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Study: Emerging Cancer Drugs May Cause Bone Tumors

IAP antagonists over-activate bone-destroying osteoclasts (Feb. 12)

Cancer drugs should kill tumors, not encourage their spread. But new evidence suggests that an otherwise promising class of drugs may actually increase the risk of tumors spreading to bone, according to researchers at the Washington University School of Medicine in St. Louis, Missouri.

The investigational drugs — IAP antagonists — block survival signals that many cancer cells rely on to stay alive. Working with mice, the investigators found that targeting the same protein that makes tumors vulnerable to death also over-activates osteoclasts, which are responsible for breaking down bone.

The new research appears in the February issue of Cancer Discovery.

Senior author Deborah V. Novack, MD, PhD, urges oncologists to think about protecting bone in patients taking IAP antagonists, including patients with cancers that don’t typically spread to bone. Numerous IAP antagonists are in early 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 over-activate osteoclasts, destroying bone that is not replaced. In mice, the researchers showed that the drug led to osteoporosis, creating an environment that encouraged tumor growth in degrading bone, even while simultaneously killing breast cancer cells elsewhere.

After showing that the problem with IAP antagonists is specific to bone, Novack and her colleagues tested bisphosphonates, which inhibit osteoclasts and are used to treat osteoporosis. The bisphosphonates protected bone from the negative effects of the new drugs.

IAP antagonists are currently available only to patients enrolled in phase I or II clinical trials. While these kinds of studies examine the short-term safety and efficacy 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,” said lead author Chang Yang, MD, PhD. “If the cancer is going to metastasize to bone, it may take 6 months to 2 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 agreed to provide Novack and her colleagues with its drug — called BV6 — to evaluate in the study. Because the investigators could not obtain other proprietary IAP antagonists, they made two other similar drug compounds and found them to have the same detrimental effects on bone.

“The osteoporosis and spread of tumors we see in bone are unintended side effects of IAP antagonists, but they’re not off-target effects,” Novack said. “They’re based on the mechanism of action for the entire class of drugs.”

Source: Washington University; February 12, 2013.

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