Therapeutic target ID’d for deadly childhood muscle cancer
SAN ANTONIO (Aug. 14, 2008)—Curbing the activity of a substance called “platelet-derived growth factor receptor A” dramatically reduced aggressiveness of an often-untreatable childhood muscle cancer in mice and cells, a new study from The University of Texas Health Science Center at San Antonio and partner institutions shows.
Research sites included the UT Health Science Center’s Greehey Children’s Cancer Research Institute (Greehey CCRI) and the university’s departments of Cellular and Structural Biology, Pediatrics, Medicine, and Epidemiology and Biostatistics. National collaborators are from the University of Virginia, Ohio State University, the Columbus Children’s Research Institute, and the Taussig Cancer Center and Lerner Research Institute at the Cleveland Clinic.
The work is reported in the most recent online advance issue of the journal Oncogene (http://www.nature.com/onc/journal/vaop/ncurrent/abs/onc2008255a.html).
Childhood muscle cancers, also called rhabdomyosarcomas, are the most common soft tissue sarcomas of childhood. The alveolar subtype is particularly difficult to treat because at diagnosis more than half of the children have lymph node involvement or distant metastasis (spread), the authors wrote.
“The way this disease grows and spreads has perplexed clinicians and researchers for nearly three decades, during which time the dismal outcome for metastatic alveolar rhabdomyosarcoma has remained essentially unchanged despite improvements in surgical technique, radiation delivery and chemotherapy,” said co-author Charles Keller, M.D., assistant professor of Cellular and Structural Biology at the Greehey CCRI.
The cure rate for the metastatic form is estimated to be 20 percent or lower. Dr. Keller said the findings offer a promising avenue for improving that outcome. “A therapeutic strategy for children with muscle cancer might be developed that would target this growth receptor and possibly similar ones at the same time,” he said. “The benefit to the patient is that such treatments are clinically available today for adult cancer patients who have other diseases. Importantly, too, the way these targeted therapies work is less toxic than chemotherapy.”
The researchers studied genetically engineered mice with tumors that develop the mutations, and frequent metastases, inherent to alveolar rhabdomyosarcomas. Dr. Keller developed this specialized mouse tumor model while training in the laboratory of 2007 Nobel Laureate Mario Capecchi, Ph.D., at the University of Utah.
In the current study, assays performed in the Keller laboratory by postdoctoral trainee Eri Taniguchi, Ph.D., showed that platelet-derived growth factor receptor A, and two proteins that mediate its effects, were highly activated in both the primary and metastatic tumors.
Using three different methods to dampen the platelet-derived growth factor receptor, the scientists noted significant reduction of tumor cell growth both in the mice and in cell cultures.
“We believe this clearly establishes platelet-derived growth factor receptor A as a potential future therapeutic target in alveolar rhabdomyosarcoma,” Dr. Keller said.
NCI grant support
This work is supported by a five year, $1.5 million grant recently awarded by the National Cancer Institute (NCI) to the Keller laboratory, and it is also the foundation for the Greehey CCRI’s forthcoming membership in the NCI’s Pediatric Preclinical Testing Program. Dr. Keller will lead the Greehey CCRI Pediatric Preclinical Testing Initiative.
One tempering factor in the study is this finding: while two-thirds of the mice showed a response, one-third developed resistance to the therapy after two weeks. This mimics resistance rates seen with adult cancers treated with a receptor inhibitor. Ongoing studies at the Greehey CCRI now aim to determine how resistance can be overcome. “Moving our results to the clinic will require close attention and further study of how tumors become resistant to this drug,” Dr. Keller said.
Co-authors from the UT Health Science Center are the lead author, Dr. Taniguchi; Koichi Nishijo, M.D., Ph.D., and Amanda T. McCleish, all at the Greehey CCRI; Joel E. Michalek, Ph.D., departments of Epidemiology and Biostatistics and Pediatrics; Marcia H. Grayson and Anthony J. Infante, M.D., Ph.D., Pediatrics; and Hanna E. Abboud, M.D., the Jay Stein Professor in Medicine/Nephrology.
Dr. Keller and other faculty at the Greehey CCRI are members of the Cancer Therapy & Research Center at the UT Health Science Center.
The University of Texas Health Science Center at San Antonio is the leading research institution in South Texas and one of the major health sciences universities in the world. With an operating budget of $576 million, the Health Science Center is the chief catalyst for the $15.3 billion biosciences and health care sector in San Antonio’s economy. The Health Science Center has had an estimated $35 billion impact on the region since inception and has expanded to six campuses in San Antonio, Laredo, Harlingen and Edinburg. More than 23,000 graduates (physicians, dentists, nurses, scientists and allied health professionals) serve in their fields, including many in Texas. Health Science Center faculty are international leaders in cancer, cardiovascular disease, diabetes, aging, stroke prevention, kidney disease, orthopaedics, research imaging, transplant surgery, psychiatry and clinical neurosciences, pain management, genetics, nursing, allied health, dentistry and many other fields. For more information, visit www.uthscsa.edu.