Drug-Resistant GIST: Identifying Patients and Finding Solutions

Patients with gastrointestinal stromal tumors (GIST) should always have their tumors tested, as the results could indicate how likely they are to respond to treatments, and if they should talk to their health care team about clinical trials or novel therapeutic options.

In a recent webinar presented by the Life Raft Group, Shruti Bhargava, a postdoctoral fellow at the UC San Diego School of Medicine, discussed the importance of the tumors being tested for succinate dehydrogenase (SDH) deficiency.

SDH is an enzyme that can be found on GIST cells. Disease that lacks SDH is less likely to respond to tyrosine kinase inhibitors (TKIs), which are commonly used to treat GIST. SDH-deficient GIST tends to occur in younger adults and is likely to metastasize.

Clinicians can determine if a cancer is SDH deficient through something called an immunohistochemical test, which take a sample of the tumor and then uses stains to see if it has certain proteins on it.

Since SDH-deficient GIST makes up only about 10% of all GIST cases, there is a pressing need for more data on these patients.

“We have limited patient-derived tumor models, and we need better models to understand the disease biology, as well as to screen novel drug candidates,” Bhargava said. “At the clinical side, we have limited therapeutic options, and we do need better options available for the SDH-deficient GIST patients.”

Bhargava and her team created cell models in her lab of SDH-deficient GIST to potentially identify new drugs that can work in this population.

“Until now, we have seen that our models to recapitulate the parent human characteristics are resistant to TKIs but are sensitive to a novel drug that we have identifies as the same as temozolomide,” Bhargava said.

Temodar (temozolomide) is a drug that is typically used to treat brain tumors that could be promising in SDH-deficient GIST as well. The drug works by causing DNA damage in cancer cells, which makes them nonviable and ultimately die.

Bhargava and her team explained that in the first clinical trial testing the drug in this patient population, there was tumor shrinkage in SDH-deficient GIST when given Temodar.

Researchers are now enrolling patients with advanced, SDH-deficient GIST in a phase 2 clinical trial examining how efficacious Temodar is in treating their disease.

“In summary, we have now established tumor models which are very similar to the patient tumors, which can be used to understand the biology and also find novel drug targets,” Bhargava said.

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