TAMPA, Fla. (Oct. 10, 2017) - Developing new drugs to treat cancer can be a painstaking process taking over a decade from start to Food and Drug Administration approval. Scientists are trying to develop innovative strategies to identify and test new drugs quicker and more efficiently. A team of researchers at Moffitt Cancer Center used cellular drug screening, functional proteomics and computer-based modeling to determine whether drugs with well-known targets may be repurposed for use against other biological targets. They found that an FDA approved drug for non-small cell lung cancer called ceritinib has anti-cancer activity against previously unknown targets. Their results were published today in the journal, Nature Chemical Biology.
For the past 20 years, there has been an emphasis on targeted cancer therapy - targeting a specific driver of cancer development to minimize side effects typically seen with chemotherapy. This personalized approach has been successful in certain types of cancer that are primarily driven by a single DNA alteration, such as found in chronic myeloid leukemia. However, the majority of cancers are not caused by a single mutation; rather, cancer is more commonly caused by a large network of mutations and alterations. Some researchers, including those from Moffitt, are beginning to rethink the targeted approach to cancer therapy. They believe that developing drugs that act on multiple targets, called a polypharmacology approach, may more effectively treat those cancers that have a network of alterations.
In order to identify drugs that act on multiple targets, Moffitt researchers screened 240 drugs that are either FDA approved or in clinical development. They noticed that the drug ceritinib acts differently than other drugs in its class. Ceritinib targets a protein called ALK, and is approved to treat patients with ALK-rearranged metastatic non-small cell lung cancer. Their research found that ceritinib also inhibits the growth of lung cancer cells that do not have genetic alterations in the ALK gene.
After an extensive set of experiments to learn how ceritinib worked in cells without ALK rearrangements, they discovered the drug inhibits several other previously unknown targets, and that these signals converge onto a protein known to be responsible for causing drug resistance to paclitaxel. Importantly, the researchers showed that ceritinib combined with paclitaxel was more effective than either agent alone at reducing cell viability.
These findings suggest that ceritinib together with paclitaxel may be effective against other cancers that do not have ALK rearrangements, and that this drug combination may be used to target a network of changes in cancer.
"The results also demonstrate the benefits of using a combined screening, proteomics and computer-based modeling approach to identify drugs that act on multiple targets and to determine how they function," said study lead author Uwe Rix, Ph.D., assistant member of the Drug Discovery Program at Moffitt. "In the future, this strategy may facilitate further drug repurposing efforts and lead to an increase in new therapy options for patients with difficult-to-treat diseases."
This work was supported by grants from the National Cancer Institute (R01 CA181746, F99 CA212456, P50 CA119997, and P30 CA076292).
About Moffitt Cancer Center
Moffitt is dedicated to one lifesaving mission: to contribute to the prevention and cure of cancer. The Tampa-based facility is one of only 49 National Cancer Institute-designated Comprehensive Cancer Centers, a distinction that recognizes Moffitt's excellence in research, clinical trials, prevention and cancer control. Moffitt is listed as one of the top 10 cancer hospitals in the nation and has been listed in U.S. News & World Report as one of the "Best Hospitals" for cancer care since 1999. Moffitt devotes more than 2 million square feet to research and patient care. Moffitt's expert nursing staff is recognized by the American Nurses Credentialing Center with Magnet® status, its highest distinction. With more than 5,700 team members, Moffitt has an economic impact in the state of $2.1 billion. For more information, call 1-888-MOFFITT (1-888-663-3488), visit MOFFITT.org, and follow the momentum on Facebook, Twitter and YouTube.
Nature Chemical Biology