Compound Screening Identifies Novel Treatment Options for Gastrointestinal Stromal Tumors
Using high-throughput screening of already FDA-approved chemotherapeutic agents in gastrointestinal stromal tumors (GIST) cell lines, researchers have discovered that GIST cells display a high sensitivity to transcriptional and topoisomerase II inhibitors. The finding could bring new treatments to the clinic quickly. The research was conducted by Boichuk et al and is published in Cancer Research.
Researchers from the University of Pittsburgh performed a compound screen on 89 FDA-approved anticancer drugs contained in two imatinib (Gleevec)-sensitive and three imatinib-resistant human GIST cell lines, patient-derived primary GIST cells, and two xenograft mouse models. A total of 37 compounds were identified as having antitumor activity in at least one GIST cell line for at least one of the concentrations tested.
Study Findings
The researchers found that the cells were highly sensitive to drugs targeting gene transcription or inhibiting topoisomerase II. Two compounds, gene transcription inhibitor mithramycin A, which is in clinical trials to treat Ewing sarcoma, and topoisomerase II inhibitor mitoxantrone, which is used in the treatment of metastatic breast cancer and leukemia, were chosen for further investigation. Both agents were found to be highly active in the GIST cell lines. In addition, the mechanism of action of each drug was linked to a specific underlying biology of these tumors.
“These are very encouraging results,” Anette Duensing, MD, Assistant Professor of Pathology at the University of Pittsburgh and senior author of the study, said in a statement. “The next step will be moving our findings to clinical exploration to see if the results we found in the lab hold up in patients.”
Improving Long-Term Disease Control
Although imatinib mesylate is highly effective as first-line treatment for patients with metastatic or unresectable GIST, greatly improving their prognosis, complete remissions are rare and the majority of patients eventually develop resistance to the drug, which is why new therapies are urgently needed, said the study authors.
“Our study provides a framework for the future development of mono- or combination therapies and biomarkers predicting the individual response of patients with GIST with an aim toward more complete remissions and improved long-term disease control,” they wrote.
According to the NCI, although gastrointestinal stromal tumors comprise less than 1% of all gastrointestinal tumors, they are the most common mesenchymal tumors of the gastrointestinal tract. It is estimated that there are between 3,000 and 6,000 new cases of GIST each year in the United States.
Dr. Duensing is the corresponding author for the Cancer Research article.
The research was funded by the American Cancer Society, the Life Raft Group, GIST Cancer Research Fund, and the Howard Hughes Medical Institute. The researchers reported no conflicts of interest.
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