Evaluating a Novel Autophagy Inhibitor in KRAS-Driven Lung Cancer

项目摘要 自噬是由激酶ULK 1控制的细胞内再循环过程，其在存活中是重要的。 和KRAS突变型肺肿瘤的生长。我们的团队和其他人已经证明，营养应激的非小细胞 肺癌（NSCLC）细胞对ULK 1抑制高度敏感，这表明营养耗尽导致了 肿瘤生长可能会产生对自噬抑制的脆弱性。因为这个领域缺乏有效性和选择性 小分子抑制剂，靶向ULK 1在体内，我们已经开发和出版了一种有效的和选择性的 ULK 1抑制剂，ULK-101。在本申请中，我们建议进行临床前研究，以进一步开发ULK-101作为 抗癌剂，我们将评估该化合物单独使用和与分子靶向药物联合使用。 治疗我们假设ULK-101将通过抑制ULK 1来抑制自噬，从而减少 KRAS驱动肺肿瘤生长并提高治疗效果。为了验证我们的假设，我们提出了 以下目标： 具体目标#1：确定有效和选择性ULK 1抑制剂对自噬和肿瘤的疗效 突变型KRAS驱动的NSCLC中的负荷。在目标1中，我们将建立ULK-1抑制自噬的水平。 101在移植的肺肿瘤细胞中。这些KRASG 12 C肺癌异种移植物模型将用于测试 ULK-101治疗减少肿瘤进展和KRAS和ULK 1双重靶向假设 将是KRASG 12 C驱动的肺肿瘤的有效策略。 具体目标#2：确定ULK 1抑制剂在基因工程中的治疗潜力 NSCLC小鼠模型。在目标2中，我们将测试小分子抑制剂ULK-101是否会减少肿瘤细胞的生长， 在NSCLC的KrasLSL-G12 D和KrasLSL-G12 C小鼠模型中作为单药负荷。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），以显示在NSCLC的临床试验的承诺。这里使用的小鼠模型补充了 异种移植模型，通过具有功能性免疫系统的小鼠、适当部位的肿瘤和疾病 与人类肺癌的进展平行的进展。 我们将利用KRAS驱动的肿瘤中独特的脆弱性，通过抑制自噬途径， 分子靶向治疗ULK-101虽然直接针对KRAS历来具有挑战性， 是最近在等位基因特异性抑制剂方面的一个突破，这是由临床试验中有希望的早期结果所推动的 AMG-510，一种G12 C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等其他治疗药物联合使用，将提供必要的数据，作为 新的和更有效的治疗肺癌患者。

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.