Researchers from the Washington University School of Medicine in St. Louis have found that IAP antagonists (inhibitor of apoptosis protein), used for treating cancer, may increase the risk of tumors spreading to bone. Using a mouse model, the investigators found that targeting the same protein that makes tumors vulnerable to death also overactivates osteoclasts. The research appears in the February issue of Cancer Discovery.
“These investigational drugs are getting broad attention right now because they seem to be very effective against primary tumors, ” says senior author Deborah V. Novack, M.D., Ph.D., associate professor of medicine, in the February 12, 2013 news release. “There is also excitement because until now, these drugs have not appeared to have major side effects.”
“We found that bisphosphonate treatment protected bone from the negative effects of these drugs, ” Dr. Novack says. “While bisphosphonates are common for breast cancer patients, they’re not, for example, commonly given to lung cancer patients. But since IAP antagonists are now in lung cancer trials, we’re saying doctors may want to consider bisphosphonate treatment for lung cancer or other cancer patients receiving these drugs. Or at least closely monitor the bone status.”
IAP antagonists are now only available to patients enrolled in Phase 1 or 2 clinical trials. While these kinds of trials examine the short-term safety and effectiveness of new drugs, the researchers say they may not catch bone metastasis.
“These trials do not necessarily look for long-term effects of the drugs, ” says Chang Yang, M.D., Ph.D., staff scientist and the paper’s first author. “If the cancer is going to metastasize to bone, it may take six months to two years to see that outcome. This may not be seen during the clinical trial.”
Numerous drug companies are developing IAP antagonists intended for many kinds of cancer, but only Genentech, Inc. agreed to provide the researchers with its drug, BV6, to evaluate in the study. Because the investigators could not obtain other proprietary IAP antagonists, they also made two other similar drug compounds and found them to have the same detrimental effects on the bone.
In order to ensure that over-stimulated osteoclasts are the only culprit in the bone metastasis associated with these new drugs, the team performed studies in mice that lack the ability to dial up the production of osteoclasts. Even when given IAP antagonists, these mice were protected from osteoporosis and osteoclast activation. Given the combined results of these studies, Dr. Novack says that these results are unlikely to be a quirk of a particular compound.
“The osteoporosis and spread of tumors we see in bone are unintended side effects of IAP antagonists, but they’re not off-target effects, ” she says. “They’re based on the mechanism of action for the entire class of drugs.”
