Phase III Trial Shows Biomarkers Predict p53 Gene Therapy Efficacy
Discovery Allows Selection of Treatment for Squamous Cell Carcinoma of the Head and Neck
In most cases, patients with recurrent, late-stage squamous cell carcinoma of the head and neck are facing a disease that is incurable. The vast majority of patients do not respond to standard therapies after a recurrence, and even if they do, the median survival is only four to six months. Those factors point to a clear need for improved therapies.
One of the first Phase III gene therapy clinical trials has determined that biomarkers can predict the efficacy of gene therapy in these recurrent cancers. W. Jarrard Goodwin, M.D., director of the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, was one of the study's senior authors. The results have been published in the December 15 issue of Clinical Cancer Research, a journal of the American Association for Cancer Research.
Goodwin explains that using biomarkers to predict the efficacy of a treatment is critically important for patients with short life expectancies. "If we can better predict which treatment will be the most effective," he says, "we can apply that therapy as quickly as possible. The very low levels of side effects and toxicity seen in this study are also exciting."
P53 is a tumor suppressor gene that acts as a cell cycle regulator. In virtually all cases of recurrent squamous cell carcinoma of the head and neck (SCCHN), the p53 tumor suppressor pathway is dysfunctional. This occurs either by the presence of a mutated p53 genotype or by overexpression of p53 inhibitors HDM2 or HDM4. Because this tumor suppressor gene plays such a critical role in the development of SCCHN, it has made gene therapy to restore p53 function a logical targeted treatment for this disease.
The team of nearly 20 physician-scientists hypothesized that tumor profiles that would be favorable for gene therapy would have wild-type p53 gene configurations, as compared to high-level expression of mutated p53 proteins.
The phase III trial enrolled 116 patients at sites across the United States and in Europe between April 2001 and April 2008. The Head and Neck Site Disease Group at Sylvester was among the most productive in the study. Each of the patients with recurrent SCCHN had previously been treated with either radiotherapy and/or surgery, with or without chemotherapy. Patients were randomly assigned to receive either adenoviral p53 gene therapy or methotrexate, a drug used to slow the growth of cancer cells.
Goodwin and the team of investigators found that 74 percent of patients with favorable p53 biomarkers (wild-type gene configurations) experienced significant tumor responses with gene therapy. Conversely, patients with unfavorable p53 biomarkers (high levels of mutation), did not show a marked tumor response following gene therapy. The study concludes that biomarker profiles are effective at predicting which patients will benefit from p53 gene therapy against this particular disease.
Goodwin says the findings are a "significant benefit to clinicians who need to identify an effective therapy for their patients." Joseph Rosenblatt, M.D., professor of medicine and associate director of clinical and translational research at Sylvester, describes the study as "an important milestone in gene targeting of p53."
Physicians believe the findings will open the door to new applications of biomarker predictions. "We think these results," says Goodwin, "should encourage the identification of other predictive markers to guide cancer therapies."