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Evaluating a Novel Autophagy Inhibitor in KRAS-Driven Lung Cancer

评估 KRAS 驱动的肺癌中的新型自噬抑制剂

基本信息

批准号：
10197467
负责人：
Jeffrey Paul MacKeigan
金额：
$ 40.24万
依托单位：
MICHIGAN STATE UNIVERSITY
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：
2021-04-06 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10197467
关键词：
Address Adjuvant Affect Alleles Antimalarials Antineoplastic Agents Autophagocytosis CRISPR/Cas technology Cancer Model Cancer Patient Cancer cell line Cell Culture Techniques Cell Line Cell Survival Cells Clinical Clinical Drug Development Clinical Trials Complement DNA Binding Data Development Disease Progression Drug Targeting Drug usage Endocytosis Face Foundations Genetic Genetic Engineering Growth Half-Life Human Hydroxychloroquine Immune Immune system Impairment In Vitro K-ras mouse model KRAS oncogenesis KRAS2 gene Laboratories Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mediating Metabolic Modeling Mus Mutation Non-Small-Cell Lung Carcinoma Nude Mice Nutrient Nutrient Depletion Oncogenic Oncology Pathway interactions Phagocytosis Pharmacology Phosphotransferases Play Pre-Clinical Model Process Publishing Recycling Research Retinal Diseases Role Signal Transduction Site Specificity Stress Testing Therapeutic Time Tissues Treatment Efficacy Tumor Burden Tumor Tissue Xenograft Model Xenograft procedure anti-cancer cancer cell cancer therapy chemoproteomics clinically relevant detection of nutrient effective therapy improved in vivo inhibition of autophagy inhibitor/antagonist lung cancer cell molecular targeted therapies mouse model mutant neoplastic cell novel partial response pre-clinical precision medicine preclinical study side effect small molecule small molecule inhibitor subcutaneous tool development treatment strategy tumor tumor growth tumor metabolism tumor progression

项目摘要

PROJECT SUMMARY Autophagy is an intracellular recycling process controlled by the kinase ULK1 that is important in the survival and growth of KRAS mutant lung tumors. Our team and others have shown that nutrient-stressed non-small cell lung cancer (NSCLC) cells are highly sensitive to ULK1 inhibition, which suggests that nutrient depletion caused by tumor growth may create vulnerability to autophagy inhibition. Because the field lacks potent and selective small-molecule inhibitors that target ULK1 in vivo, we have developed and published a potent and selective ULK1 inhibitor, ULK-101. In this application, we propose preclinical studies to further develop ULK-101 as an anti-cancer agent, and we will evaluate the compound both alone and in combination with molecularly-targeted therapies. We hypothesize that ULK-101 will suppress autophagy through ULK1 inhibition and thereby reduce KRAS-driven lung tumor growth and improve therapeutic efficacy. To test our hypothesis, we propose the following aims: Specific Aim #1: Determine the efficacy of a potent and selective ULK1 inhibitor on autophagy and tumor burden in mutant KRAS-driven NSCLC. In Aim 1, we will establish the level of autophagy inhibition by ULK- 101 in engrafted lung tumor cells. These KRASG12C lung cancer xenograft models will be used to test the hypothesis that ULK-101 treatment reduces tumor progression and that dual targeting of both KRAS and ULK1 will be an effective strategy for KRASG12C driven lung tumors. Specific Aim #2: Establish the therapeutic potential of an ULK1 inhibitor in genetically engineered NSCLC mouse models. In Aim 2, we will test whether the small molecule inhibitor ULK-101 will decrease tumor burden as a single agent in a KrasLSL-G12D and KrasLSL-G12C mouse models of NSCLC. Further, we expect that ULK-101 will enhance the sensitivity of tumors to clinically relevant therapies, including the first KRAS-targeted drug (AMG-510), to show promise in clinical trials of NSCLC. The mouse models used here complement the xenograft models by featuring mice with a functional immune system, tumors at the appropriate site, and disease progression that parallels the progression of human lung cancer. We will exploit a unique vulnerability in KRAS-driven tumors by inhibiting the autophagy pathway with a novel molecularly targeted therapy, ULK-101. While directly targeting KRAS has historically proven challenging, there has been a recent breakthrough with allele-specific inhibitors, prompted by promising early results in clinical trials with AMG-510, a G12C-specific KRAS inhibitor. Ultimately, we hope that evaluating ULK-101 as a single agent and in combination with other therapeutics like AMG-510, will provide essential data to serve as a foundation for new and more effective treatments for lung cancer patients.

项目总结

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Quantitative Analysis of Autophagy in Single Cells: Differential Response to Amino Acid and Glucose Starvation.

单细胞自噬的定量分析：对氨基酸和葡萄糖饥饿的差异反应。

DOI：
10.1101/2023.12.01.569679
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Martin,KatieR;Celano,StephanieL;Sheldon,RyanD;Jones,RussellG;MacKeigan,JeffreyP
通讯作者：
MacKeigan,JeffreyP

Molecular dynamics simulations provide insights into ULK-101 potency and selectivity toward autophagic kinases ULK1/2.

分子动力学模拟可深入了解 ULK-101 对自噬激酶 ULK1/2 的效力和选择性。