Emily J Tonogai1,2, Shan Huang3, Rachel C Botham1,2, Matthew R Berry4, Stephen K Joslyn5, Gregory B Daniel6, Zixin Chen7, Jianghong Rao7, Xiang Zhang8, Falguni Basuli8, John H Rossmeisl9, Gregory J Riggins10, Amy K LeBlanc3, Timothy M Fan2,4,11, Paul J Hergenrother1,2,11. 1. Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA. 2. Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA. 3. Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA. 4. Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA. 5. VetCT Australia, Fremantle, West Australia, Australia. 6. Radiology, Department of Small Animal Clinical Sciences, Virgina-Maryland College of Veterinary Medicine, Blacksburg, Virginia, USA. 7. Departments of Radiology and Chemistry, Stanford Medicine, Stanford, California, USA. 8. Chemistry and Synthesis Center, NHLBI, NIH, Bethesda, Maryland, USA. 9. Neurology and Neurosurgery, Department of Small Animal Clinical Sciences, Virgina-Maryland College of Veterinary Medicine, Blacksburg, Virginia, USA. 10. Department of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. 11. Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
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.
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.
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