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Feb 13, 2014

Teaching Old Drugs New Tricks

  • University of Pittsburgh Cancer Institute (UPCI) researchers report that they screened a library of FDA-approved anticancer drugs and found several potential possibilities to try if a rare and specific type of cancer had become resistant to standard drug therapies. The big surprise was that previously these approved drugs would not have been considered for the treatment of these gastrointestinal stromal tumors (GISTs).

    The study (“Unbiased Compound Screening Identifies Unexpected Drug Sensitivities and Novel Treatment Options for Gastrointestinal Stromal Tumors”), which will be published in the February 15th issue of Cancer Research, demonstrates that high-throughput screening of already FDA-approved drugs can identify possible new therapies, says the research team.

    “Drug repurposing builds upon previous research and development efforts, and detailed information about the drug formulation and safety is usually available, meaning that it can be ready for clinical trials much faster than a brand-new drug,” said senior author Anette Duensing, M.D., assistant professor of pathology at UPCI.

    Dr. Duensing and her team ran the screening on 89 drugs previously approved by the FDA in an attempt to find more treatment options for patients with GISTs, which are uncommon tumors that begin in the walls of the gastrointestinal tract. According to the American Cancer Society, about 5,000 cases of GISTs occur each year in the U.S. with an estimated five-year survival rate of 45% in patients with advanced disease.

    GISTs are caused by a single gene mutation and can be successfully treated with the targeted therapy drug imatinib, known by the trade name Gleevec. However, about half of the patients treated with Gleevec become resistant to the drug within the first two years of treatment.

    After studying how samples of GIST responded to various concentrations of the 89 drugs in the laboratory, Dr. Duensing and her colleagues identified 37 compounds that showed some anticancer activity in at least one of the concentrations tested.

    “We discovered that GIST cells display high sensitivity to transcriptional inhibitors and topoisomerase II inhibitors. Mechanistically, these compounds exploited the cells' dependency on continuous KIT [a gene that codes for receptor tyrosine kinases] expression and/or intrinsic DNA damage response defects, explaining their activity in GIST,” write the investigators. “Mithramycin A, an indirect inhibitor of the SP1 transcription factor, and mitoxantrone, a topoisomerase II inhibitor, exerted significant antitumor effects in mouse xenograft models of human GIST. Moreover, these compounds were active in patient-derived imatinib-resistant primary GIST cells, achieving efficacy at clinically relevant concentrations. Taken together, our findings reveal that GIST cells have an unexpectedly high and specific sensitivity to certain types of FDA-approved chemotherapeutic agents.”

    “These are very encouraging results,” noted Dr. Duensing. “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.”



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