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.

项目概要自噬是一种由激酶 ULK1 控制的细胞内回收过程，对于生存至关重要和 KRAS 突变肺肿瘤的生长。我们的团队和其他人已经证明，营养紧张的非小细胞肺癌 (NSCLC) 细胞对 ULK1 抑制高度敏感，这表明营养耗尽导致肿瘤生长可能会导致自噬抑制的脆弱性。因为该领域缺乏有效且有选择性的为了体内靶向 ULK1 的小分子抑制剂，我们开发并发表了一种有效的、选择性的 ULK1 抑制剂，ULK-101。在此应用中，我们建议进行临床前研究，以进一步开发 ULK-101 作为抗癌剂，我们将单独评估该化合物以及与分子靶向药物联合使用疗法。我们假设 ULK-101 将通过抑制 ULK1 来抑制自噬，从而减少 KRAS 驱动肺部肿瘤生长并提高治疗效果。为了检验我们的假设，我们提出以下目标：具体目标#1：确定有效且选择性的 ULK1 抑制剂对自噬和肿瘤的功效突变 KRAS 驱动的 NSCLC 的负担。在目标 1 中，我们将确定 ULK- 的自噬抑制水平 101 植入肺肿瘤细胞中。这些 KRASG12C 肺癌异种移植模型将用于测试假设 ULK-101 治疗可减少肿瘤进展，并且 KRAS 和 ULK1 双重靶向将是治疗 KRASG12C 驱动的肺部肿瘤的有效策略。具体目标#2：确定 ULK1 抑制剂在基因工程中的治疗潜力非小细胞肺癌小鼠模型。在目标2中，我们将测试小分子抑制剂ULK-101是否会减少肿瘤在 NSCLC 的 KrasLSL-G12D 和 KrasLSL-G12C 小鼠模型中作为单一药物的负担。此外，我们预计 ULK-101 将增强肿瘤对临床相关疗法的敏感性，包括第一个 KRAS 靶向疗法药物（AMG-510），在非小细胞肺癌（NSCLC）的临床试验中显示出希望。这里使用的小鼠模型补充了异种移植模型以具有功能性免疫系统、适当部位的肿瘤和疾病的小鼠为特征与人类肺癌的进展相似。我们将通过一种新的抑制自噬途径来利用 KRAS 驱动的肿瘤的独特脆弱性分子靶向治疗，ULK-101。虽然历史证明直接针对 KRAS 具有挑战性，但临床试验的早期结果令人鼓舞，是等位基因特异性抑制剂最近取得的突破 AMG-510，一种 G12C 特异性 KRAS 抑制剂。最终，我们希望将 ULK-101 作为单一药物进行评估并与 AMG-510 等其他疗法相结合，将提供必要的数据作为基础为肺癌患者提供新的、更有效的治疗方法。

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。