2026-09-22T16:38:59Z https://www.ideals.illinois.edu/oai-pmh

oai:www.ideals.illinois.edu:2142/117518 2025-11-07 col_2142_5131 col_2142_14789 com_2142_5130 com_2142_14788 com_2142_8903

Hergenrother, Paul J Hergenrother, Paul J Mitchell, Douglas A Chan, Jefferson Mehta, Angad P 2022-12 application/pdf en text Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2024-12-01 The student, Emily Tonogai, accepted the attached license on 2022-08-02 at 12:58. The student, Emily Tonogai, submitted this Dissertation for approval on 2022-08-02 at 13:05. This Dissertation was approved for publication on 2022-08-17 at 09:28. DSpace SAF Submission Ingestion Package generated from Vireo submission #18441 on 2023-04-12 at 11:34:08 Identifying the basis for anticancer synergy with PAC-1, with applications to meningioma Tonogai, Emily J. 2022-08-17 cancer meningioma uveal melanoma PAC-1 caspase procaspase small molecule comparative oncology canine The procaspase-3/-7 activator, PAC-1, selectively activates apoptosis in cancerous cells by leveraging the overexpression of caspase-3 in a broad spectrum of cancer types. This unique mechanism is thought to contribute to the ability of PAC-1 to synergize with a variety of different therapeutics, which has been demonstrated in numerous literature reports. Herein, previously reported combinations with PAC-1 in different cancer types will be reviewed and recent research on new combinations will be described. In particular, focus will be placed on PAC-1 in combination with temozolomide (TMZ) and hydroxyurea (HU) in high-grade meningioma, a rare form of brain cancer with no FDA-approved therapies. PAC-1 + TMZ was found to have activity in canine patients with meningioma. Additionally, recent work has demonstrated the synergy of PAC-1 in combination with the NTRK/ROS1/ALK inhibitor entrectinib, in metastatic uveal melanoma which has led to a clinical trial. Further efforts to evaluate the synergy of this combination and understand its mechanism will also be described. While PAC-1 has been reported to synergize with a broad spectrum of therapeutics, the underlying mechanism of this synergy has not yet been investigated. The diversity of caspase substrates cleaved during apoptosis may contribute to the ability of PAC-1 to synergize with such a wide variety of different therapies. To begin investigating the source of PAC-1’s broad synergy, the effect of PAC-1 on proteins involved in DNA repair pathways are investigated as many of these have been reported as caspase substrates. Understanding the proteins affected by PAC-1- induced caspase activity may inform our understanding of published PAC-1 combinations as well as aid in the design of novel combinations. Thesis eng https://hdl.handle.net/2142/117518 Copyright 2022 Emily Tonogai Ph.D. Dissertation Chemistry University of Illinois at Urbana-Champaign Chemistry