Small heat shock proteins in cancer therapy and prognosis.

Hsp27 and clusterin (CLU are stress-activated small heat shock proteins that are up-regulated in many cancers where they play important roles in stress-induced protein homeostasis (proteostasis), inhibition of cell death pathways, and modulation of pro-survival signaling and transcriptional networks. They are associated with poor prognosis and treatment resistance in many cancers, protecting cells from many varied therapeutic stressors that induce apoptosis, including androgen or estrogen withdrawal, radiation, cytotoxic chemotherapy, and biologic agents. Both Hsp27 and sCLU are ATP-independent molecular chaperones making them less amenable to inhibition by small molecules, and so strategies to inhibit Hsp27 and sCLU at the gene-expression level are appealing. Indeed, known nucleotide sequences of cancer-relevant genes offer the possibility to rapidly design antisense oligonucleotides (ASO) for loss-of-function and preclinical proof-of-principle studies and subsequent clinical use. Here, we will review the rationale for Hsp27 and sCLU as therapeutic targets in cancer, and update the current status of pre-clinical and clinical studies using Hsp27 and CLU inhibitors, OGX-427 and OGX-011, respectively. This article is part of a Directed Issue entitled: Small HSPs in physiology and pathology.