# Characterization of drug mechanisms of lethality in vivo

> **NIH NIH R21** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $430,684

## Abstract

PROJECT SUMMARY/ABSTRACT
Understanding mechanisms of drug action is important for identifying settings in which a drug will be effective,
and for interpreting – even predicting – potential mechanisms of drug resistance. For anti-cancer drugs, a key
aspect of their mechanism of action is the mechanism by which these drugs promote cell death. The first
identified death pathway was apoptosis, a form of death that is now reasonably understood. In addition, it has
long been known that cells can also die in non-apoptotic ways. The conventional wisdom had been that these
necrotic forms of death are not regulated; that is, that they do not result from activation of defined signaling
cascades or use of specific effector molecules. It is now clear that this traditional thinking is incorrect. Several
distinct forms of regulated necrosis have now been identified. As the definition of regulated cell death has
expanded, so has our understanding that anti-cancer drugs generally have the capacity to activate multiple
types of cell death. The exact composition of death types, and how/why these vary across contexts remains
challenging to study due to the lack of tools for simultaneously evaluating all mechanisms of cell death from a
single sample. To address these issues, we propose to develop a targeted sgRNA library that can be used to
infer which type of death is activated in vivo. This proposal focuses on the development, optimization, and
failure testing of this new tool, to establish the utility and resolution limits of this method. Our tool will be
evaluated in the context of drugs that inhibit histone deacetylases (HDACs), which we have previously found to
induce varied forms of cell death across doses and environments. The methods developed in this proposal
have the potential to be transformative by providing the first insights into the mechanisms of regulation for
many understudied types of necrotic death and by enabling new studies that explore how these mechanisms
vary across dose, time, and disease contexts.

## Key facts

- **NIH application ID:** 10952172
- **Project number:** 1R21CA294000-01
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Michael Jungho Lee
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $430,684
- **Award type:** 1
- **Project period:** 2024-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10952172

## Citation

> US National Institutes of Health, RePORTER application 10952172, Characterization of drug mechanisms of lethality in vivo (1R21CA294000-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10952172. Licensed CC0.

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