Most gastrointestinal stromal tumors (GISTs), a type of connective tissue cancer, respond to therapies that target the mutated enzymes driving their growth. But 10% to 20% of such tumors have no driver mutations in their genome. Researchers led by Ludwig Harvard Co-director George Demetri and investigator Bradley Bernstein have identified what drives these cancers and shown, in preclinical studies, how they might be treated. Their findings reveal how epigenetic changes—chemical modifications to DNA and its protein packaging that alter how genes are read, not abnormalities in the gene sequences themselves—can lead to the development of GISTs and other cancers. An epigenetic abnormality dismantles an element of chromosomal structure (an insulator) that prevents a cancer-promoting growth factor gene, FGF4, from contacting a stretch of DNA that serves as an “on” switch for gene expression. The researchers also showed how another epigenetic abnormality similarly causes aberrant contacts between an on-switch and the KIT gene that is activated by somatic mutations in the majority of GIST patients. They demonstrated that human GISTs growing as patient-derived xenografts in mice could be suppressed with FGF receptor inhibitors, either alone or in combination with a standard kinase inhibitor therapy for GIST called sunitinib. The work was published in October in Nature.
This article appeared in the April 2020 issue of Ludwig Link. Click here to download a PDF (1 MB).