Compound was synthesized to target Hsp90, which was found to build up in the mitochondria of tumor cells, according to research published in Cell.
Researchers at the University of Massachusetts Medical School (UMMS) report that they have defined a method to target and kill a cancer chaperone without damaging nearby healthy cells. These proteins promote tumor cell stability and survival.
The scientists sought to define the mechanism by which a specific chaperone known as heat shock protein 90 (Hsp90) leads to tumor cell stability and survival and understand why suppression of Hsp90 has not been successful in clinical trials.
The UMMS team believes that Hsp90 and TRAP-1 protect mitochondria in tumor cells from fulfilling their role in cell death. Their conclusions are based on the observation of an abundant pool of Hsp90 and its related molecule TRAP-1 in the mitochondria of only tumor cells.
“We have identified this mitochondrial accumulation of Hsp90 and TRAP-1 as a critical adaptive mechanism that makes cancer cells less susceptible to the unfavorable environment of tumors and to various anticancer agents,” says Dario C. Altieri, M.D., the Eleanor Eustis Farrington Chair in Cancer Research and professor and chair of cancer biology.
The scientists point out that the lack of effectiveness of current Hsp90 inhibitors is probably because they do not penetrate the mitochondria. Dr. Altieri and colleagues went on to synthesize an existing Hsp90 inhibitor so that it was able to reach the mitochondria.
This modified compound induced massive tumor cell death by eliminating the protective function of Hsp90, according to the research group. Notably, because the accumulation of Hsp90 and TRAP-1 only occurs in tumor cells, drugs conceived to target Hsp90 would largely spare normal cells, according to the investigators.
“We can now take a class of drugs and make them better and more efficacious by engineering them to accumulate in the mitochondria,” Dr. Altieri explains.
The study is published in the October 19 issue of Cell.
