Scientists identify molecular mechanism underlying tumor selectivity of Hsp90 inhibitors
Malignant cells are dependent on novel activated form of molecular chaperone
A newly identified biochemical difference between malignant cells and normal cells points to a novel molecular target for the development of selective anti-cancer drugs, according to research published today in the journal Nature by scientists from Conforma Therapeutics. Conforma scientists have shown that Heat-Shock Protein 90 (Hsp90), a molecular "chaperone" that maintains the stability and functional shape of many oncogenic signaling proteins, exists in a specific activated, high-affinity form in tumor cells that differs from the "resting" form of Hsp90 found in normal cells. This novel, activated Hsp90 explains the selectivity of Hsp90 inhibitors for tumor cells, including compounds identified by Conforma that bind to tumor-derived Hsp90 with 100-fold greater affinity than to Hsp90 derived from normal cells.
"This discovery explains why Hsp90-directed drugs kill tumor cells at doses that are not toxic to normal tissues," said Lawrence C. Fritz, Ph.D., president and chief executive officer of Conforma Therapeutics and an author of the paper. "We hope to begin testing our ideas and compounds in human clinical trials early next year."
Hsp90 is a molecular chaperone – a protein that maintains the stability and function of many signalling proteins including oncogenic proteins that are upregulated in cancers. Drug molecules can bind Hsp90 and induce the degradation of its oncogenic "client proteins," thereby generating potent anti-tumor activity at well-tolerated doses in animals. However, scientists have often questioned the specificity of Hsp90 as a molecular cancer target since Hsp90 is an abundant protein that is present in all cells. Conforma scientists have resolved this paradox by showing that tumor cells specifically contain Hsp90 complexes in an activated, high-affinity conformation. These data clarify the role of Hsp90 in cancer and support the development of Hsp90 inhibitors as an important new class of anti-tumor agents.
"Our research answers several fundamental questions regarding chaperone proteins and cancer," said Adeela Kamal, Ph.D., Conforma senior research scientist and first author of the Nature article.
The new work indicates that as tumor cells progressively overexpress and accumulate mutant signaling proteins, Hsp90 becomes engaged in active chaperoning and stabilization of these oncoproteins. In this process, bound co-chaperone proteins induce the tumor Hsp90 to adopt a novel high-affinity form. Progressive dependence on the activated, high-affinity chaperone makes Hsp90 an Achilles heel of tumor cells by distinguishing these malignant cells from normal cells bearing non-activated Hsp90.
"The activation of Hsp90 chaperones has been found in every tumor type we have investigated," said Francis Burrows, Ph.D., Conformas director of biological research and senior author of the Nature article. "Accordingly, we are optimistic that Hsp90 antagonists will have broad activity against diverse human cancers."
About Conforma Therapeutics
Conforma Therapeutics, a San Diego-based biopharmaceutical company, is focused on the design and development of novel drugs for the selective treatment of cancer. Conforma is developing drugs that target the cellular HSP90 family of molecular "chaperones" that control protein shape or conformation, including that of key signaling molecules involved in the growth and survival of tumor cells. HSP90-directed drugs selectively induce the degradation of these cancer-promoting proteins, leading to tumor cell death. In addition to cancer, Conformas technology also promises to have applications in other areas of medicine, including inflammation, virology, and central nervous disorders. Additional information regarding Conforma is available at www.conformacorp.com.
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