Burnham Institute for Medical Research (Burnham) has been selected as a comprehensive center in a new National Cancer Institute (NCI) Chemical Biology Consortium, an integrated network of chemical biologists, molecular oncologists and chemical screening centers. The consortium will establish a new paradigm in the use of public-private partnerships to translate knowledge from leading academic institutions into new drug treatments for patients with cancer. Both the La Jolla, Calif. campus of Burnham and its new Lake Nona campus in Orlando, Fla. will participate in the consortium.

The highly collaborative program will use state-of-the-art communications, data-sharing and project management tools. The NCI seeks to coordinate their own drug discovery efforts with those of academic institutions and private-sector companies in order to expedite the development of promising new therapeutics for cancer and to speed their entry into oncologic practice. The strategy is to expand current NCI programs in personalized medicine by applying a collaborative approach to assemble the skills and resources necessary to identify and advance novel drug candidates in high-risk, under-represented areas of cancer biology.

“Burnham’s strategic focus for the past five years has been on building our capabilities in chemical genomics and drug discovery,” said John Reed, M.D., Ph.D., president and CEO of Burnham. “The Chemical Biology Consortium gives Burnham an additional platform to use our advanced technologies, some of which are virtually unprecedented in the not-for-profit research world. We welcome the opportunity to contribute to this national effort to develop innovative cancer medicines of the future.”

The network allows scientists from around the country to use the expertise and resources of the screening centers to identify compounds that serve as research tools in the process of validating targets for more advanced drug discovery efforts. The NCI Chemical Biology Consortium, in which Burnham will partner as one of three comprehensive centers in the nation, will discover and refine compounds directed at cancer-relevant targets, advancing these potential therapies from the laboratory and into human clinical trials.

In September 2008, Burnham was awarded a $98 million grant to establish one of four comprehensive national screening centers as part of the National Institute of Health’s (NIH) Molecular Libraries Probe Production Centers Network (MLPCN). Burnham’s chemical genomics center recently received a gift of $10 million from philanthropist Conrad Prebys resulting in the renaming of the center to The Conrad Prebys Center for Chemical Genomics.

The Chemical Biology Consortium project has been funded in whole or in part with Federal Funds from the National Cancer Institute, National Institutes of Health, under Contract No. NO1-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

Source:
Josh Baxt

Burnham Institute

A new material developed at the University of Virginia - an oxygen nanosensor that couples a light-emitting dye with a biopolymer - simplifies the imaging of oxygen-deficient regions of tumors. Such tumors are associated with increased cancer aggressiveness and are particularly difficult to treat.

Oxygen nanosensors are powerful new research tools that one day may also be used for the diagnosis and detection of diseases and for planning treatment strategies.

The new material is based on poly(lactic acid), a biorenewable, biodegradable polymer that is safe for the body and the environment, and is easy and inexpensive to fabricate in many forms, including films, fibers and nanoparticles. It is useful for medical research as well as environmental research, sustainable design and green products, too.

The versatile sensor material is the result of research combining green chemistry with nanotechnology, and is reported in the current online edition of the journal Nature Materials.

Chemists at the University of Virginia developed the material and consulted with cancer researchers at the U.Va. Cancer Center and Duke University Medical Center to determine possible applications.

Guoqing Zhang, a U.Va. chemistry doctoral candidate, working with Cassandra Fraser, a U.Va. chemistry professor, synthesized the new material by combining a corn-based biopolymer with a dye that is both fluorescent and phosphorescent. The phosphorescence appears as a long-lived afterglow that is only evident under low oxygen or oxygen-free conditions.

Zhang devised a method to adjust the relative intensities of short-lived blue fluorescence and long-lived yellow phosphorescence, ultimately creating a calibrated colorful glow that allows visualization of even minute levels of oxygen. The biomaterial displays its oxygen-sensitive phosphorescence at room or body temperature, making it ideal for use in tissues.

“We were amazed at how easy the material was to synthesize and fabricate as films and nanoparticles, and how useful it is for measuring low oxygen concentrations,” Fraser said.

“It is based on a bio-friendly material,” added Zhang. “It is safe for the body and the environment, and so we realized it could have applications not just for medical research and developing improved disease treatments, but also for new sustainable technologies.”

Cancer researchers at Duke quickly realized that the new material could be particularly useful for real-time and extended-time spatial mapping of oxygen levels in tumors. This is important because a lack of sufficient oxygen in tumors - called “hypoxia” - is a major source of resistance to radiation and chemotherapy treatment, and promotes a greater degree of malignancy.

“We have found that these nanoparticles were directly applicable to our existing tumor models,” said Greg Palmer, assistant professor of radiation oncology at Duke University Medical Center. “This technology will enable us to better characterize the influence of tumor hypoxia on tumor growth and treatment response.”

Researchers and clinicians have long sought effective ways to locate and map low-oxygen areas in the body to better understand normal and disease processes. Presently, there are no simple, easy or inexpensive methods, preclinical or clinical, for generating oxygen maps of tumors and surrounding tissues with good spatial and temporal resolution.

“The method developed here holds great promise for being able to perform measurements of tumor hypoxia cost-effectively,” said study co-author Mark Dewhirst, a professor of radiation oncology, pathology and biomedical engineering at Duke. “This kind of tool could greatly increase our knowledge about methods to eliminate tumor hypoxia, which could lead to more effective treatments.”

“Tumors that have insufficient oxygen tend to be more likely to spread from the primary site to other parts of the body,” added Michael Weber, director of U.Va.’s Cancer Center. “Despite the overall importance of tumor hypoxia, it is very difficult to measure directly and most methods that are available are very expensive.”

The new material currently is being used in preclinical studies to gain insight into cancer biology and treatment response, which could be useful for drug development and testing.

“This technology enables entirely new insights to be obtained, allowing imaging of tumor hypoxia on the scale of tumor cells and small blood vessels,” Palmer said.

Eventually the material could be used as an injectable nanosensor, potentially providing continual data on oxygen levels, biological processes and therapy responsiveness.

Hypoxia also is linked to cardiovascular disease, stroke and diabetes, so the material developed by Zhang and Fraser could have applications in several areas of medicine.

Applications for the light-emitting biomaterial beyond medicine include molecular probes for cell biology, imaging agents for visualizing fluid and aerodynamics, and oxygen sensors for food and drug packaging, tamper resistant seals, and environmental monitoring, such as measuring oxygen levels in bodies of water.

The research is funded by the U.S. National Science Foundation, the U.S. Department of Defense, U.S. National Institutes of Health, the James and Rebecca Craig Foundation, through the U.Va. Cancer Center, and the U.Va. NanoSTAR Institute.

Source:
Fariss Samarrai

University of Virginia

GAITHERSBURG, Md. — An FDA panel unanimously endorsed the investigational biologic denosumab to treat bone loss in postmenopausal women with osteoporosis, but did not back its use in the much larger group of postmenopausal women with osteopenia.

The Reproductive Health Drugs Advisory Committee also decided that the first-in-its-class biologic appears safe and effective at treating bone loss in men with prostate cancer who are receiving androgen deprivation therapy, which depletes bone density. It voted 9 to 4, with one panelist abstaining, that the drug’s benefits outweigh the risks for use in prostate cancer patients.

However, the panel said there was a lack of data on how the drug works in breast cancer patients undergoing hormone ablation therapy.

Given the safety concerns for the drugs — namely an increased risk for infection — the committee didn’t recommend that the FDA approve denosumab for any of the preventive indications that drugmaker Amgen applied for.

Amgen was seeking approval to use the drug to prevent osteoporosis in postmenopausal women with early bone loss and in men with prostate cancer who haven’t yet lost a significant amount of bone mass.

“We don’t have enough safety data three years out to advocate for use in prevention at this point,” said Clifford Rosen, MD, a scientist at the Maine Center for Osteoporosis at St. Joseph Hospital in Bangor, Maine.

But the panel said there was plenty of data showing the drug increases bone mass density.

Just this week, two of the registration trials for denosumab were published by the New England Journal of Medicine as early online releases. Those randomized, placebo-controlled studies showed that the drug was as effective as the best bisphosphonate drugs for osteoporosis.

The studies included more than 7,800 postmenopausal women with osteoporosis and close to 1,500 men with prostate cancer and found that three years of treatment reduced radiographic spine fractures significantly.

Overall, those fractures appeared in 2.3% of the denosumab group, compared with 7.2% of patients taking placebo (P<0.001).

Or, as a representative from Amgen explained, 16 postmenopausal women would need to be treated with denosumab for three years to prevent a fracture.

“For a number needed to treat of less than 20, that’s pretty impressive for people who suffer from osteoporosis,” said panel member Rosen.

While the efficacy data was convincing, the panel was concerned with the safety data, especially an apparent increase in serious skin, ear, abdominal, and urinary tract infections in the patients taking denosumab.

According to an FDA analysis of Amgen’s pooled data from its trials, endocarditis, infected arthritis, and skin ulcers occurred more commonly in denosumab subjects.

Another concern the panel had was that Amgen failed to prove that denosumab doesn’t interfere with tumor-killing treatment in breast cancer patients. The FDA requires that so-called supportive care products for use in cancer patients be backed by data that show the product wouldn’t be detrimental to cancer outcomes.

“If there is any suspicion that there is increased cancer recurrence, it is not worth it,” said Joanne Mortimer, MD, an oncologist at City of Hope Medical Center in Durante, Calif., who specializes in breast cancer.

Representatives from Amgen said there is no evidence that denosumab worsened cancer progressions.

The panel voted 13 to 2 not to recommend denosumab be used to treat bone loss in women with breast cancer and bone loss who are undergoing hormone ablation therapy, and 14 to 0, with one member abstaining, not to recommend approval for using the drug to prevent future bone loss in breast cancer patients who have less pronounced bone loss.

There are no approved osteoporosis drugs for women with breast cancer who are undergoing hormone ablation therapy; however, some bisphosphonate drugs are currently used off-label for that indication.

If the agency follows the advice of the panel — and it usually does — denosumab, marketed as Prolia, would join the ranks of other osteoporosis drugs such as zoledronic acid (Reclast), risedronate sodium (Actonel), and ibandronate sodium (Boniva) to treat osteoporosis, which effects about 10 million Americans.

But denosumab is a “first-in-class” drug: It’s a biologic, which means it will likely be much more expensive than its competitor drugs, some of which are available as cheaper generics.

The drug also boasts an extremely convenient dosing regimen — subcutaneous injection every six months. Many clinicians believe this is a big advantage for denosumab, considering that compliance with daily oral medications for osteoporosis is notoriously poor.

Wrapping up the hearing, the panel voted 12 to 1 to require the drug to carry a Risk Evaluation and Mitigation Strategy (REMS). The REMS should carry a “communication plan” to explain to healthcare providers the specific indications.