# Understanding efficacy and FE(II)-Promoted Activation of 1,2,4-Trioxolanes in cancer

> **NIH NIH R01** · FRED HUTCHINSON CANCER CENTER · 2024 · $655,693

## Abstract

Project Summary/Abstract
Summary: Precision cancer medicine’s foundation lies in discovering and exploiting pathways that are essential
for cancer cells, but dispensable for cancer cells. While such pathways exist, they are relatively uncommon.
Much more often the oncogenic pathways activated in cancer cells are essential for many healthy cells as well,
at least in some adult tissue. This unfortunate fact is referred to as a low Therapeutic Index (TI), and frustrates
many promising cancer treatments. This project seeks to improve the TI of inhibitors of critical effectors of the
RAS MEK ERK pathway in the deadliest human cancers using Fe(II) activation of drugs and developing new,
Fe(II) activatable therapies.
Background: As cancer cells transform from normal to malignant, they incur metabolic and potentially
pharmacologic liabilities. Their handling of iron in its most dangerous form, the Fe(II) state, is particularly
dysregulated, leading to an increased labile iron pool (LIP). We invented a new way to preferentially target tumor
cells based on increased avidity for, and elevated concentrations of labile Fe2+ with an Iron-Activated Drug
Conjugate (FeADC) ap
pro
ach inspired by a clinically validated 1,2,4-trioxolane (TRX) moiety with Fe2+-
dependent pharmacology. The cancer cell then activates the FeADC and is exposed to the payload. We are
focusing on MEK inhibitors because 1) their therapeutic index is low, 2) they hold promise in KRAS-driven solid
tumors and 3) the KRAS oncogene drives increases in the LIP to a level we think exploitable.
Methods: First we will validate the efficacy of our modified MEK inhibitor and a modified chemotherapeutic in an
autochthonous, immunocompetent model of mouse lung cancer driven by KrasG12D. We will then use cutting edge
functional screening to identify the cellular enzymes needed to activate (uncage) the FeADC into active payloads
in the cancer cell. We will then further develop the Fe(II)-Promoted Activation of 1,2,4-Trioxolanes to induce a
specialized form of cellular death known as ferroptosis in cancer cells.
Impact: This project focuses on a improving the therapeutic index of targeted inhibitors, especially in the most
underserved tumors; those with KRAS mutations. We have the potential to immediately impact a large swath of
anticancer therapeutics via our flexible and powerful prodrug approach. Through better understanding of the
mechanisms of cellular Fe(II)-Promoted Activation of 1,2,4-Trioxolanes, we may also develop new classes of
anticancer compounds called FeADCs and leveraging ferroptosis as a therapeutic endpoint in our developmental
studies.

## Key facts

- **NIH application ID:** 11062969
- **Project number:** 7R01CA260860-04
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Eric Collisson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $655,693
- **Award type:** 7
- **Project period:** 2021-04-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11062969

## Citation

> US National Institutes of Health, RePORTER application 11062969, Understanding efficacy and FE(II)-Promoted Activation of 1,2,4-Trioxolanes in cancer (7R01CA260860-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11062969. Licensed CC0.

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