Lung Cancer Discovery

Researchers with The University of Texas MD Anderson Cancer Center have uncovered new information on the regulation of programmed death-ligand 1 (PD-L1) and its role in the most common form of lung cancer. Details about how PD-L1, a protein that allows cancer to elude the disease-fighting immune system, is regulated by the tumor suppressor gene p53 show therapeutic promise in the treatment of non-small cell lung cancer (NSCLC).

The team uncovered a mechanism showing that p53 activates miR-34a microRNA to regulate the PD-L1. According to James Welsh, MD, associate professor of radiation oncology at MD Anderson, and the study’s lead investigator, p53 is the most mutated or abnormal gene found in cancer.

“The vast majority of solid tumors have abnormal signaling,” he said. “Often referred to as the guardian of the genome, p53 can get lost, leading to chaos in the cancer cell. This allows many new mutations to develop which can make the cancer more aggressive.”

Elusive Cells
Welsh and his fellow investigators found that when lost, p53 leads to an increase in PD-L1, thereby allowing the cancer cells to hide from the immune system. The team presented the study data at the 2015 American Association for Cancer Research (AACR) Annual Meeting in Philadelphia on April 20.

According to Maria Angelica Cortez, PhD, instructor of experimental radiation oncology at MD Anderson, the findings suggest that tumors with p53 mutation, found in about 50% of the patients, might correlate with enhanced response to PD-L1 inhibitors compared to patients without this mutation.

The tumor suppressor protein p53 protects normal cells from cancer formation, according to Cortez. “PD-L1 helps cancer cells to evade the immune system, and although clinical studies have shown promise for targeting PDL1 signaling in non-small cell lung cancer, little is known about the regulation of PD-L1 expression,” Cortez shared.

The investigators were in search of new ways to treat cancer and launched the study to help their patients who suffer from NSCLC. The most common type of lung cancer, NSCLC comprises about 85% to 90% of lung cancer cases. Lung cancer is the leading cancer killer in both men and women in the United States.

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NSCLC is classified into three types: adenocarcinomas, often found in an outer area of the lung; squamous cell carcinomas, usually found in the center of the lung next to a bronchus; and large cell carcinomas, which can occur in any part of the lung. Of the three subtypes, large cell carcinomas tend to grow and spread at the greatest speed.

The findings are important to future NSCLC treatments, Welsh explained, because p53 is commonly abnormal in patients with NSCLC. “The solid tumor kills more patients than any other solid tumor,” he said. “We are also looking for biomarkers in NSCLC to let us know who pdl1 works in, and p53 might help us with that.”

Signaling Pathways
The team’s interpretation of the mechanics behind the signaling pathways may open up new therapy options for patients. The study investigators are looking into how their findings might be applied to existing treatments. In general, they believe current therapies that inhibit PD-L1 do not always work properly.

“Protein inhibition therapy holds promise for treatment of NSCLC.”

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The mouse study found that MRX34, an investigational drug, increased the immune system’s CD8 cells when combined with radiotherapy. “Our results suggest that miR-34a delivery combined with standard therapies, such as radiotherapy, may represent a novel therapeutic approach for lung cancer,” said Cortez.

MRX34, a compound that delivers miR-34a in tumors, is currently being tested in patients with liver cancer at MD Anderson, according to Cortez. MD Anderson has launched a Phase I study of the micro ribonucleic acid (microRNA) MRX34 in patients with primary liver cancer or those with liver metastasis from other cancers.

In the clinical trial, the drug is administered intravenously, twice per week for three weeks in a row and then one week off. Additionally, patients with hematologic malignancies will be evaluated on a treatment schedule of five days in a row with two weeks off.

Rebecca Mayer Knutsen is a staff writer. Contact:

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