Treatment with radiation is a hallmark for glioblastoma patients. After surgery to remove as much of the tumor as possible, radiation is used to treat patients in almost every instance, regardless if they are pursuing standard of care treatment (radiation and chemotherapy), a clinical trial, or off-label use of another medication.
As one of the few approved treatments for brain tumors, many patients stake their hopes – and future – on radiation’s potential to destroy their tumor. Unfortunately, this isn’t always the case.
For glioblastoma patients, treatment with radiation seems to offer only limited, temporary effectiveness. This led Defeat GBM-funded researcher Dr. Frank Furnari of Ludwig Cancer Research and the University of California, San Diego to ask the question, “Why is this the case?”
Radiation works as a cancer treatment by damaging the DNA in tumors that if not repaired in a timely fashion will result in the tumor cells’ death.
Researchers have long known that, through evolution, human cells have developed a number of methods to survive even in the toughest conditions – including when their DNA is damaged.
Using his funding through the National Brain Tumor Society’s Defeat GBM Research Collaborative, Dr. Furnari – and other Defeat GBM leaders including Drs. John de Groot, Erik Sulman, Paul Mischel, and Webster Cavenee – began studying how glioma tumors can repair DNA damage caused by radiation and continue to grow.
In 2012, Dr. Furnari and his colleagues identified that a modified (altered) form of a protein found in cells called “PTEN” is associated with shorter survival of glioblastoma patients that have been treated with radiation.
In a new study published on February 28 in the journal Cancer Cell, Dr. Furnari – with Drs. De Groot, Sulman, Cavenee, and others – examined if this specific modification to PTEN actually initiates a sequence of molecular events that result in the repair of the damaged DNA following radiation treatment.
The team found that the modification to PTEN – called “pY240” – they had previously identified does indeed promote effective DNA repair. Glioblastoma cells with this alteration can survive after radiation treatment, while cells without this alteration are susceptible (or “sensitive”) to radiation. This finding suggests that pY240-PTEN status in tumors could predict which patients are more likely to benefit from radiation. More importantly, it could lead to new treatment strategies blocking this specific alteration to improve glioma patients’ response to radiation and survival.
And the researchers began doing just that.
Dr. Furnari and his team investigated how this specific alteration occurs to PTEN, and how they could block it from happening. They found that the pY240 modification of PTEN was caused by another protein called FGFR2. When glioma cells are hit with radiation, part of the FGFR2 protein travels to the cell’s nucleus where it attaches (or “binds”) to PTEN. This results in the pY240 modification to PTEN, which in turn sets in motion a chain of events ultimately leading to the recruitment of an enzyme called “RAD51” which accumulates at the site of the DNA damage caused by the radiation and is involved in fixing the break.
“These results suggest that FGFR-mediated pY240-PTEN is a key mechanism of radiation resistance and is an actionable target for improving radiotherapy,” the researchers said in the new paper.
Since FGFR2 started this whole process by binding to PTEN and making the pY240 alteration, the researchers next evaluated using a type of drug called an “FGFR inhibitor” to block FGFR2 from modifying Y240-PTEN. Testing this approach in the laboratory, Dr. Furnari and his team found that combining the FGFR inhibitor with radiation did increase survival in models of glioblastoma.
“We [identified] pY240-PTEN as a predictor for FGFR application and thus illustrated a unique approach to precision medicine,” the authors wrote. “Our data shows that pY240-PTEN mediates resistance to DNA damage through enhancement of the DNA repair process…FGFR inhibitors sensitized cells to DNA damage and extended survival in preclinical GBM models treated with [radiation]. Therefore, understanding the genetic status of PTEN in tumors…may help to determine more effective treatments for GBM patients.”
Dr. Furnari and colleagues are now looking to start a pilot clinical trial combining FGFR inhibitor with radiation in recurrent glioblastoma patients.
Further down the line, the researchers believe their data can have even more implications for developing new treatment strategies to improve patient outcomes. They hypothesize that testing for PTEN in patients tumors in the future could direct a number of separate treatment approaches.
“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,” Dr. Furanari concluded in a press release about the new study.
Visit www.defeatgbm.org to learn more and/or support the Defeat GBM Research Collaborative.