Novel Gene Therapy Targets Solid Tumors

Cancer researchers have developed a novel method for treating solid tumors by infecting them with a virus engineered to carry the gene for a protein that inhibits an enzyme that is critical for tumor growth.

Previous research had shown that oncolytic herpes simplex virus (oHSV) could infect and kill human cancer cells without harming normal, healthy cells or causing disease. Elaborating on this knowledge, investigators Cincinnati Children's Hospital Medical Center (OH, USA) genetically engineered oHSV to carry the gene that encodes for the protein human tissue inhibitor of metalloproteinase 3 (TIMP3).

Metalloproteinase 3, a member of the group of enzymes known as matrix metalloproteinases (MMP), collectively is capable of degrading most kinds of extracellular matrix proteins. They are known to be involved in the cleavage of cell surface receptors, the release of apoptotic ligands (such as the FAS ligand), and chemokine activation or inactivation. MMPs are also thought to play a major role in cellular activities such as proliferation, migration (adhesion/dispersion), differentiation, angiogenesis, apoptosis, and host defense. The MMPs are inhibited by specific endogenous tissue inhibitor of metalloproteinases (TIMPs), which comprise a family of four protease inhibitors: TIMP1, TIMP2, TIMP3 and TIMP4.

Results published in the February 15, 2008, issue of the journal Cancer Research revealed that treatment with the engineered virus (called rQT3) reduced new blood vessel development and increased toxicity to neuroblastoma and peripheral nerve sheath tumor-cells. In addition, rQT3 treatment resulted in longer life spans in mice carrying these tumors as compared to mouse models receiving just saline or other treatments.

"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,” explained senior author Dr. Timothy Cripe, a physician and researcher at Cincinnati Children's Hospital Medical Center. "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.”


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Cincinnati Children's Hospital Medical Center