Understanding Efficacy and Fe(II)-Promoted Activation of 1,2,4-Trioxolanes in Cancer

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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.