Tumor-targeting viral therapy slows neuroblastoma, malignant peripheral nerve sheath tumors

February 15, 2008

CINCINNATI -Researchers in a multi-institutional study led by Cincinnati Children's Hospital Medical Center slowed the growth of two particularly stubborn solid tumor cancers - neuroblastoma and peripheral nerve sheath tumors -without harming healthy tissues by inserting instructions to inhibit tissue growth into an engineered virus, according to study results published in the February 15 Cancer Research.

"Malignant solid tumors are still very difficult to treat effectively, especially without causing harm to normal tissues, so we need to find innovative therapeutic approaches," said Timothy Cripe, M.D., Ph.D., a physician and researcher at Cincinnati Children's. "In our study, this tumor-targeting viral therapy enhanced anti-tumor activity by stimulating multiple biological processes, including directly killing the cancer cells and reducing the formation of blood vessels that fed the tumors. These data support continuing development and study of our tumor-targeted viral therapy to fight cancer."

Previous research has documented that oncolytic herpes simplex virus (oHSV) and similar viruses can infect and kill human cancer cells without harming normal, healthy cells or causing disease. In their study, Dr. Cripe and his colleagues genetically armed oHSV with a gene that carries instructions for a cancer-fighting protein, human tissue inhibitor of metalloproteinase 3 (TIMP3). TIMP3 blocks enzymes that aid the development and progression of cancer, called matrix of metalloproteinases (MMP). Specifically, MMPs help break down molecules that are important for the structural support and normal development of cells, organs and maintenance of tissues. When MMP activity becomes unbalanced, the enzyme plays a well-documented role in the formation of invasive and metastatic cancers, including pediatric neuroblastoma, the most common solid cancer tumor in childhood.

Researchers dubbed the tumor-targeted viral therapy created by combining of TIMP and oHSV as rQT3. In laboratory studies involving human cancer cells and mice designed to develop neuroblastoma or peripheral nerve sheath tumors, rQT3 reduced new blood vessel development and increased toxicity to both kinds of tumor cells. In addition, rQT3 treatment resulted in longer life spans in mice compared to mouse models receiving just saline or other treatments.

Dr. Cripe said the researchers also discovered that rQT3 reduced the number of circulating endothelial progenitors (CEP). CEPs are derived from blood marrow and circulate in the blood. They have the ability to become cells that line blood vessels to promote blood flow.

"Our findings suggest that therapeutic viruses can act systemically by limiting the mobilization and recruitment of bone-barrow derived progenitors, both CEPs and others, that contribute to the tumor microenvironment and growth, resulting in the restriction of new blood vessel growth that can feed tumors," Dr. Cripe said.

Neuroblastoma is a solid tumor cancer that begins in the sympathetic nervous system and most often strikes children younger than 5 years old. For children younger than 2, or those with a single mass tumor, the combination of surgery and chemotherapy has led to cure rates of 90 to 95 percent. In older children or those with metastatic disease, neuroblastoma is a much harder to fight. Tumor cells are often able to survive ordinary doses of chemotherapy and radiation, leading to relapses that are difficult to cure. During the last three decades, Cincinnati Children's has been a leader in developing high-dose chemotherapy used in combination with bone marrow transplants and other drug treatments to help improve outcomes for patients with high-risk neuroblastoma. Malignant peripheral nerve sheath tumors are cancers affecting the connective tissue surrounding nerves. The first-line treatment is surgical removal with chemotherapy or radiotherapy used as auxiliary therapies.
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The study included the University of Cincinnati College of Medicine and the Dardinger Laboratory for Neuro-Oncology and Neurosciences/Department of Neurological Surgery and Comprehensive Cancer Center at Ohio State University. Other researchers in the study include, Yonatan Y. Mahller, Sachin S. Vaikunth, Maria C. Ripberger, William H. Baird, Yoshinaga Saeki, Jose A. Cancelas and Timothy M. Crombleholme. Funding support came from the National Institutes of Health and Cincinnati Children's Division of Hematology/Oncology.

Cincinnati Children's, one of the top five children's hospitals in the nation according to Child magazine, is a 475-bed institution devoted to bringing the world the joy of healthier kids. Cincinnati Children's is dedicated to providing care that is timely, efficient, effective, family-centered, equitable and safe. For its efforts to transform the way health care is provided, Cincinnati Children's received the 2006 American Hospital Association-McKesson Quest for Quality Prize®. Cincinnati Children's ranks second nationally among all pediatric centers in research grants from the National Institutes of Health and is a teaching affiliate of the University of Cincinnati College of Medicine. The Cincinnati Children's vision is to be the leader in improving child health.

Cincinnati Children's Hospital Medical Center

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