NIDCR scientists may be first to show that p38 is highly active in head and neck cancers
Better treatment options are needed for people diagnosed with head and neck cancers because the current therapies of surgery, radiation therapy, and chemotherapy control cancer at the cost of normal tissues, sometimes damaging them permanently. That’s why scientists are searching for drugs known as targeted therapies to target and kill cancer cells without harming healthy tissues. J. Silvio Gutkind, Ph.D., chief of NIDCR’s Oral and Pharyngeal Cancer Branch, studies the molecular basis of cancer to understand what makes cancer cells grow and spread. The ultimate goal is to identify drugs that will turn off the signals that make cancers large and invasive. In a recent article in the journal Molecular Oncology, Dr. Gutkind’s team reported that p38 kinase is active in head and neck cancer cells and blocking p38 may help prevent cancers from growing. Although p38 is known to play a role in breast and bladder cancers, these results may be the first to show that p38 plays a highly active role in head and neck cancers.
In an experiment involving tissue samples of hundreds of head and neck cancer patients, the NIDCR team found that p38 kinase was active in most samples. The most malignant tissue samples had the highest activity of p38, and the least malignant samples had the lowest p38 activity. The normal oral tissue used as a control had no p38 activity. When the team used a gene knockdown technique to turn off p38 activity in human oral cancer cells and transplanted those cells into lab mice, the oral cancers without p38 activity were smaller than those with p38 activity. In addition, turning off p38 activity diminished the growth of new blood vessels, which cancers rely on for growth and the ability to spread to other parts of the body.
The next phase of the study was to test SB203580—a drug that is known to block p38 activity. As expected, SB203580 reduced the growth of head and neck cancer cells in the lab. After that, the team tested the effects of SB203580 in an animal model of head and neck cancer. Such animal models are used to test the effects of drugs before they are tested in humans, and one way that scientists develop an animal model of human cancer is by transplanting human tumors into mice. When the NIDCR team used the drug SB203580 to treat human head and neck cancers that had been transplanted into lab mice, SB203580 made the cancers smaller.
The next step, Dr. Gutkind says, is to test a new generation of drugs that inhibit p38. His team has developed new mouse models of metastatic oral cancer (cancer that has spread beyond the mouth), and he hopes to demonstrate that preventing the activation of p38 not only diminishes the growth of the oral cancer and the new blood vessels that feed the cancer, but also reduces the cancer’s ability to spread to nearby lymph nodes and spread throughout the body.
Leelahavanichkul K, Amornphimoltham P, Molinolo AA, Basile JR, Koontongkaew S, Gutkind JS. A role for p38 MAPK in head and neck cancer cell growth and tumor-induced angiogenesis and lymphangiogenesis. Mol Oncol. 2014 Feb;8(1):105-18.