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

了解 1,2,4-三氧戊环在癌症中的功效和 Fe(II) 促进的激活

基本信息

批准号：
10622460
负责人：
Eric Collisson
金额：
$ 62.51万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10622460
关键词：
Adult Alkylating Agents Antimalarials Antineoplastic Agents Area Avidity Cancer Patient Cells Cessation of life Chemistry Clinic Clinical Colorectal Cancer Cytotoxic agent DNA Dangerousness Development Dose Drug Delivery Systems Drug Tolerance Drug resistance Enzymes Exposure to FDA approved Foundations Frustration Genetically Engineered Mouse Growth Hepatotoxicity Human Immune checkpoint inhibitor Immunocompetent Iron KRAS2 gene KRASG12D Left Lung Adenocarcinoma MAP Kinase Gene MEK inhibition MEKs Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Maximum Tolerated Dose Medical Medical Oncologist Metabolic Methods Modality Modeling Molecular Target Mutation Normal Cell Oncogenes Oncogenic Oncology Oxidation-Reduction Pancreatic Adenocarcinoma Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Pharmaceutical Preparations Pharmacology Pre-Clinical Model Predisposition Process Prodrugs Productivity Proliferating Property Selection for Treatments Signal Transduction Solid Neoplasm Technology Therapeutic Therapeutic Index Tissues Toxic effect Treatment Efficacy Work anti-cancer anti-cancer therapeutic biomarker development cancer cell cancer therapy cell transformation cost drug development efficacy validation flexibility human subject improved in vivo inhibitor innovation invention kinase inhibitor malignant phenotype mouse model neoplastic cell novel novel strategies novel therapeutics patient derived xenograft model pharmacologic pre-clinical precision oncology preservation pressure screening small molecule success targeted agent tumor

项目摘要

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.

项目摘要/摘要摘要：精密癌症医学的基础在于发现和利用必不可少的途径对于癌细胞，但对于癌细胞来说是可分配的。尽管存在这样的途径，但它们并不常见。在癌细胞中激活的致癌途径更常见，对于许多健康细胞也至关重要至少在某些成年组织中。这个不幸的事实被称为低治疗指数（TI），并感到沮丧许多人承诺癌症治疗。该项目旨在改善抑制剂的TI，具有关键影响的抑制剂使用Fe（II）激活药物并开发新的， Fe（II）可激活疗法。背景：随着癌细胞从正常转化为恶性肿瘤，它们会产生代谢，并可能药理学负债。他们以最危险的形式处理铁（II）状态，尤其是失调，导致不稳定铁池（唇）增加。我们发明了一种优先针对肿瘤的新方法基于铁激活药物的浓度增加的流长和不稳定的Fe2+浓度升高的细胞共轭（FEADC）AP Pro ACH受到临床验证的1,2,4-三氧烷（TRX）部分的启发。依赖的药理学。然后，癌细胞激活FEADC并暴露于有效载荷。我们是专注于MEK抑制剂，因为1）他们的治疗指数较低，2）他们在KRAS驱动的固体中有希望肿瘤和3）KRAS癌基因驱动器的唇部驱动升至我们认为可以利用的水平。方法：首先，我们将验证我们改良的MEK抑制剂的效率和在 KRASG12D的小鼠肺癌驱动器自动防腐，免疫功能模型。然后，我们将使用尖端功能筛选以识别激活FADC所需的细胞酶在癌细胞中。然后，我们将进一步发展1,2,4-三氧烷的Fe（II）促进的激活以诱导A 细胞死亡的专门形式被称为癌细胞中的铁凋亡。影响：该项目着重于改善靶向抑制剂的治疗指数，尤其是在最多服务不足的肿瘤；具有KRAS突变的人。我们有可能立即影响通过我们的灵活而强大的前药方法，抗癌疗法。通过更好地理解细胞Fe（II）的机理1,2,4-三氧烷的激活，我们还可能开发新的类别抗癌化合物称为FEADC，并利用铁铁作用是我们发育中的治疗终点研究。