Researchers team up with students in unconventional approach to cancer drug development.
May 15, 2017
Cells constantly turn proteins on and off with the help of molecular “switches,” called phosphate molecules. The tiny molecules get tossed around within cells, attaching to specific regions of proteins only to be removed later on by specific enzymes. The highly regulated process is one way cancer cells control tumor proteins, making it a huge target for drug developers.
“All the drugs we currently have to treat our cancer patients target what we call kinases, which attach phosphate molecules to proteins. But equally important to this are the enzymes that take the phosphate off,” said Goutham Narla, MD, PhD, Pardee-Gerstacker Professor in Cancer Research, Associate Professor at Case Western Reserve University School of Medicine and member of the Case Comprehensive Cancer Center. According to Narla, medications that help certain enzymes remove phosphate molecules may also have cancer-fighting properties.
One such enzyme—PP2A— “turns off” tumor proteins by removing phosphate molecules attached to them. But as Narla indicated, “This tumor suppressor is turned off in pretty much every major cancer. Its inactivation is essential for a normal cell to become a cancer cell.” In a recent study published in the Journal of Clinical Investigation, Narla decided to take an unconventional approach to cancer drug development by seeking molecules that directly turn on PP2A, in an effort to reactivate its tumor suppressor properties.
Forty-five researchers, including eight undergraduate students from the Young Scientist Foundation and Mark R. Chance, PhD, Vice Dean for Research at Case Western Reserve School of Medicine, collaborated to screen a series of small molecule activators of PP2A, calling them SMAPs for short. The prototype drug molecules were created from FDA-approved medications with the help of Michael Ohlmeyer, PhD, Associate Professor at Icahn School of Medicine at Mount Sinai.
In the new study, one particular SMAP attached to a subunit of the PP2A protein in cancer cells, effectively activating the enzyme. As Narla explained, “This is the first example ever of a cancer drug that directly binds to and activates an enzyme that removes phosphate molecules. There are indirect ways that have been shown to get at these kinds of enzymes, but this is the first example of a direct activation of one. Our drug actually binds to and turns on PP2A.”
The prototype drug also prevented lung cancer cells from growing in mice. Mice injected with the SMAP had fewer lung cancer tumors than mice who received placebo, with minimal side effects. In the mouse models, the drug was comparably effective to currently available combination therapies used to treat lung cancer patients.
The novel approach to cancer drug development could have broad applicability to other human cancers. Said Narla, “There are some 2,000 plus papers on the role of PP2A in cancer. Breast cancer, prostate cancer, lung cancer, brain cancer, childhood cancers, ovarian cancer, endometrial cancer, every major cancer involves the inactivation of this protein. Molecules that allow us to turn it back on, like the one in our study, have the potential to work in a broad range of cancer patients.”
Several of the authors have filed patents on their novel SMAP technology and are moving it through the drug development pipeline. Said Narla, “We are continuing to test our drug in a large series of animal models. If things continue to go well, we hope to start clinical trials next year with this drug. Our initial clinical trials would be quite broad, and would include a number of diverse cancer patients, including patients with lung cancer.”
Narla was also quick to note the contributions of the youngest authors on the study, who helped conduct the experiments. “The Young Scientists supported by the Young Scientist Foundation, www.ysf.org, were integral to these discoveries. I think their contributions highlight, in an increasingly competitive funding environment, the importance of STEM and the benefit of engaging youth early on in biomedical research.”
Founded in 1843, Case Western Reserve University School of Medicine is the largest medical research institution in Ohio and is among the nation's top medical schools for research funding from the National Institutes of Health. The School of Medicine is recognized throughout the international medical community for outstanding achievements in teaching. The School's innovative and pioneering Western Reserve2 curriculum interweaves four themes--research and scholarship, clinical mastery, leadership, and civic professionalism--to prepare students for the practice of evidence-based medicine in the rapidly changing health care environment of the 21st century. Nine Nobel Laureates have been affiliated with the School of Medicine.
Annually, the School of Medicine trains more than 800 MD and MD/PhD students and ranks in the top 25 among U.S. research-oriented medical schools as designated by U.S. News & World Report's "Guide to Graduate Education."
The School of Medicine is affiliated with University Hospitals Cleveland Medical Center, MetroHealth Medical Center, the Louis Stokes Cleveland Department of Veterans Affairs Medical Center, and the Cleveland Clinic, with which it established the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in 2002. case.edu/medicine.