1. Brophy Marcus, Mary

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A novel approach for fighting small cell lung cancer (SCLC), an aggressive disease with high recurrence rates, significantly reduced tumors in preclinical research, noted the authors of a new study. In mouse models, scientists used a cocktail of immune checkpoint blockade along with targeted therapies that block normal DNA damage repair (DDR) to shrink SCLC tumors.

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The researchers from The University of Texas MD Anderson Cancer Center published their findings in Cancer Discovery (2019; doi:10.1158/2159-8290.CD-18-1020). Their work, says author Lauren Averett Byers, MD, suggests that the PARP inhibitor olaparib and checkpoint kinase 1, an inhibitor of another DDR protein, increased protein and surface expression of PD-L1.


The result was a rapid immune response-the SCLC cells responded to immunotherapy, stated Byers, Associate Professor in the Department of Thoracic Head and Neck Medical Oncology at MD Anderson Cancer Center.


In the U.S. more people die from lung cancer than any other type of cancer, according to the CDC. About 10-15 percent have SCLC.


"Small cell lung cancer is one of the most aggressive forms of cancer and even though it initially responds to chemotherapy or radiation, patients rapidly relapse. Our treatments, once the cancer occurs, have really been limited. This is a disease that, despite a lot of efforts over recent decades, has seen very little progress," Byers said, noting that the average survival in patients with metastatic disease is about 1 year.


Even with the recent use of immunotherapy to treat SCLC in combination with chemotherapy, Byers said the benefit of immunotherapy has still been pretty modest. SCLC is tricky-it ducks the immune system very effectively, she explained.


So, Byers and colleagues have been studying ways to "further enhance the response" to immunotherapy.


Therapeutic Targets

"A few years ago, we identified new therapeutic targets we thought were really promising. This included many proteins such as PARP. We've shown in my lab that PARP inhibitors and other targeted therapies that inhibit the DNA repair proteins have anti-cancer activity in small cell lung cancer models," she said.


They hypothesized that if they combined PARP or CHK1 inhibitors-drugs that cause DNA damage-with immune therapies, that the response to the immune therapy would improve, and in fact, when they tested their theory in mouse models of SCLC, the tumors shrunk significantly.


"Using either a PARP inhibitor or a CHK1 inhibitor, we saw really dramatic and pretty quick tumor regression when we combined those drugs with the anti PD-L1 agent. Many of the animals we treated had complete responses. They became undetectable by the end of the experiment. We were really excited by that. We went back and tested additional models and saw similar responses in those," Byers said.


The response was fast, she said, noting that the PARP inhibitor and immunotherapy combo led to a complete regression of tumors in all treated mice in a week. The CHK1 and immunotherapy treatment led to total regression in 60 percent of the mice that received it.


The DDR inhibitors created an immune response in the mice, that caused an increase in cancer-killing immune cells in the tumors, Byers said.


"It was responding to the STING pathway," she explained. "Our cells have to be good at detecting infections. One way they do that is by looking for certain types of little bits of DNA that might be from a virus or bacteria and stimulating the innate immune system."


She said the STING pathway responded to DNA damage to activate the immune system, making SCLC cells responsive to immunotherapy treatment. "After we understood the mechanism, it made sense.


"We recognize mice are not people," Byers added, so the next step is to see how the combination therapy works in humans with SCLC.


Duke medical oncologist Neal Ready, MD, PhD, Professor of Medicine at Duke University School of Medicine, said it's noteworthy research but still early in the research process.


"These studies are interesting and they justify studying those combinations in humans, but we wouldn't draw any direct inferences from the [animal] studies. We wouldn't look at the mouse studies and assume the combinations would work in humans," Ready said, noting that researchers have yet to find a molecular target in SCLC that would enable scientists to create a targeted, personalized therapy for this form of lung cancer.


He said of the new findings, "It's very interesting data and I think people in the field think that it justifies carrying on with this line of research."


"We're excited and hope this can be taken right away into clinical trials," Byers said. "We know a lot of patients are not getting much benefit or are getting limited benefit from immunotherapy and we think this will be the next step in how to build on that and get more patients responding to treatment."


Mary Brophy Marcus is a contributing writer.