Designer Compound May Provide Customized Cancer Therapy

Scientists are finally making progress toward uncovering the molecular ambiguities that underlie cancer progression and treatment resistance. Two recent studies provide insights into the processes that may clarify why the small-molecule compound ABT-737 is emerging as a novel and effective anticancer agent.

The studies, published in the November 2006 issue of the journal Cancer Cell, also demonstrate that pharmacologic manipulation of certain signaling molecules can make resistant cancer cells sensitive to treatment with ABT-737. These studies provide validation for the hypothesis that evaluation of the molecular profile of individual tumors can provide beneficial information for guiding treatment decisions.

Cell survival molecules such as BCL-2 are abnormally regulated and overactive in many tumors and are believed to promote cancer progression and protect cancer cells from cancer therapies. In healthy cells, BH3 proteins bind to and suppress BCL-2. Therefore, researchers have attempted to create compounds that are similar to these natural antagonists to use as weapons against cancer cells. The synthetic BH3 mimetic ABT-737 has been shown to interact strongly with BCL-2 but weakly with other BCL-2 family members, such as MCL-1, and has been described as an excellent candidate for further research.

Dr. Michael Andreeff and colleagues, from the University of Texas M.D. Anderson Cancer Center (MDACC; Houston, USA), discovered that ABT-737 successfully kills acute myeloid leukemia (AML) cells without affecting normal blood cells. However, the researchers noted that cancer cells with high levels of the cell survival molecule MCL-1 were much less sensitive to ABT-737 treatment. Further studies demonstrated that pharmacologic inhibition of MCL-1 or inhibition of MCL-1 through RNA interference restored sensitivity of leukemic cells and definitively identified MCL-1 as an ABT-737 resistance factor. The researchers suggest that specific BCL-2 family proteins may define resistance to this BH3 mimetic.

In a separate study, Dr. David C.S. Huang and colleagues from the Walter and Eliza Hall Institute of Medical Research (Melbourne, Australia) demonstrated that resistant cells can be sensitized to ABT-737 by using varied approaches that destabilize or inactivate MCL-1. Dr. Huang's team concluded that ABT-737 should be effective against tumors that exhibit BCL-2 overexpression and low MCL-1 levels or when used in combination with MCL-1 inhibitors.

"The mechanistic insights provided here suggest ways in which ABT-737 might be used efficaciously as a single agent and in combination therapy. Our studies provide a rational basis for designing clinical trials of this highly promising agent and a benchmark for systematically evaluating BH3 mimetic compounds,” wrote Dr. Huang in his article.



Related Links:
University of Texas M.D. Anderson Cancer Center
Walter and Eliza Hall Institute of Medical Research