Gene Found to Have Powerful Anti-Tumor Activity

Researchers at The University of Texas M. D. Anderson Cancer Center have identified several molecular mechanisms that give the E1A gene, once thought to cause cancer when altered, its powerful anti-tumor activity.

Dr. Mien-Chie Hung, chairman of the Department of Molecular and Cellular Oncology at M. D. Anderson, discussed the increasing potential of E1A gene therapy in the treatment of cancer at the American Association for Cancer Research conference held recently in New Orleans.

"Clinical and basic science research studies strongly suggest that the adenoviral type 5 E1A gene is an effective tumor suppressor gene," said Dr. Hung, who cited results of a multi-center study involving the E1A gene as an important example.

The Phase II study enrolled 20 patients with recurrent cancers of the head and neck. Of those individuals with squamous cell carcinoma, one experienced a complete response to the therapy, while another eight had partial response or stabilization of the disease. Results of the study, which was sponsored by Targeted Genetics Corporation, were presented at the annual meeting of the American Society of Clinical Oncology last year.

These promising results, Dr. Hung said, eventually will lead to Phase III clinical trials for head and neck cancer, which will compare the effects of E1A gene therapy with standard treatment, determining which approach is more beneficial to patients.

Sponsored by Targeted Genetics Corporation, multi-center Phase I clinical trials using the E1A gene for the study of breast and ovarian cancer also have been completed. Phase II protocols in ovarian cancer were recently initiated at M. D. Anderson. During the Phase I trials, which evaluate the efficacy and toxicity of a new drug or therapy, M. D. Anderson investigators observed that the E1A gene effectively down-regulated HER2/neu, an oncogene commonly overexpressed in breast and ovarian cancer. Researchers have known for some time that the E1A gene can halt overproduction of HER2/neu. Now they are seeing the gene's potential in performing a number of other cancer-fighting tasks, including inhibiting key enzymes implicated in the spread and development of cancer, and sensitizing the effects of traditional cancer therapies.

Dr. Hung said the E1A gene is associated with multiple mechanisms that may contribute to anti-tumor activity. Recent findings of studies conducted at M. D. Anderson have shown that the E1A gene has the ability to:

• Inhibit expression of an enzyme implicated in tumor growth and regulation. The receptor tyrosine kinase known as Axl instructs tumor cells to multiply. Researchers found that the E1A gene can suppress Axl expression and, consequently, inhibit cell growth. Axl is one of many enzymes, including the epidermal growth factors, HER2/neu and Src, that are responsible for a variety of cellular processes involved in tumor development.
• Inactivate key mechanisms involved in the signaling pathway that controls tumor cell division and drug sensitization. Researchers have discovered that the E1A gene can obstruct the AKT/NF-kB cell signal in cancer cells and, in turn, make them more sensitive to the effects of traditional therapies. When activated, AKT/NF-kB molecules form a protective shield around cancer cells, often making them resistant to radiation therapy, chemotherapy and biological agents. Dr. Hung said these findings will lead to further studies that combine E1A gene therapy with existing therapeutic approaches. "We suspect it will produce a powerful synergistic effect on tumor cells," he said.
• Induce a bystander effect by inhibiting angiogenesis and causing cell death. A bystander effect occurs when neighboring cancer cells, which have not been specifically targeted with the corrective gene, also are destroyed. In pre-clinical gene therapy studies, researchers discovered that the E1A gene can bring about this response by cutting off the tumor's blood supply, leaving it to die. "This finding is especially important," Dr. Hung said, "because it is impossible to deliver a gene to every cancer cell. Knowing the E1A gene can have this effect is critical to the future application of gene therapy."
• Incite cancer cells to release a lethal substance. Dr. Hung said cancer cells expressing the E1A gene secrete a proapoptic factor before they die. This factor, which has yet to be identified, spreads to surrounding tumor cells and kills them. "Understanding the molecular mechanisms that give the E1A gene its powerful anti-tumor activity and the integral steps associated with cancer development is critical," Dr. Hung said. "We have identified many mechanisms, but certainly not all. Each discovery brings us one step closer to developing more targeted and effective therapies for several cancers."

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©2006 Texas Medical Center

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