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Stopping cancer in its tracks
Research revives prospects for a generation of failed cancer drugs using combination therapies
By Levi Gadye, PhD / Thu Jul 19, 2018
Cancer, fundamentally, is a problem of too much growth. For decades, health care providers have tried and failed to slow tumor growth using drugs that interfere with a particular signaling pathway, called PI3K, which is known to operate in proliferating cancer cells.
Recent findings in the laboratory of Sourav Bandyopadhyay, PhD, have finally revealed just how cancer resists these drugs. Tumors can actually reroute certain growth signals through an alternative pathway, called AURKA, that is unaffected by PI3K drugs. The work was published in Nature Chemical Biology on June 25, 2018.
The laboratory group further showed that blocking PI3K and AURKA simultaneously, using already-available drugs, could overcome resistance to P13K-targeting drugs in cell cultures and mouse models of breast cancer.
Bandyopadhyay, the senior author of the study, is a faculty member in the Department of Bioengineering and Therapeutic Sciences, a joint department of the UCSF Schools of Pharmacy and Medicine. He is also an affiliate of the UCSF Helen Diller Family Comprehensive Cancer Center and the Quantitative Biosciences Institute.
“The failure of PI3 kinase drugs has been a huge mystery,” Bandyopadhyay told the UCSF News Center. Both PI3K and AURKA are kinases, a common type of signaling proteins. “Every pharma company in the cancer space has tried to target the PI3 kinase pathway, with little success. Now we may know why.”
Bandyopadhyay solved this conundrum by surveying kinase signaling in laboratory-grown human breast cancer cell lines. Cancer cells with ongoing AURKA signaling managed to resist drugs that blocked P13K, leading the researchers to test the effects of combination therapies that blocked both pathways.
In the lab, the combination approach was a success, and Bandyopadhyay is hopeful that these findings will translate to cancer patients.
“This work has immediate clinical implications, and we hope this study spurs interest in combining these two classes of embattled cancer drugs,” he told UCSF News. “These data clearly warrant clinical testing and we are working to put together a phase 1 clinical trial to test such drug combinations in patients.”
Other authors on the study include first author Hayley Donnella; James Webber, PhD; Khyati Shah, PhD; Kevan Shokat, PhD; Rebecca Levin, PhD; Andrei Goga, MD; John Gordan, MD; Roman Camarda; and Olga Momcilovic, PhD, all from UCSF, as well as James Korkola, PhD, and Nora Bayani from Oregon Health and Sciences University.
The study was funded by the U.S. National Institutes of Health, the U.S. Department of Defense, the Prospect Creek Foundation, the American Cancer Society, the Gazarian Foundation, and by OHSU Pilot Project Funding.
About the School: The UCSF School of Pharmacy is a premier graduate-level academic organization dedicated to improving health through precise therapeutics. It succeeds through innovative research, by educating PharmD health professional and PhD science students, and by caring for the therapeutics needs of patients while exploring innovative new models of patient care. The School was founded in 1872 as the first pharmacy school in the American West. It is an integral part of UC San Francisco, a leading university dedicated to promoting health worldwide.