Researchers at the San Diego branch of the Ludwig Institute for Cancer Research at University of California San Diego, with colleagues around the country, report that inhibiting activity of a specific protein in glioblastomas (GBM) boosts their sensitivity to radiation, thus improving treatment prospects for one of the most common and aggressive forms of brain cancer.
The findings are published in the February 28, 2019 on line issue of
GBM are extremely difficult to treat, with a median survival rate of 15 to 16 months, meaning that half of all patients survive to this length of time. Radiation and chemotherapy are the standard-of-care treatments, both intended to damage and destroy DNA in cancer cells, but their efficiency declines as tumors develop therapeutic resistance.
In their new paper, senior author Frank B. Furnari, PhD, professor of pathology at UC San Diego School of Medicine and member of Ludwig San Diego, first author Jianhui Ma, PhD, a postdoctoral fellow, and colleagues identified a mechanism used by GBM to promote therapeutic resistance: phosphorylation of a protein called phosphatase and tensin homolog or PTEN, which is encoded by the PTEN gene.
Normally, PTEN acts as a tumor suppressor, but mutations or modifications can produce the opposite effect. Specifically, the researchers found that phosphorylation of PTEN — the adding of a phosphate molecule to an amino acid called tyrosine Y240 in cancer cells — promoted DNA repair in tumors, reversing the effects of therapeutic radiation.
When scientists blocked Y240 phosphorylation in mouse models of GBM using inhibitors of the fibroblast growth factor receptor, the cancer cells became sensitive to radiation and more died, extending survival in the mice.
“These findings are novel and provide a foundation to move forward with a clinical trial and hopefully expand our findings to other cancer types that use this mechanism to evade therapy,” said Furnari.
The work follows up on a 2017 study, published in Nature Communications, in which Furnari and colleagues elucidated how
PTEN regulates development of GBMs.
Co-authors of this study include: Jorge A. Benitez, Shunichiro Miki, Claudio Ponte du Albuquerque, Ciro Zanca, Rachel Reed, Antonia Boyer, Tomoyuki Koga, Andrew K. Shiau, Huilin Zhou and Timothy C. Gahman, Ludwig San Diego; Jie Li and Clark C. Chen, University of Minnesota; Thais Galatro and Suely Kazue Nagahashi Marie, University of Sao Paulo; Laura Orellana and Erik Lindahl, KTH Royal Institute of Technology, Sweden; Nissi M. Varki, UC San Diego; Tim R. Fenton, University of Kent, UK; John DeGroot and Erik P. Sulman, University of Texas; Webster K. Cavenee and Richard D. Kolodner, Ludwig San Diego and UC San Diego.
Funding for this research came, in part, from the Defeat GBM Research Collaborative, the James S. McDonnell Foundation, the National Institutes of Health (grants R01-NSO80939, R01-GM26017, 5R01-GM116897, P50-CA127001, R01-NS097649, P01-HK107150), the Ludwig Institute for Cancer Research, the Doris Duke Charitable Foundation Clinical Scientist Development Award, the Sontag Foundation Distinguished Scientist Award, the Kimmel Scholar Award (BWF 1006774.01), the Lawski Foundation and the National Cancer Institute Cancer Center Support Grant (P30CA23100).