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

• 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
• 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

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 自噬是一种细胞内循环过程，由对生存至关重要的蛋白激酶ULK1控制。 以及KRAS突变肺肿瘤的生长。我们的团队和其他人已经证明了营养应激的非小细胞 肺癌(NSCLC)细胞对ULK1抑制高度敏感，这表明营养耗竭导致 通过肿瘤的生长可能造成对自噬抑制的脆弱性。因为这一领域缺乏强有力和选择性 在体内靶向ULK1的小分子抑制剂，我们已经开发并发表了一种有效的和选择性的 ULK1抑制剂，ULK-101。在这个应用中，我们建议进行临床前研究，以进一步开发ULK-101作为一种 抗癌药物，我们将对该化合物进行单独和结合分子靶向的评估 治疗。我们假设ULK-101将通过抑制ULK1抑制自噬，从而减少 KRAS驱动肺肿瘤生长，提高治疗效果。为了检验我们的假设，我们提出了 以下目标： 特定目标#1：确定一种有效和选择性的ULK1抑制剂对自噬和肿瘤的疗效 突变的KRAS驱动的非小细胞肺癌的负担。在目标1中，我们将建立ULK-1抑制自噬的水平。 101在肺移植瘤细胞中的表达。这些KRASG12C肺癌移植模型将用于测试 假设ULK-101治疗减缓肿瘤进展以及KRAS和ULK1的双重靶向 将是治疗KRASG12C驱动的肺癌的有效策略。 具体目标#2：在基因工程中建立ULK1抑制剂的治疗潜力 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是否会降低肿瘤 在非小细胞肺癌KrasLSL-G12D和KrasLSL-G12C小鼠模型中作为单一药物。此外，我们预计 ULK-101将增强肿瘤对临床相关治疗的敏感性，包括第一个KRAS靶向治疗 药物(AMG-510)，在非小细胞肺癌的临床试验中显示出希望。这里使用的鼠标模型是对 以免疫系统正常的小鼠、适当部位的肿瘤和疾病为特征的异种移植模型 与人类肺癌的进展相平行的进展。 我们将利用KRAS驱动的肿瘤中的一个独特的漏洞，通过一种新型的抑制自噬途径来实现 分子靶向治疗，ULK-101。虽然直接针对KRAS在历史上被证明具有挑战性，但在那里 最近在等位基因特异性抑制剂方面取得了突破，这是由临床试验中有希望的早期结果推动的 使用G12C特异性KRAS抑制剂AMG-510。最终，我们希望将ULK-101作为一种单一的药物进行评估 与AMG-510等其他疗法相结合，将提供必要的数据作为基础 肺癌患者的新的更有效的治疗方法。

项目成果

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
• 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。

• DOI: 10.1101/2023.12.01.569261
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Vaughan,RobertM;Dickson,BradleyM;Martin,KatieR;MacKeigan,JeffreyP
• 通讯作者: MacKeigan,JeffreyP