Dana-Farber Science Backs Development of Targeted Therapy for Rare GIST Cancer

Some things are best kept under lock and key, like oncogenes, which are genes that are associated with cancer growth because they signal cells to grow rapidly. They are valuable to certain cells at key moments, such as during early development of organs, but most of the time, cells keep them tucked away using the epigenetic equivalent of an ironclad safe. 

In 2019, the lab of Brad Bernstein, MD, PhD, discovered that the cellular safeguards keeping an oncogene called FGF locked away were being broken in a form of cancer called SDH-deficient gastrointestinal stromal tumor (GIST). The finding inspired Dana-Farber physician-scientist Suzanne George, MD, to design and initiate clinical trials of targeted FGFR inhibitors for patients with SDH-deficient GIST, bringing hope to patients with this rare and difficult-to-treat disease. 

“SDH-deficient GIST is a challenging disease that is very different from the more common KIT-mutant GIST, which has seen a lot of therapeutic advances,” says George, chief of the Division of Sarcoma at Dana-Farber. “It was really exciting for us to understand the biology of this rare cancer and connect it to a potential new treatment.” 

GIST is a type of sarcoma that develops in the gastrointestinal tract and can affect both adults and children. Most GIST tumors are driven by mutations in a cancer-driving gene called KIT and are treated with KIT inhibitors. But 10 to 15% of cases have no mutations in KIT or other oncogenes and therefore have few options for targeted treatments.    

Unraveling a rare disease 

The defining feature of this rare GIST subtype is a deficiency in an enzyme in cells called succinate dehydrogenase (SDH). This deficiency, which can be identified as part of the diagnostic process, is caused by mutations in genes that affect metabolism, which is unusual. Cancer-related mutations tend to affect genes that govern cell growth and proliferation. 

“The SDH-deficiency was really interesting to us because in most tumors you have a mutation of an oncogene that explains the growth of cancer cells, but SDH-deficiency doesn’t provide an explanation for tumor growth,” says Bernstein, who is Chair of Cancer Biology at Dana-Farber. “We wanted to know why the cells were growing so rapidly. Why are they cancer?” 

The team found that this metabolic flaw in cells causes an epigenetic shift that changes which genes are hidden and which are available for use. Normally, the genome uses a specific pattern of methylation, the attachment of chemical markers, to keep certain genetic instructions locked away.  

The SDH-deficiency changes the methylation pattern safeguarding a gene called fibroblastic growth factor (FGF), releasing the lock and turning it into a cancer-driving gene. The finding was surprising because methylation is typically thought to turn off genes, but in this case, the methylation switches them on.  

“This was exciting for us, and exciting for the field because the gene that got switched on was a cancer-causing gene that we knew how to drug,” says Bernstein. 

Bernstein immediately contacted George and her colleagues to get samples of SDH-deficient GIST tumors from patients with the disease. They created a patient-derived tumor model and ran experiments to determine if an FGF receptor (FGFR) inhibitor would slow tumor growth.  

FGFR inhibition suppressed tumor growth for a sustained period. This data provided the kind of evidence George needed to start designing a clinical trial to test this treatment approach in patients.  

“Being right next to our clinical colleagues at Dana-Farber enabled us to move our laboratory findings into human-relevant models immediately,” says Bernstein, who published these findings in Nature. “With this kind of collaborative environment, we’re seeing more examples of a foundational molecular discovery jumping right into the clinic very quickly.” 

 

Bringing discoveries into the clinic 

The science supporting the potential of an FGFR inhibitor to benefit patients with SDH-deficient GIST was strong enough for George to get access to an FGFR inhibitor called rogaratinib for use in a clinical trial. She was also able to initiate the trial through the National Cancer Institute’s Experimental Therapeutics Clinical Trials Network. This network is national, so the trial was offered at multiple sites. 

“This network allowed patients to have access to the study in regions across the U.S., which is what we needed to reach patients with this rare disease,” says George. 

The trial, which enrolled 24 patients, is the largest prospective study done in this patient group to date. Approximately 40% of patients responded to the medicine, and a small number of patients had such long-lasting responses that they are still taking the medicine today. 

“We’re really excited about the durability of these responses,” says George, who published these findings in Nature Medicine. 

Rogaratinib, however, is not being developed further by the pharmaceutical company, so George has designed a new phase 2 trial called PEMIGIST that will offer patients with locally advanced or metastatic SDH-deficient GIST a different drug in the same class, called pemigatinib.  

Pemigatinib is already approved for the treatment of bile duct cancer. This trial is an investigator-initiated trial sponsored by the Gateway for Cancer Research and is open at Dana-Farber and four other sites across the U.S.  

Written by: Beth Dougherty
Medically Reviewed By: Brad Bernstein, MD, PhD