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Based on data from NBTS’s Defeat GBM Research Collaborative and with support from the Sharpe family, Dr. Paul Mischel (Stanford University) and his team found that the antidepressant drug, fluoxetine (common brand name: Prozac), targets tumor metabolism and inhibits epidermal growth factor (EGFR) signaling, triggering the killing of glioblastoma (GBM) cells in laboratory models. Dr. Mischel’s research also found that “combining fluoxetine with temozolomide, a standard of care for GBM, causes massive increases in GBM cell death and complete tumor regression in mice.” These findings need to validated in other preclinical settings and then potentially be tested in a prospective human clinical trial.
Working as part of the National Brain Tumor Society’s Defeat GBM Research Collaborative from 2013-2020, Dr. Paul Mischel has made a series of paradigm-shifting discoveries that could significantly improve the treatment of glioblastoma (GBM) in some patients.
At the outset of the Defeat GBM initiative, Dr. Mischel set out to understand why treatments that, in theory, should have worked ultimately failed. He focused specifically on alterations related to a gene called “EGFR” (epidermal growth factor receptor), the most common oncogene found in GBM patients. Nearly 60 percent of GBM patients have an abnormality related to their EGFR gene.
Dr. Paul Mischel
Several other cancers outside of the brain are also driven by EGFR alterations, but treatments that have worked for these tumors have failed to help GBM patients in the same way. Dr. Mischel and his team hypothesized that something must be happening in brain cancer cells that is unique from cells elsewhere in the body.
The Mischel lab discovered that glioblastoma cells have distinctively disrupted metabolisms. These metabolic changes fuel a unique process by which GBM cells become dependent on certain molecules, especially lipids that are critical to the construction of plasma membranes — the structures that act as the interface between the inside of the cell and the outside world and that are important for sending cancer-causing signals. Dr. Mischel and colleagues began to study whether potential changes to the lipid composition of cell membranes could affect how EGFR alterations impact glioblastoma cells.
Finding the attack point: SMPD1 is discovered
The Mischel lab homed in on lipid molecules called “sphingomyelin” that are critical for organizing how outside signals, or messages, are passed through the plasma membrane and then down into cells. Then, by analyzing a large cancer research database, they identified an enzyme involved in breaking down sphingomyelin called SMPD1 that appeared to be critical to the survival of GBM cells.
The team then tested whether glioblastoma cells could be made vulnerable to drugs that could block SMPD1.
Finding the attack approach: Prozac offers hope
The team — which included Junfeng Bi from Dr. Mischel’s lab and key collaborators Ben Cravatt at the Scripps Research Institute as well as Andrey Rzhetsky and Atif Khan at the University of Chicago — searched through drug databases to identify compounds that could potentially block SMPD1, pointing to the drug fluoxetine, commonly known as Prozac, which has been used to treat depression and several related disorders since the 1980s. Now off-patent, the drug is one of the most commonly prescribed medications in the United States.
Fluoxetine is considered part of a class of drugs called SSRIs, as it’s used to treat depression and other mood disorders by helping to control the amount of serotonin in the brain. But recently, it was discovered that fluoxetine could also potentially block the activity of SMPD1.
Because the drug is already available, has been prescribed for years, is able to get past the blood-brain barrier, and is generally considered very safe in certain doses for depression, Dr. Mischel wanted to test if fluoxetine could, indeed, be used to block SMPD1 in glioblastoma cells.
Dr. Mischel’s research studies in male lab mice that had GBM tumors with extra copies of EGFR, revealed that fluoxetine did indeed block SMPD1 activity and was able to significantly reduce tumor growth and prolong survival in these animals with no observed toxicity.
Improving the attack approach: Past records offer insights on combination with temozolomide
To complement this experimental data, the team also analyzed a database of medical insurance records from 2003-2017. Dr. Mischel’s analysis identified 238 adult GBM patients who received standard of care treatments (chemotherapy with temozolomide and radiation) and also happened to be taking fluoxetine for depression or another disorder. These patients appeared to have survived longer than those in the database who weren’t also on fluoxetine. This was not true for GBM patients happening to take other SSRIs during their treatment.
The Mischel lab took the research an additional step forward, next combining fluoxetine with temozolomide in a new set of experiments in laboratory models. In these experiments, the combination — given at the higher doses tested — shrank the tumors, and six out of eight mice showed no signs of tumor recurrence after 5 months of treatment. Fluoxetine, when directly combined with temozolomide, and then used ongoing after chemotherapy, demonstrated an exciting ability to significantly improve the treatment of GBM animal models.
Understanding how it works: Studies unveil the mechanics behind the potential new treatment
The researchers wanted to know exactly how and why the drug might be making such a difference. Specifically, they wanted to go back to the issues of EGFR and the plasma membrane.
Dr. Mischel’s team found that SMPD1 breaks down sphingomyelin, and that blocking SMPD1’s function with fluoxetine allows increased levels of sphingomyelin to accumulate in GBM cells’ plasma membranes. With elevated levels of sphingomyelin in the plasma membrane, the extra EGFRs typically found in GBM cells are effectively pushed out of the membrane and are unable to receive, and then transmit, errant signals that normally would tell tumors to keep growing.
Dr. Mischel also found that treatment with fluoxetine, in addition to inhibiting SMPD1, might suppress elements of a cell’s DNA damage repair process. Since temozolomide works by damaging tumor cells’ DNA, combining fluoxetine with temozolomide seemed to increase the effect of the chemotherapy, as well.
Looking ahead: Prospective clinical trial needed
“By identifying the enhanced dependence of GBMs on SMPD1, showing how it’s required for constructing plasma membranes and controlling signals that would drive tumor growth, and by finding fluoxetine’s unique ability to block SMPD1, we have identified a potentially effective new way of treating GBM with a safe, repurposed, FDA-approved drug and determined the molecular mechanistic basis underlying it,” said Dr. Mischel.
While these findings offer reason for hope, the effect of fluoxetine now needs to be validated in further preclinical research and then confirmed in clinical trials.
“A well-controlled, randomized clinical trial will be needed to determine whether the addition of fluoxetine to standard of care improves survival of patients with GBM as well as to optimize dosing,” said Dr. Mischel.
Dr. Mischel and his team would also like to conduct future research to more completely understand the spectrum of patients with GBM who could potentially benefit from this treatment, beyond the 60 percent with EGFR abnormalities.
We found that GBM cells of many different mutational backgrounds were highly sensitive to fluoxetine, although not quite as sensitive as tumor cells containing amplified EGFRvIII or wild-type EGFR. We hypothesize that this sensitivity is mediated through lysosomal stress, which merits further study. Further, besides the DNA repair pathway, other downstream pathways may also potentially contribute to the sensitivity of GBM cells to fluoxetine-temozolomide combination therapy.
Attribution: Dr. Mischel
This exciting series of studies and analyses were recently published in the scientific journal Cell Reports. It represents a novel research approach combining NBTS-funded discovery science, big data analysis, real-world evidence, and new NBTS-funded preclinical research.
