GIST May Respond to Other FDA-Approved Drugs

A recent exploratory study found that gastrointestinal stromal tumor (GIST) cells showed unexpected sensitivity to certain kinds of chemotherapy drugs not typically associated with the diseases’ treatment.

Study author Anette Duensing, MD, of the Cancer Virology Program at the University of Pittsburgh Cancer Institute, and colleagues believe that these results offer immediate new treatment options for advanced-stage patients.

“Two drug classes of classic chemotherapy drugs were found to be effective in GIST cells,” Duensing said. “This is surprising because GISTs are commonly thought to be resistant to chemotherapy.”

GISTs, which are caused by KIT or platelet-derived growth factor receptor activation, are commonly given first-line treatment with the small molecule kinase inhibitor imatinib. However, about half of patients develop resistance during the first 2 years of treatment. According to Duensing, FDA-approved second- and third-line treatments often do not offer much additional tumor control.

“Screening almost 100 FDA-approved cancer drugs at once offers the opportunity to bring our findings into the clinic quickly,” Duensing said.

In the study, Duensing and colleagues used imatinib-sensitive and imatinib-resistant human GIST cell lines to perform apoptosis and cell viability studies using Caspase-Glo and CellTiter-Glo luminescence-based assays. The cells were then cultured and incubated with the respective compounds or with a dimethyl sulfoxide control. The researchers then tested 89 FDA-approved anticancer drugs on the cultured cells, performing each screen in triplicate at both a 1 mcmol/L and 10 mcmol/L concentrations. The results of the study were published in Cancer Research.

“Results from the triplicate screens were averaged and normalized to their respective average dimethyl sulfoxide control,” the researchers wrote. “These results were then combined into a ‘response score’ … Hits were defined as having a response score ≥ twofold over dimethyl sulfoxide-treated cells.”

Thirty-seven compounds were found to have antitumor activity in at least one GIST cell line. However, the most effective compound identified was the proteasome inhibitor bortezomib, which had strong activity in all tested cell lines.

Results of the analysis indicated that GIST cells had a high sensitivity to transcriptional inhibitors and topoisomerase II inhibitors, compounds which “exploited the cells’ dependency on continuous KIT expression and/or intrinsic DNA damage response defects.”

The researchers also found that mithramycin A and mitoxantrone were active in patient-derived imatinib resistant primary GIST cells.

“The drug/drug classes that were found to be effective in GIST cells can immediately be taken into clinical trials,” Duensing said.