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Ziv Gil, MD, PhD

Applied Cancer Research Laboratory at Rambam

Ziv Gil, MD, PhD M.D., Ph.D.

Applied Cancer Research Laboratory at Rambam

Cutting-edge research by investigators at the Rambam Medical Center in Haifa, Israel, is pointing towards development of new treatment for pancreatic cancer, one of the most deadly and difficult cancers to manage successfully. In contrast with other cancers that have seen a reduction in incidence thanks to therapeutic advances and early detection and awareness campaigns, rates of pancreatic cancer have been slowly going up over the past 10 years. The American Cancer Society estimates that about 45,220 new cases will be diagnosed in the United States in 2013 and about 38,460 people will die from the disease this year. Lifetime risk of having pancreatic cancer is about one in 78.

The poor prognosis for many patients is often associated with nerve invasion, a form of direct spread of cancer, which occurs in more than 80% of patients with pancreatic cancer. Because the cancer is distributed along nerves, it cannot be treated at a specific site, and patients receive only palliative care to alleviate painful symptoms. The research team, led by Ziv Gil, MD, PhD, Head of the Applied Cancer Research Laboratory at Rambam, is investigating the mechanism that triggers nerve invasion in pancreatic cancer and identifying specific targets for drugs that can effectively reduce it. 

“Treatment directed against nerve invasion could prevent cancer spread, prolong survival, and reduce morbidity,” said Gil. The research is funded by a grant from the Israel Cancer Research Fund (ICRF), an international charitable organization founded in 1975 by a group of American and Canadian researchers, oncologists, and lay people. ICRF is the largest U.S.-based charity solely devoted to supporting cancer research in Israel and receives its total income from private donations.

“Treatment directed against nerve invasion could prevent cancer spread, prolong survival and reduce morbidity…Our long-term goal is to understand the mechanism that triggers progression of pancreatic cancer and to develop the means to inhibit it.”

Ziv Gil, MD, PhD

Experiments performed during the first part of the research suggest the existence of a link between tumor-infiltrating macrophages (large white blood cells that reside in tissue and bone marrow) and pancreatic cancer cells, which contributes to nerve invasion. Tumor-associated macrophages secrete proteins that in turn trigger secretion of a strong growth factor that stimulates the increase and spread of cancer cells. Normal macrophages, however, play an important part in the body’s immune system. The experiments conducted by Gil and his team showed that macrophages located in the endoneurium (the innermost connective tissue that surrounds individual nerve fibres in a bundle) act as a first line of defense in response to nerve injury and inflammation – until they are overrun by blood-borne, tumor-associated macrophages originating in bone marrow.

Based on their findings, the research team developed a central hypothesis that endoneurial macrophages “play a key role in the progression and dissemination” of pancreatic cancer, said Gil. Although there has been intensive investigation on the role of tumor-associated macrophages in other cancer types, this is the first time it has been explored specifically with regard to nerve invasion in pancreatic cancer.  “Our long-term goal is to understand the mechanism that triggers progression of pancreatic cancer and to develop the means to inhibit it,” he explained. 

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