Summary: Researchers at UCLA report that trifluoperazine, a dopamine receptor antagonist once commonly used to treat schizophrenia, when combined with radiation therapy can delay glioblastoma tumor growth and extend survival in preclinical models.
Source: UCLA
UCLA Jonsson Comprehensive Cancer Center researchers have discovered that adding an existing drug to standard radiation therapy improved survival in mice with glioblastoma, an aggressive and hard-to-treat brain tumor.
Published in Proceedings of the National Academy of Sciences, the study shows that combining radiation with the antipsychotic drug trifluoperazine (TFP) not only targets glioblastoma cells but also blocks a common resistance mechanism. The combination prevented radiation-induced conversion of non-stem tumor cells into glioma-initiating cells, a process that contributes to recurrence and poor outcomes. Because median survival for patients with glioblastoma remains only 12 to 18 months after diagnosis, approaches that limit resistance to therapy are urgently needed.
Radiation therapy is a cornerstone of cancer treatment and can be curative in many settings. In glioblastoma, however, tumor cells frequently develop resistance. The study identifies “phenotype conversion” as a key contributor to that resistance: radiation can trigger certain non–tumor-initiating cells to acquire stem-like, tumor-forming properties, creating new, treatment-resistant cell populations.
“Radiotherapy is one of the few therapies that extends survival for glioblastoma patients, but on its own it has limited benefit in our aggressive preclinical models,” said senior author Dr. Frank Pajonk, professor of radiation oncology at the David Geffen School of Medicine at UCLA and a member of the Jonsson Comprehensive Cancer Center. “Trifluoperazine alone showed little effect, but when combined with radiation the results were striking. The drug does not sensitize cells to radiation; rather, it prevents the emergence of resistant glioma stem cells.”
The UCLA team screened more than 83,000 compounds using shared institutional resources to identify drugs capable of blocking radiation-induced phenotype conversion. Nearly 300 candidate compounds emerged from that screen, among them trifluoperazine, a dopamine receptor antagonist with the ability to interfere with the conversion process and potentially improve radiation efficacy.
Testing trifluoperazine in mice bearing patient-derived orthotopic glioblastoma tumors, the researchers found that the drug plus a single dose of radiation significantly delayed tumor growth and extended overall survival. In the study, the combination treatment extended survival beyond 200 days in all treated mice, compared with a median of 67.7 days in the group that received only radiation.
“Many preclinical glioblastoma studies report modest survival gains that rarely translate to clinical benefit,” Pajonk added. “Here we observed dramatic improvements in overall survival in mouse models, which is encouraging and supports the idea that this strategy may be translatable to patients.”
The team’s mechanistic work indicates that TFP reduces radiation-induced expression of Nanog mRNA, activates GSK3, and triggers post-translational reductions in p-Akt, Sox2, and β-catenin protein levels. Importantly, TFP did not change the intrinsic radiosensitivity of established glioma-initiating cells, suggesting its main benefit is preventing the formation of new, treatment-resistant induced glioma-initiating cells (iGICs) after radiation.
Building on these results, the researchers plan to open a clinical trial this summer to evaluate a dopamine receptor antagonist combined with radiation in patients with recurrent glioblastoma. “We aim to identify combinations with radiation that are well tolerated and can halt radiation resistance in humans,” said co-author Dr. Leia Nghiemphu, associate professor of clinical neurology at the Geffen School of Medicine and principal investigator on the upcoming trial.
About this glioblastoma research article
Source:
UCLA
Media Contacts:
Press Office – UCLA
Image Source:
The image is in the public domain.
Original Research: Closed access
“The dopamine receptor antagonist trifluoperazine prevents phenotype conversion and improves survival in mouse models of glioblastoma” by Kruttika Bhat et al., PNAS, doi: 10.1073/pnas.1920154117.
Abstract
The dopamine receptor antagonist trifluoperazine prevents phenotype conversion and improves survival in mouse models of glioblastoma
Glioblastoma (GBM) is the most lethal adult brain cancer and remains universally fatal. Radiation therapy adds roughly six months of survival compared with surgery alone, but progress has stalled for decades. This study reports that radiation can induce a glioma-initiating cell phenotype and identifies trifluoperazine (TFP) as a compound that interferes with this conversion. TFP reduces radiation-induced Nanog mRNA expression, activates GSK3, and leads to post-translational decreases in p-Akt, Sox2, and β-catenin proteins. TFP does not change the intrinsic radiation sensitivity of existing glioma-initiating cells (GICs). Continuous TFP treatment combined with a single dose of radiation reduced the number of GICs in vivo and prolonged survival in syngeneic and patient-derived orthotopic xenograft (PDOX) mouse models. These findings suggest that pairing a dopamine receptor antagonist with radiation may enhance radiotherapy efficacy in GBM by preventing radiation-induced conversion of radiosensitive non-GICs into treatment-resistant induced GICs (iGICs).
Feel Free To Share This Brain Cancer News.