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Principal Investigator: Eric Collisson
Organization: FRED HUTCHINSON CANCER CENTER
Fiscal Year: 2024
Award: $655,693
Funding agency: National Cancer Institute
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.
Terms: <21+ years old><Adult><Adult Human><Alkylating Agents><Alkylators><Anti-Cancer Agents><Anti-malarials><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Area><Avidity><Body Tissues><C-K-RAS><Cancer Drug><Cancer Genes><Cancer Patient><Cancer Treatment><Cancer-Promoting Gene><Cancers><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cessation of life><Checkpoint inhibitor><Chemistry><Clinic><Clinical><Colorectal Cancer><Cytotoxic agent><Cytotoxic drug><DNA><Dangerousness><Death><Deoxyribonucleic Acid><Development><Dose><Drug Delivery><Drug Delivery Systems><Drug Precursors><Drug Tolerance><Drug resistance><Drugs><Enzyme Gene><Enzymes><Exposure to><Extracellular Signal-Regulated Kinase Gene><FDA approved><Fe element><Foundations><Frustration><GEM model><GEMM model><Generalized Growth><Genetic Alteration><Genetic Change><Genetic defect><Genetically Engineered Mouse><Growth><Hepatotoxic effect><Hepatotoxicity><Human><Immune checkpoint inhibitor><Immunocompetent><Intracellular Communication and Signaling><Iron><K-RAS2A><K-RAS2B><K-Ras><K-Ras 2A><K-Ras-2 Oncogene><KRAS><KRAS(G12D)><KRAS2><KRAS2 gene><KRASG12D><Ki-RAS><Left><Liver Toxicity><Lung Adenocarcinoma><MAP Kinase Gene><MAPK><MEK inhibition><MEKs><Malignant><Malignant - descriptor><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Malignant neoplasm of pancreas><Maximal Tolerated Dose><Maximally Tolerated Dose><Maximum Tolerated Dose><Medical><Medical Oncologist><Medication><Metabolic><Methods><Mitogen-Activated Protein Kinase Gene><Modality><Modeling><Modern Man><Molecular Target><Mutation><Neoplastic Disease Chemotherapeutic Agents><Normal Cell><Oncogene K-Ras><Oncogenes><Oncogenic><Oncology><Oncology Cancer><Oxidation-Reduction><PDX model><Pancreas Adenocarcinoma><Pancreas Cancer><Pancreas Ductal Adenocarcinoma><Pancreatic Adenocarcinoma><Pancreatic Cancer><Pancreatic Ductal Adenocarcinoma><Pathway interactions><Patient derived xenograft><Patients><Pharmaceutical Preparations><Pharmacology><Pre-Clinical Model><Preclinical Models><Predisposition><Pro-Drugs><Process><Prodrugs><Productivity><Proliferating><Property><Pulmonary Cancer><Pulmonary malignant Neoplasm><RASK2><Redox><Selection for Treatments><Signal Transduction><Signal Transduction Systems><Signaling><Solid Neoplasm><Solid Tumor><Susceptibility><Technology><Therapeutic><Therapeutic Index><Tissue Growth><Tissues><Toxic effect><Toxic effect on liver cells><Toxicities><Transforming Genes><Treatment Efficacy><Tumor Cell><Tumor-Specific Treatment Agents><Work><adulthood><anti-cancer><anti-cancer drug><anti-cancer therapeutic><anti-cancer therapy><anti-malarial agents><anti-malarial drugs><biological signal transduction><biomarker development><cancer cell><cancer therapy><cancer-directed therapy><cell transformation><cost><developmental><drug development><drug resistant><drug/agent><efficacy validation><flexibility><flexible><genetically engineered mouse model><genetically engineered murine model><genome mutation><hepatic toxicity><hepatoxicity><human subject><immune check point inhibitor><immune competent><improved><in vivo><individualized cancer care><individualized oncology><inhibitor><innovate><innovation><innovative><intervention efficacy><invention><kinase inhibitor><lung cancer><malignancy><malignant phenotype><mouse model><murine model><neoplasm/cancer><neoplastic cell><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutics><novel therapy><ontogeny><oxidation reduction reaction><pancreatic malignancy><pathway><patient derived xenograft model><personalized oncology><pharmacologic><pre-clinical><precision cancer care><precision cancer medicine><precision oncology><preclinical><preservation><pressure><resistance to Drug><resistant to Drug><screening><screenings><selection of treatment><small molecule><success><targeted agent><therapeutic efficacy><therapy efficacy><therapy selection><transformed cells><treatment selection><tumor><v-Ki-RAS2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog><validate efficacy>