Mice provide insight into therapy-induced cancers in humans

October 17, 2005

Scientists have developed a new tool that may prove to be invaluable for investigating the long-term mutagenic effects of chemotherapy and radiation, therapies that are widely used for the treatment of cancer. The research study, published in the October issue of Cancer Cell, provides evidence that a genetically engineered mouse model faithfully recapitulates treatment-associated cancers that occur in humans and may be useful for investigating the mechanisms involved in the development of therapy-induced cancers and for testing preventive strategies.

Secondary malignant neoplasms (SMNs) are new cancers that patients develop as a result of having received chemotherapy or radiation to treat a different type of cancer that may have occurred years earlier. To make matters worse, many of these secondary cancers are notoriously resistant to treatment. The occurrence of SMNs is a serious concern for doctors and patients, as the use of intensive radiation and chemotherapy has been more successful in curing primary cancers and has dramatically increased survival rates in children and adults. Unfortunately, as a result of treatment success, the incidence of SMNs has also risen. "The lack of relevant animal models of SMNs has impeded efforts to understand how mutagenic cancer therapeutics induce tumors in vivo, and to test preventive strategies," explains study author Dr. Kevin Shannon, a pediatric oncologist at the University of California, San Francisco.

Dr. Shannon and colleagues used a strain of mice developed in the laboratory of Dr. Tyler Jacks that carry a mutation in a tumor suppressor gene called Nf1. They selected this strain based on clinical data suggesting that humans who inherit this mutation are predisposed to SMNs. Nf1 mutant mice that were exposed to radiation, or radiation combined with chemotherapy, developed secondary cancers that are common in humans including leukemia, sarcoma, and breast cancers. "These animals develop a similar spectrum of malignancies as human patients who are treated with radiation and alkylating agents, and provide a tractable system for performing mechanistic studies, for comparing the mutagenic potential of different regimens, and for testing preventive strategies," offers Dr. Shannon. The study authors also suggest that this mouse model may be useful for testing novel therapeutic strategies for tumors that are resistant to conventional cancer therapies.
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The researchers included Urszula Pyzel, Yien-Ming Kuo, Lewis Teel, Jennifer Haaga, Jeannette Bonifas, Jane Fridlyand, Andrew Horvai, Scott C. Kogan, Bing Huey, Donna G. Albertson, and Kevin M. Shannon of the University of California, San Francisco in San Francisco, California; Richard C. Chao,of the University of California, San Francisco in San Francisco, California and the Department of Veterans' Affairs Medical Center in San Francisco, California; (Present address: Pfizer Global Research and Development, in San Diego, California); Alexander Borowsky, of the University of California, Davis, in Davis, California; and Tyler E. Jacks, of the Massachusetts Institute of Technology, in Cambridge, Massachusetts. This work was supported by US Army Neurofibromatosis Research Program projects DAMD 17-02-1- 0638 and DAMD17-98-1-8608, NIH grants R01 CA72614 and U01 CA84221, and the Jeffrey and Karen Peterson Family Foundation (all to K.M.S.); by NIH training grant 32ES07106 (R.C.C.); and by NIH grants U01 CA84118 and R01 CA101359 (D.G.A.).

Chao et al.: "Therapy-Induced Induced Malignant Neoplasms in Nf1 Mutant Mice." Publishing in Cancer Cell Vol 8, October 2005, pages 337-348. DOI 10.1016/j.ccr.2005.08.011 www.cancercell.org

Cell Press

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