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Deeper insights at the cellular level are helping to lead lung cancer investigators toward new pathways to stop the growth of tumor cells—giving rise to new treatment possibilities for previously intractable cancers.

NFS1 Protein Protects Lung Cancer Cells

A recent study in Nature demonstrated that blocking the action of a key protein—NFS1—permits oxygen to damage a class of iron-dependent proteins in lung and breast cancer cells, slowing their growth and sensitizing them to oxidative cell death.

Human cells are known to contain 48 proteins that depend on complexes of iron and sulfur to function. These iron–sulfur clusters are dismantled when they encounter oxygen. In high-oxygen environments like the lungs, researchers say that these iron–sulfur clusters must be constantly replaced to sustain normal cell function. This replacement demand increases under abnormal cell growth.

The current study shows that lung adenocarcinoma cells survive high oxygen levels by producing more NFS1, which harvests sulfur from cysteine to make iron–sulfur clusters. The researchers also found that breast cancer cells that have spread to the lungs increase NFS1 production upon arriving in a high-oxygen environment, while cells remaining in the breast do not.

When the investigators injected cancer cells with blocked NFS1 function in the lungs of mice, they failed to form tumors. Consistent with these findings in mice, analysis of human datasets revealed that NFS1 levels were higher in lung adenocarcinoma cells than in nearby, normal lung tissue.

“Our data support the notion that NFS1 provides a central protection for cancer cells against oxygen, and we hope to take that protection away,” says lead study author , assistant professor of pathology.

As a next step, the research team is screening for experimental compounds that block the ability of NFS1 to feed the production of iron–sulfur clusters.

Combination of Pembrolizumab and Chemotherapy Doubles Survival in Lung Cancer Patients

An international phase III clinical trial led by Perlmutter Cancer Center showed that the immunotherapy drug pembrolizumab (Keytruda^®), when combined with chemotherapy, doubles the chances of survival in patients with non-squamous non-small cell lung cancer (NSNSCLC). These results were presented at the American Association for Cancer Research in April 2018 and simultaneously published online in the New England Journal of Medicine.

A total of 616 patients with untreated metastatic NSNSCLC without EGFR or ALK mutations, from nearly 120 international sites, were randomized—405 patients were treated with both pembrolizumab and platinum therapy plus pemetrexed, and 202 patients received platinum therapy plus pemetrexed with a placebo.

Response rates, overall survival, and progression-free survival were superior in the pembrolizumab and chemotherapy combination treatment group.

Of those treated with pembrolizumab and platinum plus pemetrexed, the risk of death was reduced by 51 percent, compared with those treated with platinum plus pemetrexed alone. Among patients treated with the combination therapy, the chance of progression or death was reduced by 48 percent. In other words, chance of overall and progression-free survival doubled.

“For some groups of patients with non-small cell lung cancer (NSCLC), chemotherapy has been the standard treatment for more than 30 years,” says Leena Gandhi, MD, PhD, the study’s lead author. “But for patients with non-squamous NSCLC without EGFR or ALK alterations, this study may suggest a new standard of care.”

Pembrolizumab in combination with chemotherapy is now approved by the Food and Drug Administration to treat metastatic NSCLC as a result of a previous phase II trial on which Dr. Gandhi was one of the lead investigators.