B u r n h a m C a ncer R e s e a rc h
recognized Apogossypol’s potential. The National Cancer Institute has provided special support to advance the drug toward clinical trials with an award to Drs. Pellecchia and Reed through its Rapid Access to Innovative Drugs program. Also, Coronado Biosciences, Inc., has taken the Apogossypol project under its wing and is financing the manufacturing and pre-clinical toxicology studies necessary to gain FDA approval for testing in humans. Clinical trials are anticipated for early 2009. Dr. Maurizio Pellecchia’s lab has been working on Apogossypol, a drug that helps defeat Bcl-2.
One way to restore the balance in our cells is to intervene on the genomic level. Antisense technology uses synthetic DNA (or RNA) molecules to change how genes function. Genasense, one of the first DNA-based drugs to tackle a major disease, works by essentially shutting down the gene that creates the Bcl-2 protein. By reducing production of Bcl-2 in cancer cells, Genasense helps make them more vulnerable to current treatments. In other words, by defeating the cellular mechanisms that resist radiation and chemotherapy, Genasense could make those treatments far more effective. The drug, initially created by Dr. Reed and licensed by pharmaceutical company Genta, Inc.,
has completed phase III trials and is awaiting FDA approval to treat chronic lymphocytic leukemia. Neu t r al izi ng th e Prot e in Another way to beat Bcl-2 is to attack the protein rather than the gene. Dr. Maurizio Pellecchia’s laboratory has been working with Gossypol, a natural product extracted from cotton seeds, which he discovered binds to and neutralizes the Bcl-2 protein. The team chemically modified Gossypol to improve its ability to target Bcl-2, increasing its anti-cancer properties and reducing its toxicity. Dr. Pellecchia’s research strongly suggests that this new compound, Apogossypol, has great potential as a cancer treatment. In addition to spurring
cancer cells to commit suicide, the compound also makes them less resistant to chemotherapy. Dr. Pellecchia thinks Apogossypol may be used to maximize the efficacy of various chemotherapies. “Chemotherapy only kills the weak cancer cells – those with little defense against apoptosis. With each successive cycle of chemotherapy, the cells with strong anti-apoptotic defenses survive and emerge as chemo-resistant disease that ultimately kills the patient,” says Dr. Pellecchia. “Keeping the levels of Bcl-2 in check during and between chemotherapy cycles should increase the effectiveness of chemo and could prevent the cells that over-express Bcl-2 from proliferating faster.” Other organizations have
From Bad to Good In still another advance against Bcl-2 by Burnham scientists, Drs. Xiao-kun Zhang and Arnold Satterthwait created a molecule that binds to Bcl-2 and converts it from a tumor protector to a cancer cell killer. “Our results provide insight into Bcl-2 conversion and identify a new direction for Bcl-2based drugs and cancer drug development,” says Dr. Zhang. The possibility of turning this cancer friend into a cancer foe is especially appealing, as it would turn the tables on cancer, using the cancer’s self-protective shield as a weapon to help defeat it. “It’s almost like prying a shield from an attacker and clobbering them on the head with it,” says Dr. Satterthwait. “What was once the key to the cancer’s survival now becomes the means of its destruction.”
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