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Delivering “The Guardian of the Genome”By Joe Munch
Conventional cancer therapies are most effective before a cancer has reached an advanced stage. Surgery and radiation therapy can often treat initial, localized tumors but are less appropriate for recurrent disease. And chemotherapy, while it may kill advanced cancer cells, can also damage normal tissues—with potentially deadly side effects. However, the results of a recently completed phase III trial of a gene therapy initially developed at M. D. Anderson may point to a new way of treating some relapsed or refractory cancers. The experimental agent Advexin uses a genetically modified adenovirus armed with a gene that kills cancer cells without harming normal cells. Advexin, which expresses the tumor-suppressing p53 gene, is the first gene therapy to succeed in a U.S. phase III clinical trial for cancer. Jack A. Roth, M.D., a professor in the Department of Thoracic and Cardiovascular Surgery, invented the therapy and co-founded Introgen Therapeutics, Inc., the company that makes Advexin. “The p53 protein,” Dr. Roth said, “is called ‘the guardian of the genome’ because it protects against damage to the cell. We are all constantly exposed to agents such as sunlight or tobacco smoke that can cause gene mutations. When the gene is functioning normally, p53 can actually help facilitate repair of those mutations or eliminate the damaged cell.” In most cancers, however, p53 is defective. The thinking behind the Advexin protocol was to take a normal p53 gene and put it into p53-defective tumor cells to cause apoptosis—death—of the cancer cells but not of normal cells. According to Dr. Roth, “When the p53-expressing adenovirus is injected directly into tumors, it causes the tumors to shrink or to stop growing. And in a few cases, there are very dramatic responses where the tumors disappear completely.” Positive results Introgen undertook the phase III, open-label clinical trial of Advexin at the behest of the U.S. Food and Drug Administration to confirm the results of earlier phase I and II studies of the therapy. (The results of the phase III study were presented to the American Society of Gene Therapy in May and have not yet been published in a peer-reviewed journal.) A group of 123 patients with recurrent squamous cell carcinoma of the head and neck refractory to platinum- or taxane-based chemotherapy was randomly assigned to receive intratumoral injections of Advexin or intravenous methotrexate (an antimetabolite commonly used to treat squamous cell carcinoma) every 3 weeks. One of the benefits of Advexin, the study showed, was that it is extremely safe: less than 1% of the patients treated with Advexin experienced harmful side effects, whereas 20%–30% of the patients treated with methotrexate had severe side effects such as bone marrow depression and infections; in fact, one patient died from the methotrexate treatment. But the study’s most important finding, Dr. Roth said, was that it was possible to use the p53 protein as a biomarker to predict which patients’ tumors would be responsive to p53 therapy and which would be responsive to methotrexate but not p53 therapy.
“Patients who had favorable p53 profiles—that is, patients with normal p53 protein levels or low levels of mutant p53 protein—had a significant improvement in their survival,” Dr. Roth said. “Overall survival duration, not just tumor response or time to progression, was more than twice as long as that in patients with the unfavorable p53 profile. This is the first randomized clinical trial to show gene therapy is an effective treatment. Most importantly, the p53 biomarker profiles predict which patients will benefit from p53 gene therapy.” Addressing limitations According to Dr. Roth, Advexin can be used to treat patients with extremely advanced disease that is usually not curable—for example, recurrent, refractory squamous cell carcinoma of the head and neck. However, Advexin must be injected directly into a tumor and thus would be ineffective in treating metastatic disease. “Most patients die from systemic metastases that involve multiple organ systems,” Dr. Roth said. “Gene delivery technology is being developed now that can potentially treat metastases.” One such technique is using nanoparticles to deliver p53. Nanoparticles are artificial constructs that are a little bigger than DNA or a large molecule like hemoglobin but still much smaller than cells. They can be engineered to deliver drugs or genes to cancer cells but not normal cells. Once inside a tumor cell, nanoparticles release their payload. And because they can be given systemically, nanoparticles eliminate the need for injections directly into tumors. Currently, M. D. Anderson researchers are developing nanoparticles that contain p53 and FUS1, another tumor-suppressing gene, to treat non–small cell lung cancer. Future applications Hundreds of gene therapy trials are currently under way around the world, and according to Dr. Roth, future gene therapies will likely be used concurrently or alternately with chemotherapy or radiation therapy to stimulate immune responses to cancer or as neoadjuvant therapy to prevent tumors from recurring locally after surgery. Eventually, specific gene therapies may be tailored to individual patients’ needs. “I think the basic concept of delivering genes to cancer cells has great potential,” Dr. Roth said. “Every month, we’re identifying more genes that play a role in the progression of cancer, and these genes could potentially be used as drugs if we have an efficient, effective way of delivering them.”For more information, contact Dr. Roth at 713-792-7664. Dr. Roth is a shareholder in and paid consultant to Introgen Therapeutics, Inc. The University of Texas System, which includes M. D. Anderson, is also a shareholder in Introgen. Other articles in OncoLog, October 2008 issue:
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