Cancer Institute Takes Second Look At Some Drugs for Resistant Cancers

Issue Date: 
March 3, 2014

UniversityDrugs of Pittsburgh Cancer Institute scientists have shown that old drugs might be able to do new tricks. Researchers screened a library of anticancer drugs that had previously been approved by the U.S. Food and Drug Administration but weren’t considered for use as a treatment against a rare type of cancer. The scientists were surprised to discover that several of these drugs offered treatment potential in cases where the cancer becomes resistant to standard drug treatment.

The findings, published in the Feb. 15 issue of Cancer Research, demonstrate that a specialized method of drug-industry testing called high-throughput screening can be applied to existing FDA-approved drugs to identify potential new therapies that could be rapidly moved to the clinic.

“This is known as ‘drug repurposing,’ and it is an increasingly promising way to speed up the development of treatments for cancers that do not respond well to standard therapies,” said senior author Anette Duensing, a Pitt assistant professor of pathology and member of the University of Pittsburgh Cancer Institute. “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.”

DuensingAnette Duensing and her team screened 89 drugs in an attempt to find more treatment options for patients with gastrointestinal stromal tumors, which are uncommon tumors that begin in the walls of the gastrointestinal tract. According to the American Cancer Society, about 5,000 cases of gastrointestinal stromal tumors occur each year in the United States. The estimated five-year survival rate for patients with advanced disease is 45 percent.

The tumors 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 gastrointestinal stromal tumors responded to various concentrations of the 89 drugs in the laboratory, Duensing and her colleagues identified 37 compounds that showed some anticancer activity in at least one of the concentrations tested. Importantly, they noted that the most promising candidates all belonged to only two major drug classes: inhibitors of gene transcription and so-called topoisomerase II inhibitors. Based on these findings, the research team selected the two most promising compounds for further testing—gene transcription inhibitor mithramycin A, which is in clinical trials to treat a rare bone cancer called Ewing’s sarcoma, and topoisomerase II inhibitor mitoxantrone, which is used to treat metastatic breast cancer and leukemia.

Both drugs were highly effective in fighting gastrointestinal stromal tumors in laboratory tests. Moreover, the mechanism of action of each drug was linked to the specific biology of these tumors.

“These are very encouraging results,” Duensing said. “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.”