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Old 02-13-2013, 11:32 AM
Dross Dross is offline
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Default Emerging cancer drugs may drive bone tumors

Investigational cancer drugs, IAP (inhibitor of apoptosis proteins) antagonists, may increase the risk of tumors spreading to bone. Tumors often cause bone loss, but IAP antagonist treatment accelerates the problem.

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 Washington University School of Medicine in St. Louis.

The drugs, IAP antagonists, block survival signals that many cancer cells rely on to stay alive. Working in mice, the investigators found that targeting the same protein that makes tumors vulnerable to death also overactivates cells called osteoclasts, which are responsible for tearing down bone.

“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, MD, PhD, associate professor of medicine. “There is also excitement because until now, these drugs have not appeared to have major side effects.”

The research appears in the February issue of Cancer Discovery.

In light of the study, Novack 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 overactivate 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 (inhibitor of apoptosis proteins) antagonists is specific to bone, Novack and her colleagues tested long-established 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 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, MD, PhD, 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 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 also made two other similar drug compounds and found them to have the same detrimental effects on the bone.

And to further ensure that over-stimulated osteoclasts are the only culprit in the bone metastasis associated with these new drugs, they 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.

Together, Novack says the 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 says. “They’re based on the mechanism of action for the entire class of drugs.”

Yang C, Davis JL, Zeng R, Vora P, Su X, Collins LI, Vangveravong S, Mach RH, Piwnica-Worms D, Weilbaecher KN, Faccio R, Novack DV. Anticancer IAP inhibition increases bone metastasis via unexpected osteoclast activation. Cancer Discovery. February 2013.

This study was supported by the National Institutes of Health (NIH), grant number AR052705, with additional support from AR52921 and AR53628, CA100730, and the Barnes-Jewish Foundation. Histological and microCT analysis was supported in part by the Washington University Center for Musculoskeletal Research NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), grant number AR057235. The Molecular Imaging Center was supported by NIH grant P50 CA94056. Genentech, Inc. provided BV6.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

[url]http://news.wustl.edu/news/Pages/24916.aspx

Last edited by gdpawel : 02-19-2013 at 04:41 PM. Reason: posted full article on forum board
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Old 03-01-2013, 01:46 AM
gdpawel gdpawel is offline
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Default How 'IAP Antagonist' Chemicals Kill Tumors

Chemical compounds specially designed to neutralize proteins that would otherwise allow tumor cells to cheat death have been recognized for some time by scientists as a promising new avenue for cancer therapy. Now, two studies in the November 16, 2007 issue of the journal Cell provide insight into just how these antagonists of the anti-death--so-called Inhibitor-of-Apoptosis (IAP)--proteins work to fight tumors.

The researchers reveal that the compounds hit specific IAP proteins known as cIAPs. That came as a surprise, they said, because the chemicals had originally been designed to target another of the anti-death proteins. The studies further show that the small molecule inhibitors not only block the death-defying proteins, but they also actively engage other players that lead to the death of tumor cells. Meanwhile, the chemicals seem to have little effect on healthy cells.

"There has been an effort for several years to look for IAP antagonists, which seem to be very good in causing cell death in cancer," said Domagoj Vucic of Genentech, Inc. in South San Francisco, who led one of the two studies. "It was thought they might be used in combination with other drugs. But now, we show that these chemicals are capable of inducing apoptosis all on their own."

"It appears that when you remove cIAP1 in sensitive cancer cells, it opens the tap and everything just goes [toward cell death]," added John Silke of La Trobe University in Australia, who led the other study. "cIAP1 seems to be critical in deciding the life-or-death balance."

Apoptosis or programmed cell death is a cell suicide mechanism with a major role in development and homeostasis in all animals, Vucic explained. It is now accepted that apoptosis is also an extremely important defense against tumors, Silke added.

Scientists initially discovered the IAP proteins capable of blocking cell death in, of all things, a caterpillar virus, Silke said. The IAP proteins were later found in other organisms, from flies to mammals. The proteins were also shown to rise in human cancer, making them attractive targets for the development of novel cancer therapeutics. Scientists have therefore sought to design molecules that could antagonize IAPs, taking the lead from natural IAP antagonists.

Vucic's group now shows that an IAP antagonist leads cIAPs to be marked for degradation by cellular components known as proteosomes. "This is an amazingly rapid occurrence, happening within two minutes in cells in culture after exposure to the compound," said Vishva Dixit, who is also from Genentech.

They found that treatment with the IAP antagonist led to the activation of a "NF-"B pathway" that produces another protein, called tumor necrosis factor (TNFa). "TNFa comes back and binds its receptor, triggering unimpeded apoptosis and killing cancer cells," Vucic said.

Likewise, Silke's team showed that "synthetic and naturally occurring IAP antagonists kill susceptible tumor cells through their action on cIAP1, resulting in NF-"B activation, which drives TNFa production and initiates tumor cell death." Silke noted that the congruence between the findings of the two studies is a "really good sign."

"These studies show the potential for these drugs, although there is a long road to go," Silke added. "It also demonstrates an important principle: If you can understand how something works through basic scientific discoveries, then you can really start to make targeted tumor therapies. We can begin to understand how tumors live and how to make them die."

Vucic said that a phase I clinical trial designed to test the safety of one of their IAP antagonist compounds in human patients is already underway.

The researchers include Eugene Varfolomeev, John W. Blankenship, Sarah M. Wayson, Anna V. Fedorova, Nobuhiko Kayagaki, Parie Garg, Kerry Zobel, Jasmin N. Dynek, Linda O. Elliott, Heidi J.A. Wallweber, John A. Flygare, Wayne J. Fairbrother, Kurt Deshayes, Vishva M. Dixit, and Domagoj Vucic, of Genentech, Inc., South San Francisco, CA, USA.

Citation: Cell Press (2007, November 19). How 'IAP Antagonist' Chemicals Kill Tumors. ScienceDaily. Retrieved February 19, 2013
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Old 03-05-2013, 10:12 PM
gdpawel gdpawel is offline
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Default FDA panel warns of cancer risk from osteoporosis drug

A panel of federal health experts to the Food and Drug Administration recommended that the agency no longer support the marketing of calcitonin salmon as a treatment for osteoporosis in post-menopausal women.

The panel voted 12-9 that the benefit of calcitonin salmon products in treating bone-thinning associated with osteoporosis is outweighed by a potential increase in the risk of cancer.

The drug, known chemically as calcitonin salmon is a man-made version of the hormone calcitonin that is found in salmon.

Calcitonin products include Novartis AG's Miacalcin injection and nasal spray and Unigene Laboratories Inc's nasal spray. Privately held Upsher Smith Laboratories Inc distributes Unigene's product in the United States. Generic calcitonin products are also available.

The European Medicines Agency concluded last July that calcitonin should no longer be used to treat osteoporosis, due to the drug's cancer risk. The majority of all calcitonin salmon trials showed an increased risk estimate.

They ruled that the benefits of calcitonin-containing medicines did not outweigh their risks in the treatment of osteoporosis and that they should no longer be used for this condition.

They recommended that the drugs should only be authorized for short-term use in Paget's disease, a bone disorder; for acute bone loss due to sudden immobilization; and for excess calcium in the blood caused by cancer.

The result follows an FDA staff review that found significant questions remain over whether calcitonin salmon is effective in reducing fractures. The panel voted 20-1 that companies developing new calcitonin salmon products must prove they are effective in reducing fracture risk.

The panel says the long-established bone strengthening drug should no longer be used by women because there is little evidence it works and it may actually increase the risk of cancer.

Health authorities around the world have been reviewing the drug's safety after two recent studies showed a slightly higher rate of cancer among patients taking calcitonin pills.

The FDA originally approved the drugs based on studies showing that they increased bone mineral density. However, no studies have definitely shown that higher density actually reduces bone fractures. The largest study of calcitonin, which followed 1,200 women for about five years, was plagued by logistical problems, including a high level of patients who dropped out.

The FDA often approves drugs based on so-called surrogate endpoints, or initial measures that suggest the drug will make real improvements in patient health. In cancer drugs, for example, tumor shrinkage is considered a predictor on longer survival.

In calculating survival gained by tumor shrinkage, it is approximately 2 months in 50% reduction, 3 and a half months in 75% reduction and 1 year in 99% reduction. The data indicate that in cases evaluated with reduction rates more than 90%, there may be a significant correlation between response rate and survival.

Of course, drugmakers favor this approach because it helps them get products to market sooner. But it has proven problematic for the FDA when drugs don't live up to their initial promise. Researchers opt for experiments that generate plenty of reproducible results (like tumor shrinkage). This gives the illusion that researchers have done something meaningful.
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