Abnormal overexpression of p53 is a predictive molecular biomarker

A common laboratory test that predicted poor outcome from traditional radiation and chemotherapy treatment for head and neck cancers now has been found to predict a good prognosis with treatment of p53 tumor suppressor gene therapy – making it potentially the first predictive biomarker test for a gene-based drug.

Researchers at Introgen Therapeutics, Inc., in Austin, Texas, found that patients with advanced squamous cell carcinoma of the head and neck cancer (SCCHN) whose pre-treatment tumor samples over-expressed p53 protein were significantly more likely to respond to Advexin therapy than those whose tumor showed little p53 protein. Advexin is a gene based drug, injected directly into tumors, which uses an adenoviral vector to deliver the wild type p53 gene to tumor cells.

Results were presented at the first meeting on Molecular Diagnostics in Cancer Therapeutic Development, organized by the American Association for Cancer Research.

“Not only do we now have a way to predict if the gene therapy is likely to succeed, those patients for which it does work are the hardest patients to treat,” said Laura L. Licato, Ph.D., associate director for Clinical Research at Introgen. “Accumulation of p53 has corresponded with a poor response to traditional therapies, as well as lower survival and a shorter time to disease progression.”

“Selecting those who have the best chance of responding to p53 tumor suppressor gene therapy also helps perfect clinical trial testing,” Licato said.

The researchers specifically found, in a subset of patients from phase II clinical trials, that 73 percent of patients with p53-positive tumors responded to the therapy, compared to a 14 percent response in patients with tumors that were p53-negative. Median survival also increased to 11 months for p53-positive patients, compared to 3 months for those with p53-negative tumors.

Head and neck cancer is the fifth most common cancer worldwide. Each year approximately 40,000 Americans are diagnosed with head and neck cancer, and about 11,000 patients will die.

Many cancers have a dysfunction in the p53 pathway that regulates the cell cycle, helping to protect against cancer formation, but researchers estimate that more than 50 percent of head and neck tumors over-express p53 protein. That suggests a defect in protein regulation or that the p53 gene is mutated, incapable of producing effective protein. Tumors that are p53 negative likely have a working p53 gene and protein pathway, as normal p53 levels in cells are typically low.

Advexin is farthest along in federal Food and Drug Administration (FDA) review of any experimental gene therapy, according to Introgen, and has been granted fast track designation for an application of use in head and neck cancer. Results from two phase II clinical trials involving more than 160 SCCHN patients have found that 18 percent of patients treated with Advexin achieved local regional disease control. Two other phase III trials in the disease are underway. According to Introgen's published research, Advexin has also achieved 100 percent response when combined with chemotherapy to treat locally advanced breast cancer, and a 69 percent response when used with radiation to treat non-small cell lung cancer.