Researchers at the UCLA Jonsson Comprehensive Cancer Center and colleagues have found that adding a drug once commonly used to treat schizophrenia to traditional radiation therapy helped improve overall survival in mice with glioblastoma, one of the deadliest and most difficult-to-treat brain tumors.
The findings, published in Proceedings of the National Academy of Sciences, show that a combination of radiation and the drug trifluoperazine not only targets glioblastoma cells but also helps overcome the resistance to treatment so common to this aggressive form of cancer.
The results could prove promising for patients with the disease, for whom the median survival time is only 12 to 18 months following diagnosis.
Radiation is an integral part of therapy for people with cancer and one of the most effective treatments. In many cases, it can help cure the disease.
But in glioblastoma, tumor cells often become resistant to radiation treatment because the radiation itself can induce “phenotype conversion,” a process that turns certain non-tumor stem cells into tumor-producing cells, causing the cancer to reoccur.
“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,” said the study’s senior author, Dr. Frank Pajonk, a professor of radiation oncology at the David Geffen School of Medicine at UCLA and a member of the Jonsson Cancer Center.
What is trifluoperazine?
First generation ‘typical’ antipsychotics such as trifluoperazine are an older class of antipsychotic than second generation ‘atypical’ antipsychotics. They are used primarily to treat positive symptoms including the experiences of perceptual abnormalities (hallucinations) and fixed, false, irrational beliefs (delusions).
First generation antipsychotics may cause side effects which can differ depending on which antipsychotic is being administered and on individual differences in reaction to the drug. Reactions may include dyskinesias such as repetitive, involuntary, and purposeless body or facial movements,
Parkinsonism (cogwheel muscle rigidity, pill-rolling tremor and reduced or slowed movements), akathisia (motor restlessness, especially in the legs, and resembling agitation) and dystonias such as muscle contractions causing unusual twisting of parts of the body, most often in the neck. These effects are caused by the dopamine receptor antagonist action of these drugs.
What is the evidence for trifluoperazine?
Moderate to low quality evidence shows trifluoperazine may improve global state more than placebo, it may also result in less people leaving the study early due to relapse or worsening of symptoms. However, trifluoperazine may cause drowsiness and use of antiparkinsonian drugs for movement disorders.
High quality evidence shows no differences in global state, and moderate quality evidence suggests no differences in response to treatment or study retention between trifluoperazine and other first generation antipsychotics.
Moderate quality evidence suggests no differences in adverse events between trifluoperazine and other first generation antipsychotics, apart from more extrapyramial or movement side effects with trifluoperazine in comparison with low-potency chlorpromazine.
“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.”
UCLA researchers have been exploring new ways to prevent glioblastoma tumor cells from becoming resistant to radiation by adding drugs to the treatment regimen that have traditionally been used for other purposes.
To find out if there were any existing drugs that could interfere with the radiation-induced phenotype conversion, the team screened more than 83,000 compounds through the shared resources at UCLA, which provides researchers access to specialized equipment and services to help them pursue cutting-edge research.
They were able to identify nearly 300 compounds, including the dopamine receptor antagonist trifluoperazine, that had the potential to block phenotype conversion and improve the efficacy of radiation therapy.
Once trifluoperazine was identified, it was tested on mice with patient-derived orthotopic tumors. The team found that, when used in combination with radiation, trifluoperazine successfully delayed the growth of the tumors and significantly prolonged the overall survival of the animals.
Combining radiation treatment with trifluoperazine extended survival in 100% of the mice to more than 200 days, compared to 67.7 days in the control group receiving only radiation.
“Many preclinical glioblastoma studies report fairly small increases in overall survival in mice, and that rarely translates into benefits for patients,” said Pajonk, who is also a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.
“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.”
The team plans to start a clinical trial this summer for people with recurrent glioblastoma to test using dopamine receptor antagonist with radiation therapy.
“I think we can find a combination of treatments with radiation that is very tolerable to patients and can do well,” said co-author Leia Nghiemphu, an associate professor of clinical neurology at the Geffen School of Medicine and principal investigator on the upcoming clinical trial. “The next step is to see if we can stop this resistance to radiation in humans.”
Cancer is prevalent globally, and although with growing health apprehension and therapeutic developments, its mortality rate is still alarming [1, 2]. Moreover, a recent report in 2017 estimated 23,800 new cases of brain and central nervous tumor (CNS) tumors out of 1,688,780 new cases estimated in the United States alone.
Despite the low prevalence as compared with other cancers, the statistical rate of mortality from glioma and other related brain tumors is estimated to be around 70% in the year 2017 alone .
Glioma, which refers to tumors of glial cell origin, is the most common type of central CNS tumor and constitutes more than 30% of all primary brain and CNS malignant tumors . According to the World Health Organization, glioma is classified into four different classes with different grades: astrocytoma (grade I–II), anaplastic astrocytoma (grade III), oligodendrogliomas, ependymomas, mixed gliomas, and glioblastoma multiforme (GBM) (Grade IV).
Among them, human GBM is known as the most lethal form of glioma with the worst prognosis. Currently, there is no available cure for GBM despite some therapeutic advancements in the last decade.
The common multimodal treatment for GBM, known as Stupp’s regimen, consists of surgical resection which is followed by six weeks of radiation and concurrent daily intake of the chemotherapeutic drug temozolomide (3-methyl-4-oxoimidazo[5,1-d] [1, 2, 3, 5] tetrazine-8-carboxamide, Tmz) (with treatment lasting at least 6 months) [5, 6].
Tmz is an alkylating agent that is rapidly converted at physiological pH to a short-lived active compound, 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC), and further hydrolyzed to 5-amino-imidazole-4-carboxamide (AIC) and methylhydrazine .
The methylation of N-7 and O-6 sites on guanine and the O-3 site on adenine residues confers Tmz cytotoxicity leading to cell cycle arrest at G2/M and cell death. This treatment regimen remains as the primary standard care for GBM patients for the past ten years, and typically results in a median overall patient survival of 14.6 months from date of surgical diagnosis [7, 8].
The complexity of tumor coupled with high chemoresistance and chemotoxicity further dampen the efficacy of chemotherapy drugs leading to cancer recurrence with poor therapeutic indexes [9, 10]. Moreover, current chemotherapeutic agents are incapable of exclusively targeting tumor cells and thus causing adverse side-effects such as anemia, bleeding, diarrhea, hair loss, nausea, vomiting and immunosuppression that increases the chance of infection [11, 12].
Glioma cells can develop resistance against Tmz by inducing the repair of DNA damage via expression of proteins such as O6-alkylguanine DNA alkyltransferase (AGT) that demethylates Tmz-methylated guanosine encoded in humans by the O-6-methylguanine-DNA methyltransferase (MGMT) gene .
Other than chemotherapy, human GBM is also treated by immunotherapy approaches such as monoclonal antibodies (bevacizumab, nivolumab), a peptide vaccine (rindopepimut), checkpoint inhibitors, dendritic vaccines, and adopted T cells (chimeric antigen receptors (CARs)) that aim to provide a more specific and defined immunization strategy in mediating tumor cell killing.
The addition of Novo-TTF (tumor-treating fields) to the Stupp’s regimen resulted in increased overall survival (OS; 19.6 months) and progression-free survival (PFS; 7.1 months) compared with patients who received a conventional Stupp’s regimen .
Although this improved Stupp’s regimen was suggested to be the new standard of care against GBM, the treatment only increased patients’ OS to approximately 19 months without significant improvement in prognoses.
Although usually administered as the front line of treatment for mental disorders, anti-psychotic drugs are increasingly prescribed among cancer patients to improve their quality of life [15, 16].
Generally, anti-psychotic drugs are grouped into two main classes; the typical and atypical anti-psychotic drugs. A majority of the anti-psychotic drugs are derived from the tricyclic phenothiazine chlorpromazine that was originally prescribed for neuropsychiatric disorders.
Most of the first-generation of anti-psychotic drugs were designed to weaken abnormal dopaminergic function by targeting dopamine D2 receptors which can induce Parkinson-like symptoms [17, 18]. Owing to this fact, second generation or atypical anti-psychotic drugs were developed (derived from clozapine) that function by antagonizing the serotonin 2A receptor (5-HT2A) [19, 20].
Following this, advancement in the pharmaceutical industry steered the modification of chlorpromazine leading to the development of tricyclic anti-depressants and selective serotonin reuptake inhibitors. Generally, cancer patients develop psychological issues such as feelings of despair and anxiety which further lead to depression following diagnosis (Fitzgerald et al., 2015; Walker et al., 2013).
Moreover, the various side-effects from chemotherapy and radiation can further exacerbate psychological symptoms. Therefore, anti-psychotic drugs are prescribed as a method to integrate mental healthcare during cancer treatment, which interestingly demonstrated a lowering of the cancer incidence and grade as reported in the second SMaRT (Symptom Management Research Trial in Oncology-2) study .
This observation is further strengthened by the numerous preclinical and clinical reports that demonstrate the anti-glioma efficacy of anti-psychotic drugs as monotherapy agents and adjuncts in polytherapy treatment settings (Figure 1).
This review manuscript covers the initial until the latest preclinical (Supplementary Table 1) and clinical with specific case findings of major classes and types of anti-psychotic drugs. Additionally, the current review also highlights the contradictory findings, further in-depth molecular mechanisms and future perspectives with critical review on repurposing anti-psychotic drugs as potential therapeutic for glioma (Figure 2).
Therefore, this review aims to provide comprehensive and up-to-date preclinical and clinical reports of anti-psychotic drug use as anti-glioma agents that would further rebrand and justify their repurposed use in human glioma management.
CONCLUSIONS AND FUTURE PERSPECTIVES
Since the current treatment prognosis, particularly in high-grade glioma (Grade III and IV) is hampered with tumor recurrence and chemotherapeutic resistance, curing or even prolonging the overall survival of high-grade glioma patients beyond two years remains an elusive goal.
This review describes the use of anti-psychotic drugs in preclinical and clinical studies either as monotherapies or adjuvants in treating human glioma. The long history and clinical experience of anti-psychotic drugs in other cancer models simply justify their potential to be repurposed as cheaper and effective chemotherapeutic agents.
Moreover, the use of anti-psychotic drugs as monotherapy agents or adjuvants transcend gender, age, psychological status, and glioma grade among patients. Notwithstanding, the application of anti-psychotic drugs in glioma management still require further and deeper evaluation, particularly in regard to its bioavailability, safety and optimal dosage, tumor multi-resistance and microenvironment as well as potential side-effects.
Additionally, the lack of clinical documentation that supports the use of anti-psychotic drugs in inducing cellular differentiation and tumor control in glioma therapy further necessitates its clinical evaluation.
In doing so, retrospective studies would also be beneficial in providing information regarding their safety and confirming their influence on survival and response rates in glioma patients. One of the findings in this review accentuated the encouraging and positive outcomes of VPA as an adjunct in improving the symptoms and survival among pediatric glioma patients.
In this regard, it would be interesting to determine VPA use in combination with current radio-chemotherapy settings on a larger scale in clinical trials, and hence validate its beneficial therapeutic role.
Most of the collective reports suggest a multimodal therapy approach that includes the use of anti-psychotic drugs as adjuvants to radio-chemotherapy. It is noteworthy that glioma is not a single disease and therefore, a monotherapy regime may not be suitable for every patient. Moreover, polytherapy confers the benefits of targeting multiple treatment issues such as chemoresistance due to multidrug resistant protein, epilepsy or depression onset, chemo- and radio-sensitization and tumor cell killing via pleotropic molecular targets.
In doing so, it is essential to determine whether the administration of anti-psychotic drugs may increase Tmz bioavailability during treatment which thereby might explain the radio-chemo-sensitization effects observed in both in vivo and clinical studies. Furthermore, the ability of anti-psychotics to target multiple signaling pathways via activation or inactivation of various downstream targets that underlie their anticancer effects in Tmz-resistant and Tmz-sensitive tumors further justifies their use in polytherapy.
Anti-psychotic drugs other than VPA lack clinical evaluation, which might depreciate their preclinical therapeutic efficacy. Hence, extensive retrospective, prospective, observational and randomized clinical studies are required to further validate their preclinical anti-glioma activities.
Additionally, clinical evaluations of VPA mainly reported positive impacts on high-grade glioma patients, but confounding observations in limited reports regarding low-grade glioma patients. These contradictory observations of VPA effects in glioma further necessitate wider clinical studies that include different glioma grades to justify its clinical use as an adjuvant in a polytherapy approach.
Despite the therapeutic advances offered by anti-psychotic drugs in preclinical and clinical settings, it is noteworthy that most drugs such as LiCl and VPA might possess a narrow therapeutic window and can be toxic at higher doses or chronic administration.
Patients reported pausing or stopping the intake of anti-psychotic drugs due to side-effects, and in certain cases patients demonstrated accelerated disease progression or relapse. Additionally, the high- and low-range of concentrations of anti-psychotic drugs also demonstrated contradictory glioma growth activities. Therefore, detailed pharmacokinetic and toxicity analyses are required to determine the ideal concentration that provides optimal therapeutic efficacy with marginal side-effects.
In short, based on various preclinical and clinical studies, anti-psychotic drugs hold substantial therapeutic value not only in the modulation of psychotic symptoms and seizures, but more importantly, as potential anti-neoplastic and adjuvant agents in glioma management. Hence, extensive preclinical and clinical studies would further strengthen the evidence of their therapeutic efficacy and repurpose their use in human glioma management.
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