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Hsp90 inhibitors in anti-cancer therapy

Inhibitors of a versatile molecular chaperone, Hsp90, are novel anti-cancer drugs that are currently in a front line of clinical trials. Reports indicate that these drugs are relatively well tolerated and show clear signs of therapeutic activities in diseases as malignant melanoma, breast and prostate cancer and multiple myeloma (MM). Hsp90 chaperons regulate stability and function of numerous proteins, including oncogenic kinases and transcription factors. A key challenge is to gain understanding of the major mechanisms governing responses of different tumors to the Hsp90 inhibitors (Hsp90-I) and to determine which pathways are critical in order to find predictive biomarkers for their rational use in each particular type of cancer.

Multiple myeloma (MM) is a highly malignant incurable plasma B cell tumor. Current treatments of MM include chemotherapy, proteasome inhibitor bortezomib (velcade) and immunomodulatory agents, such as lenalidomide, as well as stem cell transplantation.

Hsp90 is over-expressed in MM and critically contributes to the MM tumor cell survival. Hsp90 is required to maintain several oncogenic signaling pathways in MM cells, including IL-6/Jak/STAT3, PI3K and Ras/ERK. We found in a panel of MM cell lines and primary myeloma cells from patients that cells with IL-6-dependent CD45 expression and activated JAK/STAT pathway are particularly sensitive to an Hsp90-I 17-DMAG. The goal is now to further validate our findings in order to establish predictive biomarkers for a good response and to provide a rational for combining Hsp90-I with other drugs for treatment of MM.

This project is supported with the grant from Cancerföreningen; PI Katja Pokrovskaja Tamm, PhD.