Defining Signaling Pathways and Effective Combination Therapy to Improve Outcomes for Patients with FGFR2-Driven Biliary Cancer
Abstract
Liver cancers, including cholangiocarcinomas and hepatocellular carcinomas, are among the deadliest types of human cancer and have been rising in incidence. Cholangiocarcinomas have particularly poor outcomes. Most patients are diagnosed too late to receive surgery and are treated with chemotherapy that provides only limited benefit. An important advance over the last few years has emerged from the discovery that genetic alterations of the fibroblast growth factor receptor 2 (FGFR2) are present in approximately 20% of cholangiocarcinomas. FGFR2 is a type of enzyme called a kinase, whose function can be blocked with drugs called FGFR kinase inhibitors (FGFRi). Notably, clinical trials with FGFRi have provided unprecedented benefit for this subset of patients, leading to the Food and Drug Administration approval of two of them, infigratinib and pemigatinib. While the approval of FGFRi is a major step forward for the treatment of patients with FGFR2-driven cholangiocarcinoma, we still need to do much better to truly transform the outcomes for these patients. Unfortunately, not all patients respond to FGFRi, and those who do inevitably develop resistance. There are presently no other effective options for these patients. We have assembled at team who have a long-standing commitment to the problem and have made important contributions to the field. The team leadership includes an investigator who led the development of infigratinib. Other team members have provided key insights into how resistance to FGFRi develops and why not all patients respond. By analyzing patient samples and using cancer model systems we have developed, we have defined three major processes that are responsible for resistance. These include mutations in FGFR2 itself that prevent FGFRi from working effectively. Another process involves mutations in other genes that can substitute for FGFR2. Finally, our data indicate that resistance in other patients is due to so-called adaptive signaling, or feedback, where inhibiting FGFR turns on other biochemical pathways that protect the cancer cell. We also find that feedback processes are an important cause for the lack of response to FGFR inhibition. Our project aims to build on these insights to comprehensively develop improved therapies to FGFR2-altered cholangiocarcinoma. We will investigate therapies addressing each form of resistance we have identified. We will study outcome data and samples from a series of clinical trials that have recently begun or that will open in the next year, including trials that test next-generation FGFR inhibitors that are designed to overcome secondary mutations in FGFR2. Another new clinical trial will combine an FGFR inhibitor with an inhibitor of a second kinase (EGFR), based on laboratory findings showing that the combination is much more effective against killing cholangiocarcinoma cells than treatment with an FGFR inhibitor alone, due to overcoming adaptive signaling. To truly transform the outcomes of patients with cholangiocarcinoma, it will likely be necessary to employ multiple treatments. We will employ our model systems and new technologies to seek to develop additional new treatment strategies that can be tested in clinical trials in later years of the grant period. These include studies of a new type of antibodies targeting FGFR2 that can substitute for conventional FGFRi and have reduced toxicity. These antibodies may also help conventional FGFRi work better. We will also use an innovative genetic screening method that will comprehensively define which proteins are essential for the survival of FGFR2-altered cholangiocarcinomas and could thus be good drug targets. Finally, we will explore how FGFR2 inhibition affects the ability of the immune system to effectively attack these tumors and use this information to define optimal ways that immunotherapy can be incorporated into the treatment of these patients. More than 1 in 20 of all cancer patients has an FGFR-a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210345
Entities
People
- William R Sellers
Organizations
- Broad Institute
- United States Army