A collaboration of scientists from Weill Cornell Medical College and the Sloan-Kettering Institute has now reported that a tumor-targeting compound can reveal with great accuracy a set of altered molecular pathways that contribute to malignancy. The drug, known as PU-H71, can specifically bind to abnormal protein complexes in cancer cells, potentially leading to the development of more targeted and effective therapies that produce fewer side effects. These findings were recently published in the journal Nature Chemical Biology.
After nearly a decade of research, this compound was discovered and refined in the laboratory of Dr. Gabriela Chiosis. Dr. Chiosis initially designed the compound to inhibit heat shock protein 90, which aids other proteins with folding into correct three-dimensional shapes and proper functioning. Hsp90 plays an essential role in cells’ ability to tolerate stress. The accelerated growth and metabolism of tumors places a high degree of stress in these cells. To cope with stress, tumor cells produce a special form of Hsp90 that is tuned to specially protect those proteins required for their growth and survival. The newly developed compound specifically targets the cancer form of Hsp90 and has little impact on Hsp90 in normal cells.
Several years ago. Dr. Chiosis partnered with Dr. Ari Melnick to examine the effectiveness of the compound in treating breast cancer and lymphomas. They found the drug to have dramatic antitumor effects in animals with minimal toxicity. In addition, a new study being conducted by the pair of researchers has found a method of detecting entire networks of abnormal proteins in tumor cells – an impossible feat until now. Since many of the genes encoding these proteins are not mutated in tumors, genetic screening alone would not have been able to detect these abnormalities.
According to Dr. Melnick, "The value of this method is that it's the first time you can go and probe the functional proteome, or the whole set of proteins that are important to maintaining the tumor." This strategy opens up new possibilities for understanding the molecular basis of cancer and selectively targeting novel drug targets.
Most critically though, is that this cancer proteome method can pave the way toward personalized therapies that target multiple pathways in patients. The researchers claim, “No two tumors are exactly alike, and we don't really know what is driving cancer in one patient versus the other. If you can use this method to identify in a given individual the factors that are maintaining that patient's particular cancer, then you could develop targeted drugs that hit these specific factors -- in effect, designing personalized therapy for individual patients."