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Cancer: Trapping the escape artist

12.05.2010
Researchers deliver a better understanding of anti-cell death proteins and a potential antagonist to defeat them

Cancer uses devious means to evade treatment and survive. One prime example is the way tumors express anti-cell death (anti-apoptotic) proteins to resist chemotherapy and radiation. However, the Pellecchia laboratory at Sanford-Burnham Medical Research Institute (Sanford-Burnham) has made two recent discoveries that may help curb these anti-apoptotic proteins and make current treatments more effective.

In a paper published online in the journal Cell Death and Disease on May 6, Maurizio Pellecchia, Ph.D., and colleagues outline how the six anti-apoptotic proteins in the Bcl-2 family are expressed differently in different cancers. As a result, any therapy designed to defeat these proteins, and thus enhance the cell death caused by most cancer treatments, must target the exact anti-apoptotic protein the cancer is expressing to be effective. However, even targeting the right protein might not be enough, as cancers often express more than one and can select for an "escape" protein and continue to thrive.

"You need to inhibit all six of the anti-apoptotic proteins members of the Bcl-2 family to have a compound with therapeutic potential," says Dr. Pellecchia.

Related research may have solved that problem. The Pellecchia laboratory, in collaboration with Coronado Biosciences and Virginia Commonwealth University, has been working on just such a pan-Bcl-2 inhibitor, and may have found it in a compound called BI-97C1. A paper published online on May 5 in the Journal of Medicinal Chemistry describes how BI-97C1, an optically pure derivative of a cottonseed extract called gossypol, inhibits all six anti-apoptotic Bcl -2 family proteins. This broad spectrum approach could make current cancer treatments more effective by controlling all six of these proteins and allowing malignant cells to die.

"When we tested BI-97C1 against human prostate cancer in mice, the cancer was completely wiped out, even with one tenth the dose we had used with previous compounds," says Dr. Pellecchia.

BI-97C1 is currently licensed to Coronado Biosciences, a private, clinical stage biotech company focused on new cancer treatments. Coronado's pan Bcl-2 inhibitor program is expected to enter clinical trials soon. "We have a very productive collaboration with Dr. Pellecchia," says R.J. Tesi, M.D., president and CEO of Coronado Biosciences. "His work demonstrates the importance of inhibiting all six Bcl-2 pro-survival proteins and demonstrates how rational drug design can optimize the development of targeted therapies to treat cancer. We are anxious to move BI-97C1 from pre-clinical development into patients."

About Sanford-Burnham Medical Research Institute

Sanford-Burnham Medical Research Institute (formerly Burnham Institute for Medical Research) is dedicated to discovering the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. Sanford-Burnham, with operations in California and Florida, is one of the fastest-growing research institutes in the country. The Institute ranks among the top independent research institutions nationally for NIH grant funding and among the top organizations worldwide for its research impact. From 1999 – 2009, Sanford-Burnham ranked #1 worldwide among all types of organizations in the fields of biology and biochemistry for the impact of its research publications, defined by citations per publication, according to the Institute for Scientific Information. According to government statistics, Sanford-Burnham ranks #2 nationally among all organizations in capital efficiency of generating patents, defined by the number of patents issued per grant dollars awarded.

Sanford-Burnham utilizes a unique, collaborative approach to medical research and has established major research programs in cancer, neurodegeneration, diabetes, and infectious, inflammatory, and childhood diseases. The Institute is especially known for its world-class capabilities in stem cell research and drug discovery technologies. Sanford-Burnham is a nonprofit public benefit corporation. For more information, please visit www.sanfordburnham.org.

Josh Baxt | EurekAlert!
Further information:
http://www.sanfordburnham.org
http://www.coronadobiosciences.com

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