A new study identifies a combination therapy that may sensitize human cancer cells to a promising treatment currently being used in clinical trials. The research, published in the July issue of the journal Cancer Cell, published by Cell Press, provides a pharmacological method for enhancing the potency and effectiveness of a tumor necrosis factor (TNF) death receptor ligand against a variety of human cancers.
Potency and lack of toxicity to normal tissues make activation of TNF-a-related apoptosis-inducing ligand (TRAIL) death receptor signaling an attractive and exciting target for cancer therapy, and it is currently being tested in clinical trials. However, most cancer cells have defects in their ability to die via a cell death pathway called apoptosis, and unfortunately, TRAIL therapy is not effective in cells that have certain defects in apoptotic pathways. Dr. Wafik S. El-Deiry from the University of Pennsylvania School of Medicine and colleagues designed a series of studies to gain a better understanding of TRAIL-associated cell signaling pathways in cancer cells and to look for ways to pharmacologically optimize TRAIL therapy.
Dr. El-Deiry's group had previously established that c-Myc is a key mediator of TRAIL-induced apoptosis and that cancer cells lacking c-Myc and a functional apoptotic pathway were resistant to TRAIL. In the current study, the researchers demonstrated that expression of c-Myc in TRAIL-resistant human colon cancer cells sensitized the cells to TRAIL, even when the cells had intrinsic apoptotic defects. The researchers observed that TRAIL induced expression of two potent antiapoptotic molecules, Mcl-1 and cIAP2, and that c-Myc repressed both molecules.
The researchers also discovered that the multikinase inhibitor sorafenib prevented TRAIL-mediated induction of Mcl-1 and cIAP2, and although it had little effect on the killing of TRAIL-resistant cells when administered alone, combination with TRAIL caused significant death of previously TRAIL-resistant cancer cells in culture and TRAIL-resistant tumors in mouse models. Sorafenib was recently approved by the FDA for treatment of renal cancer and is currently undergoing investigation in over 30 clinical trials for use against a wide range of human cancers, including melanoma, prostate, ovarian, pancreatic, lung cancers, and others.
Like c-Myc, sorafenib appears to work through a mechanism that involves repression of TRAIL-induced expression of Mcl-1 and cIAP2. "These results also establish the clinical potential for combining TRAIL or other death receptor agonists with an orally bioavailable, low-toxicity multikinase inhibitor, sorafenib/Nexavar, thus providing an exciting approach for attacking cancers that harbor defective intrinsic apoptotic machinery," explains Dr. El-Deiry.
The Researchers include M. Stacey Ricci, Seok-Hyun Kim, Kazuhiro Ogi, and John P. Plastaras, University of Pennsylvania School of Medicine in Philadelphia; Jianhua Ling, The University of Texas M.D. Anderson Cancer Center in Houston; Wenge Wang, Zhaoyu Jin, Yingqiu Y. Liu, David T. Dicker, University of Pennsylvania School of Medicine in Philadelphia; Paul J. Chiao, The University of Texas M.D. Anderson Cancer Center in Houston; Keith T. Flaherty, University of Pennsylvania School of Medicine in Philadelphia; Charles D. Smith, Department of Pharmacology, Pennsylvania State University in Hershey; Wafik S. El-Deiry, University of Pennsylvania School of Medicine in Philadelphia. This work was supported in part by NIH grants CA75138, CA98101, CA97100, CA105008, and the Littlefield-AACR award for research on metastatic colon cancer (W.S.E.-D.).
Ricci et al.: "Reduction of TRAIL-Induced Mcl-1 and CIAP2 by c-Myc or Sorafenib Sensitizes Resistant Human Cancer Cells to TRAIL-Induced Death." Publishing in Cancer Cell 12, 66-80, July 2007 DOI 10.1016/j.ccr.2007.05.006
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