Dramatic progress has been made in cancer therapy with genetically targeted kinase inhibitors. These agents have revolutionized the treatment of lung cancer and melanoma as well as certain leukemias and sarcomas. Activating mutations occur in members of the fibroblast growth factor receptor (FGFR) family in multiple cancers including those of the lung, liver, stomach, brain, breast, and bladder. Until recently, there has only been limited success with FGFR inhibitors. However, a recent clinical trial in cholangiocarcinoma, a type of liver cancer, showed dramatic benefit for most patients treated. Indeed, such responses are unprecedented with any prior therapy for cholangiocarcinoma, which ranks among the most deadly of all cancers.

Studying FGFR inhibition in cholangiocarcinoma provides us with an opportunity to not only understand why these patients have benefited, but also why other patients may not and how to change treatment to help them more. The one aspect of cholangiocarcinoma that we believe has supported the treatment response is near universal activation of FGFR by genetic fusion events, where a second gene is fused to the FGFR, creating a single protein with parts of two distinct genes. These fusions have also predicted response to FGFR inhibition in other tumor types. However, we also suspect that the specific characteristics of cholangiocarcinoma, including common co-mutations and the specific requirements of biliary cells for growth may contribute.

We plan to pursue our analysis in three areas. First, we will perform a detailed study of the biochemical signaling that results from different types of FGFR mutations and how they respond to therapy. Next, we will model FGFR-driven biliary cancers in mice and analyze the biology of these tumors and their response to therapy. Finally, we will use patient samples derived from several ongoing and recently completed studies of FGFR inhibition in cholangiocarcinoma to understand drug resistance and look for new ways to reverse it.

We believe that we are uniquely positioned to unlock the current challenges in targeting FGFR-driven tumor growth for a number of cancers. We have already made major progress in identifying genetic mutations that causes the recurrence of tumors in patients whose tumors initially underwent dramatically shrinkage. Additionally, we have developed multiple model systems that allow us to rapidly develop and test improved treatment strategies. With a co-Principal Investigator who is involved in the design of new clinical trials for biliary tract cancers, we anticipate that our results will be actionable within the next 3-5 years. We also anticipate that one or several FGFR inhibitors will be approved for use in patients with cholangiocarcinoma during this time and that our findings will influence the way that these agents are used.

Combining cholangiocarcinoma with the other cancers with FGFR mutations, more than 1 in 20 cancer patients has a tumor with an FGFR mutation. These include a number of tumors that are particularly relevant to patients with Agent Orange and radiation exposures. In addition, the increased rates of hepatitis C infection and liver fluke exposure in Vietnam makes biliary tract tumors an important Veteran’s health issue; cholangiocarcinoma is also increased individuals with increased alcohol use and associated liver cirrhosis. Improving outcomes for this cancer would have a dramatic effect for Veterans and their families.