Consulting Ltd provided editorial assistance. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Treatment outcomes and survival times for patients with solid tumors are adversely affected by the development of tumor resistance to radiotherapy and widely used chemotherapy agents.
Multiple cellular pathways can lead to the emergence of resistance, and cancer therapy may result in the clonal selection of tumor cells harboring modifications that enable them to escape the cytotoxic effects of therapy.
Many men with prostate cancer will eventually develop disease refractory to hormone therapy (castrate resistant), and a substantial proportion of metastatic castration-resistant prostate cancers (mCRPC) patients do not respond to, or will become refractory to, first-line chemotherapy with the standard of care docetaxel.
A better understanding of the mechanisms of resistance would help predict its emergence and minimize unnecessary exposure to chemotherapy. New agents that can target treatment and suppress resistance pathways would be beneficial in the management of mCRPC.
Mechanisms of resistance in solid tumors include overexpression of drug transporters and metabolic enzymes, drug inactivation, alterations in drug targets and overexpression of cell survival proteins, such as those involved in the heat-shock response.
Clusterin is a small heat-shock-like protein that is overexpressed in many solid tumor types. In prostate tumors, clusterin overexpression correlates with markers of poor prognosis and is induced in response to radiation, androgen therapy and chemotherapy. Preclinical data suggest that clusterin overexpression mediates treatment resistance through antiapoptotic effects.
Antisense inhibition of clusterin with custirsen, a second-generation phosphorothioate oligonucleotide, resensitizes prostate tumors to docetaxel in vitro and in vivo with a concomitant increase in apoptotic activity in the tumor cells.
Preliminary clinical data from Phase II trials of custirsen in combination with docetaxel in men with mCRPC support the rationale for targeting the clusterin protein in prostate cancer. Large ongoing Phase III trials are investigating this approach further.