In the case of p53, gene therapy is based on a tumor-suppressing gene. Other investigations are focused on other tumor-suppressing genes, such as p16. Other genes of interest address malignant lesions through other mechanisms. For example, thymidine kinase (TK) is an apoptotic gene, and immune-based genes such as interleukin-2 (IL-2) or IL-12 may also have potential in head and neck tumors. Such genes address malignancies by causing a local secretion of immune-stimulating factors.
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September 2006In his research, Dr. O’Malley and his research partner, Daqing Li, MD, an associate professor of otorhinolaryngology-head and neck surgery at the University of Pennsylvania, where he is also the director of gene and molecular laboratories, have discovered a novel gene that disrupts the important cell process of DNA repair. The gene has not yet been named. When introduced into cancer cells, the gene makes the cancer cells more sensitive to the anti-tumor effects of radiation and/or chemotherapy. The gene, which has shown promise in animal studies, may be able to make radiation and chemotherapy more effective, or may make it possible to use lower doses of either and therefore make treatment less toxic to our patients.
Premalignant Lesions: Beyond Watchful Waiting or Excision
Dr. O’Malley said that gene therapy for premalignant lesions is also an important area of research. This area, in fact, may eventually become one of the hottest areas of gene therapy research that affects the practice of otolaryngology, he said. In theory, it would be easier to paste a little gene therapy on a precancerous lesion and prevent cancer progression rather than treat a large malignant lesion with more radical surgery once it has developed, he said. The problem is proving efficacy. It’s hard to create the long, costly study that proves it, but when it’s done, that will be a big hit.
At this point, the typical options in such cases are watchful waiting or excision. However, the problem with dysplasia or precancerous lesions within the mouth is that they reflect a genetic progression that is generally acquired through the aging process and exacerbated by smoking, alcohol, and other environmental exposures. We lose certain genes over a period of time; the progression concept holds that a cancer cell can then form, Dr. O’Malley said. We presume that dysplasia is a stage of cancer development.
A third option, then, might be to conduct a genetic analysis of the lesion in order to identify its position on the spectrum of progression. We can then put a gene therapy on in the form of a topical medication and can prevent the progression, Dr. O’Malley said. Treatments are still under investigation that tailored to the deficit. For example, if a lesion is deficient in p53 and p16, we may be able to give therapies that secrete these genes.