Promising new research from the University of California, Los Angeles (UCLA), suggests an old schizophrenia drug could significantly enhance the efficacy of radiation treatment for one of the deadliest forms of brain cancer.
The general treatment process for glioblastoma, the deadliest adult brain cancer, is surgery followed by radiation therapy alongside a drug called temozolomide. This current standard-of-care still results in a nearly 95-percent mortality rate and, although radiation therapy does generally extend median survival duration, it can result in a dispiriting catch-22 scenario.
Compared to surgery alone, radiation therapy for glioblastoma extends survival duration by up to six months. However, radiation can also trigger a process called “phenotype conversion,” making it more likely the cancer will ultimately reoccur.
Phenotype conversion occurs when radiation therapy triggers a transformation in non-tumor stem cells, turning them into glioma-initiating cells. The goal of the new research was to find a pharmacological way to stop radiation initiating this phenotype conversion.
The first step was screening 83,000 different compounds to find a molecule that could effectively cross the blood-brain barrier and inhibit radiation-induced phenotype conversion. An old anti-psychotic drug called trifluoperazine, developed in the 1950s to treat schizophrenia, arose as a promising candidate.
The next step was conducting expansive animal tests to see if the drug, combined with radiation therapy, extended general survival rates. The results were incredibly promising, with all drug-treated animals surviving past 200 days, compared to a 67-day survival rate in the animals treated only with radiation.
“Many preclinical glioblastoma studies report fairly small increases in overall survival in mice, and that rarely translates into benefits for patients,” explains Frank Pajonk, senior author on the new study. “But here we see pretty drastic effects in improved overall survival, and I find that very encouraging. It gives us hope that this is all going to translate into a benefit for people.”
These very significant animal results suggest a straightforward combination of these two treatments could dramatically increase survival rates for human patients with glioblastoma. As the drug is already FDA-approved for clinical use, the researchers suggest human trials could commence as soon as later this year.
“While radiotherapy is one of the few treatments that prolong survival in glioblastoma patients, radiation alone does very little in treating the disease in our models because we are dealing with highly aggressive tumors,” says Pajonk. “The drug trifluoperazine by itself does not do much either, but we found when you combine them, they become highly efficient. Importantly, the drug does not sensitize cells to radiation but rather prevents the occurrence of resistant glioma stem cells.”
It is unclear exactly how the drug prevents phenotype conversion in the face of radiation, but the researchers hypothesize it is due to the nature of its dopamine receptor antagonism. Trifluoperazine is not commonly used in clinical practice nowadays as newer dopamine receptor antagonists have taken its place in psychiatric treatments, due to better efficacy and lower negative side effects.
“I think we can find a combination of treatments with radiation that is very tolerable to patients and can do well,” says Leia Nghiemphu, principal investigator on the upcoming clinical trial. “The next step is to see if we can stop this resistance to radiation in humans.”
The new study was published in the journal PNAS.
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