Oncotarget: A procaspase-3 activator and temozolomide extends survival in glioma models

Here is a link to a video interview with Dr. Gregory J. Riggins about this Research on the Oncotarget YouTube Channel

Oncotarget published "Synergistic and targeted therapy with a procaspase-3 activator and temozolomide extends survival in glioma rodent models and is feasible for the treatment of canine malignant glioma patients" which studied if PAC-1 could enhance the activity of TMZ, and whether addition of PAC-1 to standard treatment would be feasible in spontaneous canine malignant gliomas.

They investigated PAC-1 as a single agent and in combination with TMZ against glioma cells in culture and in orthotopic rodent models of glioma.

Three dogs with spontaneous gliomas were treated with an analogous human glioblastoma treatment protocol, with concurrent PAC-1. Procaspase-3 is expressed in gliomas, with higher gene expression correlating with increased tumor grade and decreased prognosis.

PAC-1 is cytotoxic to glioma cells in culture and active in orthotopic rodent glioma models.

PAC-1 added to TMZ treatments in cell culture increases apoptotic death, and the combination significantly increases survival in orthotopic glioma models.

Dr. Gregory J. Riggins from Johns Hopkins University, Dr. Paul J. Hergenrother from The University of Illinois Urbana-Champaign, and Dr. Timothy M. Fan also from The University of Illinois Urbana-Champaign said, "Gliomas are the most common type of malignant primary brain tumor, with ~17,000 newly diagnosed cases each year in the United States."

Gliomas are the most common type of malignant primary brain tumor, with ~17,000 newly diagnosed cases each year in the United States

Glioblastomas are now divided into two groups based on the presence or absence of mutations in the IDH1 or IDH2 genes.

Glioblastomas are the most aggressive and frequent of the malignant gliomas, accounting for ~80% of all malignant gliomas.

Unfortunately, glioblastomas are uniformly rapid in their progression, and lethal; standard-of-care treatment with the DNA alkylator temozolomide and radiation yields a 2-year survival rate of 27% and a 5-year survival

The Riggins Research team concluded in their Oncotarget Priority Research Paper that due to the expense of imaging, radiation therapy, and chemotherapy treatment with TMZ, limited literature precedent for the expected outcome of glioblastoma therapy in canine patients exists, although anecdotally, complete regressions are rarely observed in canine brain tumors.

Figure 5: Evaluation of combining oral PAC-1 with TMZ and definitive ionizing radiation therapy in pet dogs with non-resectable gliomas A. Schematic of treatment schedule PAC-1 was administered orally from days 1-84 (as shown by the blue horizontal line). TMZ was administered orally days 29-33 and 57-61 (indicated by red arrows). B.-D. MRI of Patient 1′s glioma on Day 0 (B, pre-treatment), Day 28 (C, post PAC-1 monotherapy), and Day 84 (D, post combination therapy). Tumors have been false-colored green. Change in tumor size from Day 0 is denoted on far right side of images. Quantification in Table 1.

Thus, the demonstrated feasibility of combining PAC-1 with conventional anti-glioma therapies such as TMZ and ionizing radiation in pet dogs with spontaneous glioma provides highly valuable translational data that can be leveraged to expedite and guide the implementation of similar therapeutic strategies for human glioblastoma patients.

PAC-1 is currently being evaluated in human cancer patients in a Phase I clinical trial.

Based upon its ability to penetrate the BBB, to bypass anti-apoptotic mechanism to induce cell death, its activating mode-of-action, and the over-expression of procaspase-3 glioblastoma, PAC-1 has the potential as an orally delivered small molecule with a capacity for both single agent anti-glioblastoma activity, as well as the ability to synergize with TMZ to increase activity and achieve more durable responses in patients.

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DOI - https://doi.org/10.18632/oncotarget.19085

Full text - https://www.oncotarget.com/article/19085/text/

Correspondence to - Gregory J. Riggins - griggin1@jhmi.edu, Paul J. Hergenrother - hergenro@illinois.edu, and Timothy M. Fan - t-fan@illinois.edu

Keywords - PAC-1, procaspase-3 activator, glioblastoma, small molecule therapy

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