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

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2021-10, Vol.23 (10), p.1723-1735
• Main Authors: Tonogai, Emily J, Huang, Shan, Botham, Rachel C, Berry, Matthew R, Joslyn, Stephen K, Daniel, Gregory B, Chen, Zixin, Rao, Jianghong, Zhang, Xiang, Basuli, Falguni, Rossmeisl, John H, Riggins, Gregory J, LeBlanc, Amy K, Fan, Timothy M, Hergenrother, Paul J
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Basic and Translational Investigations; Caspase 3; Cell Culture Techniques; Cell Line, Tumor; Dogs; Humans; Hydroxyurea - pharmacology; Meningeal Neoplasms - drug therapy; Meningeal Neoplasms - veterinary; Meningioma - drug therapy; Meningioma - veterinary; Temozolomide - pharmacology
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/noab161

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.