# Small Molecule Activators of Procaspases as Anti-Cancer Agents

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2021 · $403,281

## Abstract

The overexpression of procaspase-3 (PC-3) in diverse tumor types presents an exploitable weakness in
cancer and an opportunity for selective induction of apoptotic death in cancer cells. This proposal is a
renewal of R01-CA120439, whose major goals included the investigation of the potential of the PC-3
activator PAC-1 in the treatment of glioblastoma (GBM) and metastatic osteosarcoma. These past four
years have been very successful and as a result of these studies PAC-1 is now in a single-agent Phase 1
clinical trial (for late stage human cancer patients) and a combination clinical trial (for human glioblastoma
patients), with other trials to being in 2018. Our work has shown that PAC-1 treatment, through activation
of PC-3 to caspase-3, can induce cleavage of key caspase-3 substrates in cancer cells, leading to
pronounced synergy with certain anticancer drugs. In the proposed work we will identify the most promising
PAC-1/drug combinations for the treatment of Grade II/III meningioma, taking advantage of a key feature of
PAC-1 (its blood-brain barrier penetrance) and utilizing our novel translational pathway (evaluation in pet
dogs with meningioma). We have also found that PAC-1 markedly synergizes with drugs that hit targets in
the MAPK pathway, due to the ability of PAC-1 to induce cleavage and inactivation of MEK1 and MEK2.
This discovery will be explored through investigation of PAC-1 combinations in non-small cell lung cancer
models, utilizing mouse models of metastases to the CNS. Finally, based on known caspase-3 substrates
and preliminary data, we hypothesize that PAC-1 will have considerable mechanism-based synergy with
immune checkpoint inhibitors through the facile cleavage and inactivation of the protein MLH1 by caspase-
3. Logical extension of this data would suggest that such mechanism-based synergy with PAC-1 could lead
to immune checkpoint inhibitors being active in a much higher percentage of cancer patients, an exciting
possibility. This is a hypothesis-driven proposal with high potential for fundamental and translational impact.

## Key facts

- **NIH application ID:** 10220860
- **Project number:** 5R01CA120439-14
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Paul Hergenrother
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $403,281
- **Award type:** 5
- **Project period:** 2007-08-06 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10220860

## Citation

> US National Institutes of Health, RePORTER application 10220860, Small Molecule Activators of Procaspases as Anti-Cancer Agents (5R01CA120439-14). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10220860. Licensed CC0.

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