In 2013, the Life Raft Group (LRG), a nonprofit organization for people with gastrointestinal stromal tumor (GIST), launched its Rare 13 campaign, which soon led to the designation of July 13 as GIST Awareness Day.
Ten years later, that campaign is still going strong, with advocates holding out hope that a cancer long resistant to treatment—including a particularly rare form of it—may soon become curable.
“July is Sarcoma Awareness Month, and 5000 patients are diagnosed each year in the US. If you calculate that, it comes to about 13 people per day, which is why we chose July 13,” explained Sara Rothschild, executive director of the LRG, based in Wayne, New Jersey.
To mark the occasion, LRG plans a July 13 educational webinar updating patients, caregivers, and healthcare professionals on the latest GIST research.
The online event features British clinical oncologist Ramesh Bulusu, MD, who heads the medical advisory board at GIST Cancer UK; John W. Glod, MD, PhD, an associate research physician at the pediatric oncology branch of the National Cancer Institute, a division of the National Institutes of Health (NIH); and Jason K. Sicklick, MD, an internationally recognized surgical oncologist at University of California San Diego Health.
A Rare Form of a Rare Cancer
The disease generally strikes people over the age of 50, though 10% of GIST patients have the succinate dehydrogenase (SDH)-deficient form of the disease, which usually affects people in their teens, 20s, and 30s.
“Dr. Sicklick is doing a lot of great research in the field of GIST, but specifically SDH-deficient GIST patients,” Rothschild said. “He’s created the first-ever SDH-deficient GIST cell lines. Nobody has been able to accomplish that before.”
LRG, which maintains one of the largest known registries of patients with SDH-deficient GIST, has long partnered with the Connective Tissue Oncology Society (CTOS), a nonprofit professional medical association whose members specialize in the treatment of sarcomas.
“What we set out to do with this consortium is break down the silos and share data and tissue,” Rothschild said. “Thanks to these efforts, at least 7 clinical trials have been initiated since the beginning, which is more than there’s ever been. We are showing the impact of bringing people together—and bringing research, studies, and drugs to the patients who need them.”
Dr. Glod said the study of rare diseases such as SDH-deficient GIST is quite difficult.
“In order to advance our understanding of these diseases and ultimately improve the care of people with SDH-deficient GIST, it’s critical that basic researchers, clinicians, and patients and their advocates all work together,” he said in an emailed statement.
“By collaborating with investigators throughout the country and patient advocacy groups, it is possible to learn about the natural history of rare cancers, understand the basic biology of SDH-deficient GIST, and begin to develop and test new therapies.”
Added Dr. Bulusu: “Not many physicians are aware of the complexity of managing these rare cancers. Our focus is to share expertise among the US, UK, and Europe to find better treatments for the rare subgroup of GISTs called SDH-deficient GISTS. Our international SDH-deficient GIST consortium is an example of collaboration among specialists from all over the world.”
Discoveries and Ongoing Trials Provide Hope
The current 5-year relative survival rate for GIST is 83%, though that varies from a high of 93% for patients with localized GIST, down to 55% if the GIST has spread to distant locations. It’s slightly more prevalent among males than females, and somewhat more likely to affect African Americans and Asian Pacific Islanders than Caucasians.
The disease, while still extremely rare, is likely more common than most experts realize, Dr. Sicklick said.
“There have been studies out of Europe looking at people over 50. In these studies of autopsies, what they actually found was about 1 in every 6 patients had a very tiny microscopic-size GIST in their stomach,” he told Rare Disease Advisor.
“This basically suggests that they’re almost like little tiny polyps, if you will, in the wall of our stomach that are just underappreciated. The majority of them are never going to become big tumors and cause problems but [are] probably more common than we all give credit to.”
Patients with SDH-deficient GIST have a genetic mutation that metabolizes sugar or glucose, he said.
“What happens is there’s defective metabolism of glucose in the cells. This ultimately, through a number of different steps and processes, leads to tumor formation,” Dr. Sicklick explained. “Several years ago, we identified that temozolomide was working to kill GIST cell lines that we had developed in our laboratory. We went on to basically run a clinical trial—which we have just completed—of temozolomide as a single agent in patients with SDH‑deficient GIST.”
The results of that trial will be presented later this year at the CTOS 2023 Annual Meeting, set for November 1-4, 2023, in Dublin, Ireland.
Following up on that study, Dr. Sicklick and his team found that temozolomide induces expression of a protein called death receptor 5 (DR5), which causes cells to undergo apoptosis, or programmed cell death. INBRX-109 activates DR5, so a second clinical trial is now set to look at a combination of temozolomide and INBRX-109.
This phase 1 trial, now open across 15 US sites, involves 6-9 patients in 2 dosing cohorts. A planned phase 2 trial will involve an additional 23 patients to establish safety and efficacy, while a third trial is enrolling patients to test rogaratinib as a potential therapy for SDH-deficient GIST.
“It’s an exciting time in the GIST field,” said Dr. Sicklick, noting that for years, researchers focused on the more common subtypes of GIST caused by mutations such as the KIT gene. “Now, we’re really seeing this quick evolution of treatments and additional studies for the SDH population and in some of these rare populations, where until now, we didn’t have great drugs.”
He added: “Hopefully, in the coming year or two, we should have more options available for these patients with the ultimate goal of even increasing that further and having more effective therapies for this patient population.”