Hsp90 Agents May Help Combat Urologic Cancers

Image © goa novi / Shutterstock.com

Heat shock protein 90 (Hsp90) drugs have been tested successfully in clinical trials for breast cancer, lung cancer, leukemia, multiple myeloma, and gastric cancer. Now, it appears Hsp90 drugs may have a role in combating prostate cancer, kidney cancer, and other urologic cancers.

Researchers at the SUNY Upstate Medical University are now reporting in Cell Reports that they have found a key cellular enzyme (c-Abl) may be an effective drug target in cancer cells for urologic cancers.¹ They report that these findings may be of paramount interest to clinicians because kidney cancer, in particular, is known to be resistant to current chemotherapy and radiation. The new findings may lead to new therapies for combating kidney cancer and prostate cancer, and they are therapies that are already in development.

In this study, researchers uncovered a mechanism whereby the key cellular enzyme Hsp90 could disengage from its role as chaperone of cancer cells. By acting as a guardian of cancer cells, the role of Hsp90 is to help cancer cells grow and thrive. This disruption is essential to halt the growth and kill the cancer cells.

Previous research showed that the disruption of Hsp90 from its activator (Aha1) sensitizes cancer cells to Hsp90 drugs. The Upstate researchers used specific compounds aiming at the regulator of Aha1(c-Abl1) to successfully disconnect Aha1 from Hsp90. With the regulator Aha1 disrupted, they were able to show that Hsp90 drugs can be used more effectively in inhibiting kidney cancer cells growth.

“This type of study brings Hsp90 drugs closer to a clinical trial testing in kidney cancer patients,” said lead study investigator Mehdi Mollapour, PhD, who is an assistant professor of urology and biochemistry and molecular biology at SUNY Upstate Medical University, Syracuse, NY. Mollapour said these findings will not only help enhance the efficacy of Hsp90 drugs in the clinic, but also lay a foundation for future studies aiming to understand combination therapy with Hsp90 drugs.²

Hsp90 inhibitors are currently under investigation in clinical trials in a variety of cancer patients and so investigators are searching for novel strategies to enhance their efficacy.The researchers write that “Our data also provide an explanation for previous findings on the synergistic effects of the combination of imatinib (STI571, Glivec, and Gleevec) plus 17-AAG on chronic myeloid leukemia (CML) cell lines (Radujkovic et al., 2005).” They further state that fusion of bcr-abl gene is associated with CML and imatinib can sensitizes CML cell lines to 17-AAG.²

About 61,000 new cases of kidney cancer are diagnosed each year and approximately 14,000 people die from the disease. The most common form of kidney cancer is renal cell carcinoma (RCC) and it is highly resistant to systemic chemotherapy.

References:

• Geddes D. (2015). Upstate researchers find key cellular enzyme could be effective drug target in urologic cancer cells. Upstate Medical University.
• Dunn DM, Woodford MR, Truman AW, et al. (2015). c-Abl Mediated Tyrosine Phosphorylation of Aha1 Activates Its Co-chaperone Function in Cancer Cells. Cell Reports/Science Direct, Aug 11;12(6):1006-18.