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Lung cancer study reveals new drug combination targets

Sep. 4, 2014, 9:33 AM

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A Vanderbilt lung cancer patient’s exceptional response to different types of therapies spurred research that suggests lung cancer patients with specific gene alterations may benefit from combination therapy that targets two different cancer pathways.

The study, led by Christine Lovly, M.D., Ph.D., assistant professor of Medicine and Cancer Biology, was published online this week in Nature Medicine.

Christine Lovly, M.D., Ph.D.

The work was based on an intriguing clinical observation of a female patient with advanced lung cancer who had an unexpected response to a monoclonal antibody that targets the insulin-like growth factor receptor (IGF-1R). IGF-1R helps cancer cells survive and evade anti-cancer therapies.

Remarkably, the patient remained on the IGF-1R therapy for 17 months — far longer than any other patient on the clinical trial. The Vanderbilt researchers, led by Lovly, became interested in why this particular patient’s tumor responded to the experimental therapy so dramatically. Investigators decided to test for gene mutations and found an unexpected result — the patient’s tumor was positive for an ALK gene fusion. Only about 5 percent of lung cancer patients have this gene fusion in their tumor.

ALK kinase gene fusions in lung cancer were discovered after the patient enrolled on the IGF-1R study. So there was no reason to think in advance that a patient with ALK+ lung cancer would benefit from this experimental therapy, since ALK gene fusions in lung cancer had not even been discovered when the trial was initially conceived,” Lovly said.

“Since this patient had such a dramatic and unexpected response to the IGF-1R directed therapy, and was later noted to have an ALK gene fusion in her tumor, we became interested in understanding the potential interplay between ALK and IGF-1R to try to explain this patient’s exceptional response to the IGF-1R inhibitor.”

With this new information, the patient was enrolled in another clinical trial testing crizotinib, a drug that targets ALK rearrangements, and her cancer stopped progressing for several more months.

This patient’s surprising response to different forms of therapy sparked a new line of research to identify and explain the biological mechanisms at work. Lovly and colleagues from medical centers in the United States, Germany and Australia tested the ability of IGF-1R inhibitor therapies alone or in combination with ALK inhibitors to impede the growth of ALK+ lung cancer and to overcome acquired resistance to ALK inhibitor therapies.

Working in cell lines, mouse models and patient lung tumor cells, they tested the two types of drugs and found that the combination therapy enhanced the ability to slow down the growth of ALK+ lung cancer cells. They found similar results in cell lines from ALK+ lymphoma, a different form of cancer harboring the same tumor genetic alteration.

“When used in combination, the IGF-1R inhibitor and an ALK inhibitor appear to work cooperatively to interfere with cell growth in ALK+ lung cancer cells,” Lovly said.

“We need better tools to treat diseases like lung cancer that traditionally have been resistant to therapy, and increasingly, we are finding that combination therapies may be necessary to improve outcomes for our patients. The activity of this new combination therapy is encouraging.”

Lovly said the study also stresses the need to further evaluate the ‘outlier responders’ — patients who have much better or much worse responses to different therapeutic regimens than initially anticipated.

“This type of analysis, as employed here, will help us move the field forward,” said Lovly.

Other Vanderbilt investigators participating in the study include William Pao, M.D., Ph.D., Heidi Chen, Ph.D., Yingjun Yan, M.S., Xi Chen, Ph.D., Pengcheng Lu, M.S., Hailing Jin, M.S., Monica Red-Brewer, Ph.D., Qingguo Wang, Ph.D., Zhongming Zhao, Ph.D., and Leora Horn, M.D.

Other collaborators on the study include scientists and physicians from the University of Cologne, Germany; Memorial Sloan Kettering Cancer Center, New York; Dana-Farber Cancer Institute, Boston; Peter MacCallum Cancer Center and University of Melbourne, Australia.

Support for the study includes funding from the National Cancer Institute, a division of the National Institutes of Health (P30-CA68485, CA90949), R01CA121210, P01CA129243, K12 CA9060625, CA122794, CA140594, CA163896, CA166480, CA154303, and R01LM011177).

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