Neoplasms of glial cells, known as gliomas, comprise 40-50 percent of the tumors that arise in the central nervous system. In adults, the most aggressive and deadly of these neoplasms is glioblastoma multiforme (GBM), with an occurrence of approximately 10,000 new cases per year in the U.S. Despite our rapidly growing knowledge of mutations that cause these tumors, little improvement on the median survival of 12-15 months has been achieved for GBM patients. This is due to many factors, such as the difficulty of delivering drugs into the brain; the highly invasive nature of GBMs; the tumor heterogeneity that is implicit in the name of the disease; and rapidly acquired resistance to standard of care (SOC) therapy, which primarily involves agents that damage DNA, such as radiotherapy.
In an article in Cancer Cell, Frank Furnari, PhD, a member of the Ludwig Institute for Cancer Research San Diego Branch and Professor of Pathology at the University of California, San Diego, defined a targetable mechanism that increased the sensitivity of GBM to radiation treatment.
"We discovered a new function of a gene commonly mutated in GBM," Furnari told Oncology Times. "Mutations in PTEN, as found in GBM, inactivate the protein and result in enhanced tumor cell survival and proliferation. However, our work showed that tumor cells that retain the non-mutated PTEN gene can repurpose it for a completely different function-to enhance repair of DNA damage caused by radiation, improving the survival of tumor cells challenged with SOC. In effect, what we typically consider a tumor suppressor gene actually has an oncogenic function when it is re-purposed by the tumor cell."
1 Why did your team choose to conduct this research now?
"Despite acquired resistance to SOC, ionizing radiation clearly remains the most effective therapy for GBM patients. Additionally, about half of all cancer patients will receive radiotherapy during their course of treatment. We wanted to understand how resistance to radiation occurred in GBM and possibly block the mechanism to improve patient survival. Overcoming resistance is an intense area of investigation for many in the cancer field."
2 What led you to investigate PTEN and radiation sensitivity in glioblastoma?
"When I began my research at the Ludwig Institute over 20 years ago, I had shown that PTEN, when mutated in GBM cells, resulted in enhanced tumor cell proliferation. The experimental results supported its role as a tumor suppressor gene. PTEN controlled the growth of tumor cells through an enzymatic activity that it exerted exclusively in the cytoplasmic compartment of the cell. However, what was clear from the work of other investigators was that PTEN protein could also be found in the nucleus of the cell-although its function in this location remained somewhat a mystery.
"We discovered that PTEN in the nucleus played a significant role in boosting the repair of DNA. What led us down this path of investigation was clinical data from collaborators at MD Anderson and the University of Sao Paulo, which showed that GBM cells with high levels of a phosphorylated form of PTEN in the nucleus had low levels of DNA damage, while cells with low levels of phosphorylated PTEN in the nucleus had high levels of DNA damage. These results correlated very well with survival of GBM patients from our previous study in the journal PNAS."
"Jianhui Ma, PhD, a postdoctoral researcher in my lab, and I went on to show that phosphorylated PTEN in the nucleus had the novel function of binding to and enhancing the repair of damaged DNA. Importantly, when we blocked the activity of FGFR, the enzyme responsible for PTEN phosphorylation, PTEN no longer bound to DNA and the GBM cells succumbed to the lethal effects of radiation-induced DNA damage. This suggested that we had a pharmacological way to target this novel PTEN mechanism by blocking FGFR activity, thereby making GBMs more sensitive to radiation.
"I remember the day that Jianhui showed me that a specific inhibitor of FGFR led to increased radiation sensitivity and, importantly, survival of mice with engrafted GBM. It was clear we had gone from a clinical observation to mechanism of resistance to a therapeutic strategy. Based on these results and how well mice tolerated the FGFR inhibitor and radiation treatment, we are now designing an early-phase clinical trial for patients with recurrent GBM containing intact PTEN."
3 What is the most important takeaway from the findings for practicing oncologists?
"From a basic and translational cancer biologist's perspective, it is essential to have clinical colleagues who facilitate investigation of tumor material. It was only from examining GBM samples that we were informed of this novel function of PTEN as a mediator of radiation resistance. To paraphrase Yogi Berra, 'you can observe a lot by just watching.' In this case, association of the presence of DNA damage in a tissue and the location and phosphorylation of an important tumor suppressor gene told us we needed to think differently about PTEN. I spent 20 years studying the enzymatic function of PTEN in the cytoplasm but, clearly, this protein has much more to tell us."