Preclinical Study: Three Step Treatment Strat

Research led by researchers at Cedars-Sinai Cancer and Johns Hopkins University has discovered a new three-step treatment that disrupts the pancreatic tumor microenvironment in lab mice.

The preclinical study, published in the peer-reviewed journal Gastroenterology, focuses on three drugs that prevent cancer metastases; the spread of disease to other parts of the body. The preclinical study is also the first to identify synergistic effects both within the cell and on the tumor microenvironment outside the cells.

“These three drugs, used in combination in a lab setting, prevented disease metastasis,” says Arsen Osipov, MD, program leader in the Pancreatic Cancer Multidisciplinary Clinic and Precision Medicine Program at Cedars-Sinai Cancer and senior and corresponding author of the study. “By focusing on the difficult-to-treat tumor microenvironment, we were able to amplify an immune response while attacking cancer cells.”

The three-step combinatorial strategy combined an anti-PD-1 immunotherapy antibody and a protein known as FAKi with a novel pathway called CXCR4. This combination destroyed the outer microenvironment of the tumor, attacking the tumor itself and boosting the immune system of the lab mice.

“The combined therapy prevented disease metastases and extended life,” said Osipov, also a medical oncologist and researcher in the Gastrointestinal Research Group at the Samuel Oschin Cancer Center. “This is an important step for a disease that is extremely difficult to treat and has a very low survival rate.”

The tumor microenvironment in pancreatic ductal adenocarcinoma – the most common form of pancreatic cancer – has long been resistant to therapies, including immunotherapy.

Pancreatic tumors are often aggressive and often become resistant to traditional treatments such as chemotherapy. While immune therapies have been successful in many other cancers, such as melanoma and lung cancer, the benefits in pancreatic cancer are limited.

This difficulty in treating the disease has made pancreatic cancer one of the deadliest cancers, with a five-year survival rate of just 11%.

More than 62,000 Americans are expected to be diagnosed with pancreatic cancer by 2022. And by 2030, pancreatic cancer is projected to become the second leading cause of cancer death in the United States.

“Our teams of researchers are exploring new approaches to targeting the tumor microenvironment in hopes of improving patient survival and treatment options,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Foundation Distinguished Chair. “This innovative research study highlights how simultaneously targeting both intracellular and extracellular components of the microenvironment can enhance an immune therapy response.”

As a next step, Osipov and his team plan to develop a clinical trial to further explore the treatment potential of the CXCR4 pathway.

Funding: This work was supported in part by a research grant from Halozyme, independent of Verastem Oncology and Bristol Myers Squibb, and an NIH P01 grant P01CA247886. VS-4718 was supplied by Verastem Oncology; PEGPH20 was supplied by Halozyme; and anti-CXCR4 antibody provided by Bristol Myers Squibb through the II-ON program, all independently. The views expressed in this article are those of the authors and do not necessarily represent those of Verastem Oncology, Halozyme or Bristol Myers Squibb. AB is supported by an NIH T32 CA126607 grant. AO is supported by an NIH grant K08 CA259456 and a Conquer Cancer Foundation ASCO Career Development Award. LZ is supported by an NIH grant R01 CA169702, an NIH grant R01 CA197296, an NIH grant P01CA247886, an NIH SPORE grant P50 CA062924, and an NIH Cancer Center Support Grant P30 CA006973.

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