Despite advances in cancer treatment, tumors of the pancreas remain among the most difficult to treat. To date, pancreatic cancers remain largely resistant to immune-based therapies, despite the successes of immunotherapies in treating lung cancers and melanomas.
A new study from Washington University School of Medicine in St. Louis that was published in the journal Nature Medicine, has shown that immunotherapy against pancreatic cancer can shrink these tumors if they are given in combination with drugs that break up the fibrous scar tissue in these tumors.
Physicians at Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital are using the strength of these data to conduct a phase 1 clinical trial in patients with advanced pancreatic cancer. This clinical trial will test the safety of this drug combination when given alongside standard chemotherapy.
“Pancreatic tumors are notoriously unresponsive to both conventional chemotherapy and newer forms of immunotherapeutics,” said senior author David G. DeNardo, PhD, an assistant professor of medicine. “We suspect that the fibrous environment of the tumor that is typical of pancreatic cancer may be responsible for the poor response to immune therapies that have been effective in other types of cancer.”
Pancreatic cancers are unusual among cancers since they characteristically consist of large swaths of scar tissue. These balls of fibrous tissue that surround the tumor create a protective environment for cancer cells. These scar tissue-based capsules prevent the immune system accessing the tumor cells and also limit the exposure of these tumors to chemotherapies that have been administered through the bloodstream. DeNardo and his colleagues used a mouse model of pancreatic cancer to determine if disrupting these fibrous capsules could sensitize pancreatic tumors to chemotherapy regimens.
“Proteins called focal adhesion kinases are known to be involved in the formation of fibrous tissue in many diseases, not just cancer,” DeNardo said. “So we hypothesized that blocking this pathway might diminish fibrosis and immunosuppression in pancreatic cancer.”
Focal adhesion kinase (FAK) is a protein (encoded by the PTKs gene) that controls cell adhesion and cell motility. Inhibiting FAK activity in breast cancer cells makes them less likely to spread to other organs (see Chan, K.T., et al. 2009. J. Cell Biol. doi:10.1083/jcb.200809110). Small molecules have been designed that can readily inhibit FAK, and DeNardo and his colleagues used FAK inhibitors against pancreatic cancer in combination with immunotherapy.
In their mouse study, an investigational FAK inhibitor was administered to mice in combination with a clinically approved immune therapy that activates the patient’s own T-cells so that they can effectively attack tumor cells.
Mice that had pancreatic cancer survived no longer than two months when given either a FAK inhibitor or immune therapy alone. If the FAK inhibitors were added to standard chemotherapy, the tumor response improved over chemotherapy alone. However, the three-drug combination that consisted of FAK inhibitors, immune therapy and chemotherapy, displayed the best outcomes in laboratory studies and more than tripled survival times in some mice. Some were still alive without evidence of progressing disease at six months after treatment and beyond.
The success of this mouse study provided a strong rationale for testing this drug combination in patients with advanced pancreatic cancer, according to oncologist Andrea Wang-Gillam, MD, PhD, an associate professor of medicine, who was involved with this research.
“This trial is one of about a dozen we are conducting specifically for pancreatic cancer at Washington University,” she said. “We hope to improve outcomes for these patients, especially since survival with metastatic pancreatic cancer is typically only six months to a year. The advantage of our three-pronged approach is that we are attacking the cancer in multiple ways, breaking up the fibers of the tumor microenvironment so that more immune cells and more of the chemotherapy drug can attack the tumor.”