Identifying the basis for anticancer synergy with PAC-1, with applications to meningioma

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.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2022

Author dc:creator

• Tonogai, Emily J.

Contributors dc:contributor

• Hergenrother, Paul J
• Mitchell, Douglas A
• Chan, Jefferson
• Mehta, Angad P

• cancer
• meningioma
• uveal melanoma
• PAC-1
• caspase
• procaspase
• small molecule
• comparative oncology
• canine

Statement dc:rights

• Copyright 2022 Emily Tonogai

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/117518

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F117518