In the 1970s, soil from Easter Island was found to contain fungus killing activity. The anti-fungal - compound, produced by bacteria in the soil, was dubbed rapamycin for the Polynesian name of Easter Island, Rapa Nui. Researchers soon realized the chemistry of rapamycin was rich: rapamycin was an effective immunosuppressant in preventing organ transplant rejection, and it demonstrated anti-tumor activity. Rapamycin's discovery also helped unlock the biology of a central cell signaling protein in cancer: mammalian target of rapamycin (mTOR, pronounced em tore). mTOR tells the cell when to grow by processing and integrating the various growth and survival signals received by the cell. Rapamycin, as an inhibitor of mTOR, blocks cancer cell proliferation and survival. Other rapamycin-like inhibitors of mTOR, termed "rapalogues," are currently in clinical trials for ovarian cancer.
Two mTOR inhibitors, temsirolimus and everolimus, are currently in five different phase II ovarian cancer trials in the United States. Both of these drugs have already been approved for renal cell carcinomas. Three of the ovarian clinical trials involve the combination of either temsirolimus or everolimus with Avastin, a VEGF inhibitor that interferes with the tumor's blood supply (click here to read our past newsletter on Avastin).
"mTOR inhibitors impact tumor growth in a different way than antiangiogenic therapy [Avastin]. We hope the blockade of the two pathways will be additive in its ability to slow tumor growth," says Dr. Kristen Zorn of University of Pittsburgh Medical Center and the principal investigator for one of the combination mTOR inhibitor/Avastin trials.
Anti-cancer drugs like Avastin and mTOR inhibitors are considered targeted therapies, because they are directed towards abnormal cancer proteins or pathways. Most types of ovarian cancer treatments are not targeted, but rather are cytotoxic, meaning that the treatment is toxic to all cells. But, the faster-growing cancer cells are usually more susceptible to these drugs than normal cells. Dr. William P. Tew of Memorial Sloan-Kettering Cancer Center, principal investigator of an everolimus/Avastin trial, points out that side effects are part of any cancer treatment, but that giving patients two targeted therapies may mean that patients will suffer less severeside effects than those often associated with cytotoxic therapies. He also suggests that patients begin to identify potential clinical trials early in their treatment process, so that they are aware of the trials' eligibility requirements.
Even as mTOR inhibitors have evolved from rapamycin to rapalogues temsirolimus and everolimus, they have become important tools in the fight against renal cell carcinoma, and may be effective against several other types of cancers currently in clinical trials, including breast cancer, gastric cancer, hepatocellular carcinoma, lymphoma and ovarian cancer. From the pre-clinical data, to the success against renal cell carcinoma, to the early promise in clinical trials for ovarian cancer, all indications are that the rapamycin's journey from Easter Island is far from over.
