Evaluation of a procaspase-3 activator with hydroxyurea or temozolomide against high-grade meningioma in cell culture and canine cancer patients

Abstract

Background High-grade meningioma is an aggressive type of brain cancer that is often recalcitrant to surgery and radiotherapy, leading to poor overall survival. Currently, there are no FDA-approved drugs for meningioma, highlighting the need for new therapeutic options, but development is challenging due to the lack of predictive preclinical models. Methods To leverage the known overexpression of procaspase-3 in meningioma, PAC-1, a blood-brain barrier penetrant procaspase-3 activator, was evaluated for its ability to induce apoptosis in meningioma cells. To enhance the effects of PAC-1, combinations with either hydroxyurea or temozolomide were explored in cell culture. Both combinations were further investigated in small groups of canine meningioma patients and assessed by MRI, and the novel apoptosis tracer, [ 18F]C-SNAT4, was evaluated in patients treated with PAC-1 + HU. Results In meningioma cell lines in culture, PAC-1 + HU are synergistic while PAC-1 + TMZ show additive-to-synergistic effects. In canine meningioma patients, PAC-1 + HU led to stabilization of disease and no change in apoptosis within the tumor, whereas PAC-1 + TMZ reduced tumor burden in all three canine patients treated. Conclusions Our results suggest PAC-1 + TMZ as a potentially efficacious combination for the treatment of human meningioma, and also demonstrate the utility of including pet dogs with meningioma as a means to assess anticancer strategies for this common brain tumor.

Target-Agnostic P-Glycoprotein Assessment Yields Strategies to Evade Efflux, Leading to a BRAF Inhibitor with Intracranial Efficacy

“…These include periphery-limited compounds, such as ritonavir (anti-viral), − crizotinib (anti-cancer), , binimetinib (anti-cancer), , quinidine (anti-arrhythmic), ,, prazosin (anti-hypertensive), ,, vemurafenib (anti-cancer), , and terfenadine (non-drowsy anti-histamine), ,, all of which were found to have high ERs in this assay (Figure B). Compounds that have CNS indications and/or activity, such as yohimbine (reverse sedation), , PAC-1 (anti-cancer), − naltrexone (analgesic), , propranolol (anti-arrhythmic), ,, lorlatinib (anti-cancer), ,, scopolamine (anti-emetic), , trimipramine (anti-depressant), , and chlorpheniramine (drowsy anti-histamine), ,, all exhibit low ERs (less than 2.0) in this assay (Figure B). Notable examples include crizotinib and lorlatinib, shown in Figure A, ALK/ROS1 fusion inhibitors with high (ER = 10.02) and low efflux (ER = 1.22), respectively, consistent with their periphery-limited/CNS-penetrant phenotype. , …”

The combination of PAC-1 and entrectinib for the treatment of metastatic uveal melanoma

“…The mechanism underlying the synergy observed by PAC-1 and entrectinib was then studied. First, the mode of cell death induced by the combination was assessed through analysis of PARP-1 cleavage, a key marker of apoptotic cell death and expected based on the established mechanism of PAC-1 [20,25]. PARP-1 cleavage was observed in both single-agent and combination treatment of the 92.1 cell line with PAC-1 (Fig.…”

“…The tolerability of PAC-1 in the single-agent Phase 1 clinical trial in late-stage cancer patients [18], and its known ability to synergize with anticancer drugs [20,23,25] (including kinase inhibitors [22,24]) in cell culture, rodent models, and canine cancer patients suggests promise for PAC-1/drug combinations for human cancer patients. With a suite of approved drugs and clinical trial compounds, kinase inhibitors enable a facile translational path should synergistic activity be discovered, especially for otherwise untreatable cancers.…”

“…Given that single-agent activity against UM cell lines lies on the edge of PAC-1's clinically relevant serum levels, and that PAC-1 in combination with a variety of drugs (including kinase inhibitors) has shown efficacy in cell culture and animal models [20,[22][23][24][25], we assessed PAC-1 in combination with a variety of anticancer compounds (mainly kinase inhibitors) that are FDA approved or in clinical trials. PAC-1 was assessed at 2 and 4 µM, in combination with these clinically relevant anticancer compounds against the UM cell line MEL270 in a 3 × 6 matrix format.…”

Phase I dose-escalation study of procaspase-activating compound-1 in combination with temozolomide in patients with recurrent high-grade astrocytomas

“… 8 Also the PAC-1/TMZ combination was effective in treating pet dogs with meningioma, reducing tumor burden in all treated dogs. 13 Hence, PAC-1 is an attractive compound for clinical testing in primary brain cancers, especially in combination with TMZ.…”