Medical Professional Publications

$6.3 Million Grant Furthers Childhood Sarcoma Research

(From the July 2013 Issue of PediatricsOnline)

Researchers at Nationwide Children’s Hospital will use a $6.3 million grant to further their study of pediatric sarcomas, a rare form of disease that affects bone or soft tissue and accounts for 11 percent of all childhood cancers. The project is funded by the National Institutes of Health and the National Cancer Institute.

“The ultimate goal of this project is to develop novel therapeutic approaches for advanced childhood sarcoma,” says Peter Houghton, PhD, lead researcher on the grant and director of the Center for Childhood Cancer and Blood Diseases in The Research Institute at Nationwide Children’s.

While more than 70 percent of children with sarcoma are cured, the outcome is still poor for those with advanced or metastatic disease. Specifically, the five-year, event-free survival rates are 30 percent or less in children with advanced or metastatic Ewing sarcoma, osteosarcoma or rhabdomyosarcoma. Intensive chemo-radiotherapy has not significantly altered this outcome, making the search for effective new therapies a critical pursuit.

Each of the three sarcomas targeted by this grant has distinct characteristics requiring in-depth analysis of disease pathways and treatment opportunities. “The projects will characterize the interrelationship of these pathways and identify combinatorial inhibitory approaches most likely to yield biologic activity in the clinical setting,” says Dr. Houghton, who has spent nearly three decades studying pediatric cancer to bring knowledge from the laboratory to the bedside.

The grant comes on the heels of a series of publications by Dr. Houghton and colleagues that examines the molecular and genetic underpinnings of sarcomas. One such study, published in June in Cancer Research, explored the connection between DNA repair pathways and the potency of radiation therapy.

When cancer cells are bombarded by radiation, many die. However, some are able to withstand the assault and repair DNA damage. An early step in the DNA repair pathway is activation of a checkpoint that halts the cell cycle and allows cells to repair damage before they divide.

The recent study found that one important protein in this repair pathway, FANCD2, was regulated by a signaling process called TORC1. Inhibition of TORC1 led to a rapid loss of FANCD2 in cultured cells and in cancers in mice. Without FANCD2, anticancer treatments, such as focused beam radiation therapy, were dramatically enhanced because cells could no longer repair the DNA.

Although further studies are necessary, Dr. Houghton says that these data suggest that drugs that inhibit TORC1 signaling may improve the effectiveness of radiation therapy in clinical practice. “Enhancing radiation therapy could increase cure rates for childhood cancers, or allow lower curative doses of radiation that would spare normal tissues and reduce the long-term side effects of therapy,” says Dr. Houghton.

Experts in sarcoma biology, cellular signaling pathways and drug development from Nationwide Children’s and The Ohio State University will collaborate on the grant to find answers to the questions raised by this study and related pediatric sarcoma research.

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