Cancer cells live in a stressed state caused by genomic abnormalities, deregulated biochemical pathways and microenvironmental pressures. As a result they evolve, during malignant transformation and progression, a dependency on a range of molecular chaperone systems that provide essential protein folding, oncoprotein activation and anti-apoptotic functions. This chaperone dependence creates a specific vulnerability in cancer cells that is now being actively exploited in drug discovery. Our own work has focused on using a combination of genetic techniques and chemical probes (a powerful combination, see Workman P, Collins I. Probing the probes: fitness factors for small molecule tools. Chem Biol 17 561-577 2010) to enhance our understanding of the cancer biology of molecular chaperone systems. At the same time we are heavily involved in the discovery and clinical evaluation of drugs that act on these cancer-supportive molecular machines. The trail has been blazed by HSP90 inhibitors, of which at least 13 are now in clinical development. Signs of clinical activity have been seen, most notably with 17-AAG (tanespimycin) in trastuzumab-refractory, ERRB2-positive breast cancer. The new HSP90 inhibitor NVP-AUY922, which we discovered with Vernalis and is being developed by Novartis, shows good activity in breast tumour models (Eccles SA et al NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumour growth, angiogenesis, and metastasis. Cancer Res 68 2850-2860 2008). The activity of HSP90 inhibitors is self-limited by the mechanism-based activation of the protective, HSF1-dependent heat shock response. This presentation will provide an update on the discovery, development and use of HSP90 inhibitors and will describe emerging data on the identification and validation of new potential chaperone system targets, including AHA1, CDC37 and the HSP70 family (eg Powers MV, Clarke PA, Workman P. Dual targeting of HSC70 and HSP72 inhibits HSP90 function and induces tumour-specific apoptosis. Cancer Cell 14 250-262 2008). Molecular chaperones are overexpressed in clinical breast cancers, and in many examples their expression correlates with clinical outcome. Moreover, many oncoproteins important in breast cancer are client proteins for HSP90, including ER, PR, ERBB2, AKT/PKB/and CRAF. Thus HSP90 and other chaperone inhibitors have particular potential in breast cancer. Progress towards, and future challenges for, the potential of anti-chaperone drugs to become part of the personalized cancer medicine of the future (Yap TA, Sandhu SK, Workman P, de Bono JS. Envisioning the future of early anticancer drug development. Nat Rev Cancer 10 514-523 2010) will be highlighted.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr BSF2-1.