Scientists are making progress toward unraveling the molecular mysteries that underlie cancer progression and treatment resistance. Two studies in the November 2006 issue of the journal Cancer Cell, published by Cell Press, provide mechanistic details that may explain why the small-molecule chemical ABT-737 is emerging as a unique and effective anticancer agent. The studies also demonstrate that pharmacological manipulation of specific signaling molecules can make resistant cancer cells sensitive to treatment with ABT-737. These studies provide support for the idea that examination of the molecular profile of individual tumors can provide useful information for guiding treatment decisions.
Cell survival molecules like BCL-2 are abnormally regulated and overactive in many tumors and are thought to promote cancer progression and protect cancer cells from cancer therapies. In normal cells, BH3 proteins bind to and inhibit BCL-2. Therefore, researchers have attempted to design 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 from The University of Texas M.D. Anderson Cancer Center and colleagues found that ABT-737 effectively kills acute myeloid leukemia (AML) cells without affecting normal blood cells. However, the researchers observed that cancer cells with high levels of the cell survival molecule MCL-1 were much less sensitive to ABT-737 treatment. Further experiments 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 from The Walter and Eliza Hall Institute of Medical Research in Australia and colleagues demonstrated that resistant cells can be sensitized to ABT-737 by using varied approaches that destabilize or inactivate MCL-1. Dr. Huang's group concludes 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," writes Dr. Huang.
Konopleva et al.: "Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia." Publishing in Cancer Cell, Volume 10, Issue 5, November 2006. DOI 10.1016/j.ccr.2006.10.006
The researchers include Marina Konopleva, Rooha Contractor, Twee Tsao, and Ismael Samudio of The University of Texas M.D. Anderson Cancer Center; Peter P. Ruvolo of The University of Texas M.D. Anderson Cancer Center and Institute of Molecular Medicine, University of Texas Health Science Center; Shinichi Kitada of the Burnham Institute for Medical Research; Xingming Deng of the University of Florida Shands Cancer Center; Dayong Zhai of the Burnham Institute for Medical Research; Yue-Xi Shi and Thomas Sneed of The University of Texas M.D. Anderson Cancer Center; Monique Verhaegen, and Maria Soengas of the University of Michigan; Vivian R. Ruvolo, Teresa McQueen, Wendy D. Schober, and Julie C. Watt of The University of Texas M.D. Anderson Cancer Center; Tilahun Jiffar of the Institute of Molecular Medicine, University of Texas Health Science Center; Xiaoyang Ling, Frank C. Marini, David Harris, Martin Dietrich, and Zeev Estrov of The University of Texas M.D. Anderson Cancer Center; James McCubrey of the Brody School of Medicine, East Carolina University; W. Stratford May of the University of Florida Shands Cancer Center; John C. Reed of the Burnham Institute for Medical Research; Michael Andreeff of The University of Texas M.D. Anderson Cancer Center. This work was supported by grants from the National Cancer Institute (PO1 CA55164) and the Paul and Mary Haas Chair in Genetics (to M.A.), and the Commonwealth Cancer Foundation for Research (to M.K.).
van Delft et al.: "The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized." Publishing in Cancer Cell, Volume 10, Issue 5, November 2006. DOI 10.1016/j.ccr.2006.08.027.
The researchers include Mark F. van Delft of The Walter and Eliza Hall Institute of Medical Research and The University of Melbourne; Andrew H. Wei of The Walter and Eliza Hall Institute of Medical Research; Kylie D. Mason of The Walter and Eliza Hall Institute of Medical Research and The University of Melbourne; Cassandra J. Vandenberg, Lin Chen, Peter E. Czabotar, Simon N. Willis, and Clare L. Scott, of The Walter and Eliza Hall Institute of Medical Research; Catherine L. Day of the University of Otago; Suzanne Cory, Jerry M. Adams, Andrew W. Roberts, and David C.S. Huang of The Walter and Eliza Hall Institute of Medical Research. This work was supported by grants from the Australian NHMRC (program grant 257502), US NCI (CA80188, CA43540), Leukemia and Lymphoma Society (SCOR 7015-02), Australian Cancer Research Foundation, and Marsden Fund (NZ); a Melbourne International Research Scholarship (M.F.v.D.); and fellowships from the Leukaemia Foundation of Victoria (A.H.W.), Leukemia and Lymphoma Society (C.L.S.), Cancer Council of Victoria (K.D.M., S.N.W., and A.W.R.), Sylvia and Charles Viertel Charitable Foundation (D.C.S.H.), and NHMRC (C.L.S., J.M.A., A.W.R., and D.C.S.H.).
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