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 laboratory mice.
The preclinical study, published in the reviewed journal Gastroenterology, focuses on a trio of medications that prevented cancer metastasis; the spread of disease to other parts of the body. The preclinical study is also the first to identify synergistic effects of targeting both within the cell and the tumor microenvironment outside the cells.
“These three drugs, used in combination in a laboratory, prevented disease metastasis,” said Arsen Osipov, MD, program manager in the Pancreatic Cancer Multidisciplinary Clinic and Precision Medicine Program at Cedars-Sinai Cancer and a senior and corresponding author of the study. “By focusing on the difficult-to-treat tumor microenvironment, we were able to enhance an immune response while simultaneously attacking cancer cells.”
The three-step combination strategy combined an anti-PD-1 immunotherapeutic antibody and a protein known as FAKi with a new pathway called CXCR4. This combination destroyed the external microenvironment of the tumor, attacked the tumor itself, and strengthened the immune system of the laboratory mice.
“The combination therapy prevented disease metastasis and prolonged 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 very low survival rates.”
The tumor microenvironment in pancreatic duct adenocarcinoma – the most common form of pancreatic cancer – has long been resistant to therapies, including immunotherapy.
Pancreatic tumors tend to be aggressive and often become resistant to traditional treatments such as chemotherapy. While immunotherapies have proven successful in many other forms of cancer – such as melanoma and lung cancer – benefits have been limited in pancreatic cancer.
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 in 2022. And, by the year 2030, pancreatic cancer is expected to become the second leading cause of cancer-related death in the United States.
“Our teams of researchers are exploring new methods to target the tumor microenvironment with the hope of improving survival and treatment choices for patients,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Foundation Distinguished Chair. “This pioneering research study emphasizes how simultaneously targeting both intracellular and extracellular components of the microenvironment can enhance an immunotherapeutic response.”
As a next step, Osipov and 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 provided by Verastem Oncology; PEGPH20 was provided by Halozyme; and an anti-CXCR4 antibody provided by Bristol Myers Squibb via 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 NIH T32 CA126607 grant. AO is supported by NIH grant K08 CA259456 and Conquer Cancer Foundation’s ASCO Career Development Award. LZ is supported by NIH Scholarship R01 CA169702, NIH Scholarship R01 CA197296, NIH Scholarship P01CA247886, NIH SPORE Scholarship P50 CA062924, and NIH Cancer Center Support Grant P30 CA006973.
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