Protein Found to Be a Key to Tumor Suppression in Lung Cancer, Possibly Mesothelioma

The protein p53 is one of the body’s most critical defenses in preventing the production of tumors, and if rendered defective, it could lead to uncontrolled tumor growth and metastasis in mesothelioma and other cancers. As a result, p53 protein has been gaining relevance among researchers as the key to killing cancer cells. Now, researchers believe the protein plays an even larger role than previously identified.

Sometimes called the guardian of the genome, p53 normally suppresses tumors by blocking cell growth and triggering programmed cell death or apoptosis. Researchers from the University of Texas MD Anderson Cancer Center also found that the p53 protein “protects an immune attack against lung cancer by blocking the key to an off switch on T cells.”

“Identifying this role for tumor-suppressing p53 provides both a potential biomarker for response to important new cancer immunotherapy drugs and a possible new therapeutic pathway for treatment,” said James Welsh, M.D., associate professor of Radiation Oncology at MD Anderson and senior author of the study, in a Nov. 20 press release announcing the findings.

Cancer grows by evading detection by T-cells, which seek out and kill intruder cells. When cancer disrupts certain immune system signaling pathways, cancer can effectively deactivate T-cells and proliferate freely. However, the key to fighting cancer is to keep the immune system active or to develop immunotherapy drugs that can re-activate the immune system so the body can effectively fight off cancer.

MD Anderson researchers found that p53 helps with this by blocking the PD-L1 protein, or programmed death-ligand 1, that has been shown to play a role in suppressing the immune system during cancer and other diseases. They report that p53 gets help by pulling in miR-34A (miRNA) to block PDL1. miRNAs are tiny molecules found within cells that when functioning properly, a person remains healthy. In addition, when used as therapeutic agents, miRNAs can inhibit tumor growth.

They also found that when p53 is damaged, PD-1 is overexpressed and the cancers grow. The researchers report that the “p53 gene is damaged, missing or under-expressed” in nearly 70 percent of lung cancers, making it “the most common mutation in cancer.”

“The interaction is specific: p53 activates the micro RNA miR-34a, which in turn directly blocks expression of PDL1,” said first author Maria Angelica Cortez, Ph.D., instructor of Experimental Radiation Oncology. “If you lose p53 function, then miR-34a is lost and PDL1 is over-expressed.”

According to one study, PD-L1 is expressed in approximately 20 percent of pleural mesothelioma patients.

This year the U.S. Food and Drug Administration approved pembrolizumab (Keytruda) and nivolumab (Opdivo) for treatment of metastatic lung cancer. Both drugs are PD1-inhibiting drugs. Keytruda has been found to be effective in clinical trials in fighting mesothelioma.

Another drug, MRX34, is under development that encompasses miR-34a in a liposome, according to the article. The drug is in clinical trials for advanced solid tumors, liver cancer and hematological malignancies at MD Anderson and other cancer clinics.

The researchers will now review trials of PD1 inhibitors to assess the status of p53 and miR-34a in patients. They will also determine if other biomarkers impacted the treatments.

The researchers will also combine MRX34 with a PD1 inhibitor to determine if the combination improves tumor response.

Although the research was focused on lung cancer, every new breakthrough in cancer research brings hope to mesothelioma patients. Pleural mesothelioma, an asbestos-caused cancer equally as aggressive as lung cancer, is diagnosed in close to 3,000 Americans each year.

The study can be found in the Journal of the National Cancer Institute.

More articles by Nancy Meredith

Nancy Meredith is a blog and web content writer with more than 20 years of professional experience in the Information Technology industry. She has been writing about Mesothelioma for 7 years. Follow Nancy on Google+