World Hypertension Day 2024: Theme, Significance And Why You Should Regularly Monitor BP
Neuroactive Drugs Show Promising Anti-glioblastoma Effects In Preclinical Trials
Researchers find that the antidepressant vortioxetine may offer new hope for glioblastoma patients by crossing the blood-brain barrier and significantly reducing tumor size in preclinical models.
Study: High-throughput identification of repurposable neuroactive drugs with potent anti-glioblastoma activity. Image Credit: Elif Bayraktar / Shutterstock.Com
A recent Nature Medicine study evaluates the potential to repurpose currently approved drugs to treat cancer and neurological disorders for their therapeutic effects against glioblastoma.
Current treatment strategies for glioblastomaGlioblastoma is an incurable and fatal type of brain cancer, with about 50% of patients dying within twelve months of diagnosis. The life expectancy of glioblastoma patients can be extended through radiation, chemotherapy, or surgical interventions.
Many drugs that are used to treat cancer cannot cross the blood-brain barrier (BBB), thus limiting the utility of these agents in treating brain tumors like glioblastoma. Targeted therapies have been associated with limited success in the treatment of glioblastoma due to the lack of clinically predictive patient model systems, as well as the presence of treatment-resistant glioblastoma stem cells (GSCs).
Recent studies investigating the pathophysiology of glioblastoma have reported synaptic integration of cancer cells into neural circuits, stemness signatures resembling neural development, and the modulation of specific neurotransmitter pathways in the tumor microenvironment (TME). These characteristics may reflect vulnerabilities of glioblastoma cells, which may be therapeutically relevant, particularly when investigating the potential repurposing of existing 'neuroactive' drugs (NADs).
The lack of effective treatments for managing glioblastoma emphasizes the importance of identifying neurotherapeutic vulnerabilities that can guide future drug discovery in this field. To date, the anti-cancer activity of most NADs has not been evaluated for the treatment of glioblastoma.
About the studyPharmacoscopy is an ex vivo image-based drug screening approach that has been validated in functional precision medical trials assessing the effects of novel agents in the treatment of hematological malignancies. In the current study, researchers used pharmacoscopy to simultaneously test the in vitro and in vivo efficacy of both neuroactive and oncology drug (ONCD) libraries against glioblastoma patient samples.
The neuroactive drug library consisted of drugs capable of crossing the BBB that are currently approved for the treatment of neurological diseases like Alzheimer's disease, depression, and schizophrenia. Comparatively, the ONCD drug library consisted of conventional cancer treatments, such as cyclin-dependent kinase (CDK) and receptor tyrosine kinase (RTK) inhibitors.
A total of 130 different agents were used to treat tumor tissues isolated from 27 patients who recently underwent surgery at the University Hospital Zurich. Imaging techniques and computer analysis were used to identify drugs that influenced cancer cells.
Study findingsSeveral ONCDs were capable of penetrating the BBB, which included elesclomol, osimertinib, and regorafenib.
Certain patient characteristics increased the sensitivity of their tumor cells to specific ONCDs. For example, age was associated with greater sensitivity to elesclomol, tumor samples obtained from patients with TP53 mutations were more sensitive to CDK4/6 inhibitor abemaciclib, and patients with the loss of rearranged during transfection (RET) copies were more sensitive to pazopanib.
Fifteen NADs exhibited anti-glioblastoma activity, with vortioxetine, an antidepressant, inducing significant ex vivo efficacy in about 67% of patient samples. Other potent NADs were paroxetine, fluoxetine, and brexpiprazole.
Higher sertindole sensitivity was observed among patients with fibroblast growth factor receptor 2 (FGFR2) copy number loss. Moreover, higher ex vivo sensitivity to brexpiprazole was observed in male patients.
A machine learning approach was designed to search for the convergence of secondary drug targets analyzed by regularized regression (COSTAR). This model tested over one million substances for their effectiveness against glioblastoma and documented neuroactive convergence on activating protein 1 (AP-1)/BTG-driven glioblastoma suppression. The joint signaling cascade of cancer and neural cells is important and key to elucidating the selective therapeutic efficacy of certain NADs.
Vortioxetine was consistently the most effective NAD in vivo, especially in combination with the current standard treatment. Furthermore, the survival benefits associated with vortioxetine treatment were significant and similar to those of alkylating agent temozolomide (TMZ).
Magnetic resonance imaging (MRI) scans of transplanted mice showed a significant reduction in tumor size post-treatment with vortioxetine. In vitro, vortioxetine reduced glioblastoma growth, clonogenic survival, and invasiveness.
Consistent with previously reported findings, paliperidone and citalopram were not associated with any survival benefit. The ineffectiveness of citalopram suggests that anti-glioblastoma efficacy is not conferred solely by serotonin modulation.
ConclusionsDiverse NADs, particularly the antidepressant vortioxetine, led to rapid glioblastoma cell death.
Although the study findings are promising, vortioxetine should not be used in the treatment of glioblastoma without proper medical supervision, as its efficacy has only been proven in vitro and in mice. Thus, future clinical studies are needed to evaluate the therapeutic efficacy of vortioxetine in human glioblastoma patients.
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PAH Therapy Reverses Blood Vessel Remodeling In Preclinical Model
Cereno Scientific's investigational therapy CS014 was found to reverse remodeling, meaning alterations in structure and arrangement, of pulmonary arteries in a preclinical model of pulmonary arterial hypertension (PAH).
According to the company, the new preclinical data "provide the most compelling evidence to date that CS014 offers a disease modifying approach to PAH and related pulmonary vascular diseases by robustly reversing pulmonary pathological [disease-causing] vascular remodeling and fibrosis," or tissue thickening and scarring.
The preclinical model exhibits many features of PAH, including pulmonary vascular remodeling and fibrosis, per Cereno.
"The CS014 effects in the preclinical model are impressive and give us a very good basis to target diseases of vascular remodeling and fibrosis in future clinical trials," Nicholas Oakes, PhD, Cereno's head of preclinical development, said in a company press release.
Further details and results will be disclosed in a future scientific publication, the company said.
CS014 now being tested in Phase 1 clinical trialPAH is characterized by the narrowing of the pulmonary arteries — the blood vessels that supply the lungs. Such narrowing restricts blood flow and increases blood pressure, potentially leading to right heart failure. Arterial narrowing occurs as a result of pulmonary vascular remodeling, a process that involves the uncontrolled growth of smooth muscle cells that progressively thicken the arterial walls.
CS014 works as an epigenetic modulator, meaning it makes changes to how genes are read, but not to the DNA sequence itself. It's designed to block histone deacetylase (HDAC), a class of enzymes that make DNA less accessible for the production of proteins.
The therapy is being developed to prevent thrombosis — when blood clots block veins or arteries — without increasing the risk of bleeding. According to Cereno, additional benefits are expected, including less inflammation, fibrosis, and vascular remodeling, as well as lower blood pressure.
Besides a dose-dependent reversal of vascular remodeling in the lung, the results seen in the preclinical model included statistically significant reductions in small artery vessel occlusion, less fibrosis, and smaller plexiform lesions. These lesions are a PAH hallmark characterized by complex blood vessel formations originating from remodeled pulmonary arteries.
The results suggest that CS014 may be a disease-modifying therapy for PAH, according to Cereno.
A Phase 1 clinical trial testing the therapy's safety, tolerability, and pharmacological properties started dosing patients in June. The trial will have two parts, with part one assessing the safety, tolerability and pharmacological profile of single ascending oral doses of CS014. Part two will explore the treatment candidate's safety, tolerability, and pharmacology following multiple ascending doses given over seven days.
Results of the study are expected in approximately one year.
"I am happy to share progress in our HDAC inhibitor program, adding to the plethora of evidence supporting the concept of HDAC inhibition and epigenetic modulation as relevant approaches for disease modifying therapies in cardiovascular diseases," said Sten R. Sörensen, CEO of Cereno.
The company is also developing another HDAC inhibitor, CS1, a reformulation of an antiseizure medication that also works as an epigenetic modulator. CS1 is undergoing a Phase 2 trial (NCT05224531) involving about 30 people. Preliminary results from the first participant who completed the study were positive, with reduced pulmonary hypertension and improved cardiac output — the amount of blood pumped by the heart — and physical function. Top-line data from that study are expected soon.
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