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

Tonogai, Emily J.

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

Description

Title

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

Author(s)

Tonogai, Emily J.

Issue Date

2022-08-17

Director of Research (if dissertation) or Advisor (if thesis)

Hergenrother, Paul J

Doctoral Committee Chair(s)

Hergenrother, Paul J

Committee Member(s)

• Mitchell, Douglas A
• Chan, Jefferson
• Mehta, Angad P

Department of Study

Chemistry

Discipline

Chemistry

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

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

Abstract

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.

Graduation Semester

2022-12

Type of Resource

Thesis

Copyright and License Information

Copyright 2022 Emily Tonogai

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