Harnessing mutant IDH1 as a therapeutic target in liver cancer and other solid malignancies

Massachusetts General Hospital, Boston MA

Investigators

Abstract

Project Summary This proposal focuses on the treatment of cancers with mutations in the IDH1 gene. These mutations are found in many cancers, with particularly high frequency in types of liver cancer (cholangiocarcinoma) and brain tumor (glioma), both of which are deadly malignancies. Medicines that block mutant IDH1 extend the lives of patients with these cancers. However, patients eventually develop resistance. The objective of our research is to understand how exactly these medicines slow cancer growth and why resistance ultimately arises, and to develop new treatments that combine IDH1 inhibitors with other medicines to prevent resistance and relapse and extend lifespan of patients. Our program builds on exciting discoveries we have made in understanding mutant IDH1 and identifying new treatment strategies that have promise to improve patient outcomes. The treatment of cancers with mutant IDH1 is challenging because mutant IDH1 is a poorly understood cancer gene. Mutations in IDH1 cause cells to produce a metabolite that is not usually present in cells, called 2- hydroxyglutarate (2HG). 2HG interferes with many functions in the cell, but it has been uncertain how 2HG causes cancer growth. Likewise, we know that IDH1 inhibitors reduce 2HG levels in cancer cells, but how this reduction blocks cancer growth has been elusive. In our previous research, we discovered that 2HG causes cancer cells to avoid the immune system, whereas IDH1 inhibitors cause immune cells to attack the kill cancer cells. Here, we will use patient samples to further study this pathway and to identify changes that arise in the tumors when drug resistance arises. The second key component of this proposal involves the use of mouse models and patient cell lines to continue to develop next generation therapies that give further options for patients. We will use sophisticated experimental approaches to test new combination treatments that could reduce the chance resistance will arise or overcome it in cases of recurrence. Overall, we aim to maximize the insights about how mutant IDH1 inhibitors work, develop different combination treatments that we can match to individual patients who are most likely to receive maximum benefit and establish a foundation for future treatments.