New evidence suggests that an otherwise promising class of drugs may actually increase the risk of tumors spreading to bone. The drugs, inhibitors of apoptosis (IAP) antagonists, block survival signals that many cancer cells rely on to stay alive. The investigators worked in mouse models and found that targeting the same protein that makes the tumors vulnerable to death also overactivates osteoclasts, which are the cells responsible for tearing down bone.
“These investigational drugs are getting broad attention right now because they seem to be very effective against primary tumors,” said senior author Deborah V. Novack, MD, PhD, of the Washington University School of Medicine. “There is also excitement because until now, these drugs have not appeared to have major side effects.”
In light of the study, Novack urges oncologists to think about protecting bone in patients undergoing IAP antagonist therapy, including patients with cancers that do not typically spread to bone. Numerous IAP antagonists are currently in clinical trials against breast, lung, pancreatic, ovarian, prostate, liver, skin, and blood cancers.
“For many of these cancers, doctors are not watching bone,” Novack says. “Osteoporosis is not the biggest concern when treating cancer, but if they’re not doing bone scans, they may miss a cancer spreading to bone.”
To maintain healthy bone, osteoclasts work in tandem with cells that build new bone. But IAP antagonists overactivate osteoclasts, destroying bone that is not replaced. In mice, the researchers showed that the drug led to osteoporosis, creating conditions that encouraged tumor growth in degrading bone, even while simultaneously killing breast cancer cells elsewhere. Their research was published in Cancer Discovery (2013; doi:10.1158/2159-8290.CD-12-0271).
After showing that the problem with IAP antagonists is specific to bone, Novack and her colleagues tested long-proven drugs called bisphosphonates that inhibit osteoclasts and are used to treat osteoporosis.
“We found that bisphosphonate treatment protected bone from the negative effects of these drugs,” Novack said. “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 efficacy of new drugs, the researchers say they may not catch bone metastasis.
Novack said the newly published studies have demonstrated 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 said. “They’re based on the mechanism of action for the entire class of drugs.”