ULK1 Inhibitor in Combination with Immune Checkpoint Blockade in PancreaticCancer

ULK1 抑制剂与免疫检查点阻断联合治疗胰腺癌

• 批准号: 10576633
• 负责人: Jeffrey Paul MacKeigan
• 金额: $ 21.95万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-09 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10576633
• 关键词: Address; American; Antimalarials; Autophagocytosis; Benchmarking; Cancer cell line; Cell Line; Cell Survival; Cell surface; Cells; Cessation of life; Chemotherapy and/or radiation; Clinic; Combination immunotherapy; Curative Surgery; Cyclic AMP-Dependent Protein Kinases; DNA Binding; Data; Dependence; Development; Diagnosis; Disease; Disease Progression; Environment; Excision; Extracellular Matrix Proteins; Face; Fibroblasts; Genetic; Genetic Complementation Test; Genetic Engineering; Genetically Engineered Mouse; Half-Life; Human; Hydroxychloroquine; Immune; Immune Evasion; Immune system; Immunotherapy; Impairment; Investigation; KRAS oncogenesis; KRAS2 gene; KRASG12D; Laboratories; MEKs; Major Histocompatibility Complex; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Metabolic; Modeling; Mus; Mutation; NOD/SCID mouse; Nutrient; Oncogenic; Organ; Pancreas; Pancreatic Ductal Adenocarcinoma; Patients; Phosphotransferases; Play; Pre-Clinical Model; Predisposition; Process; Qualifying; Radiation therapy; Recycling; Refractory; Reporting; Role; Site; Specificity; Starvation; Stress; Stromal Cells; Survival Rate; TP53 gene; Technology; Testing; Therapeutic; Tissues; Translations; Treatment Efficacy; Tumor Burden; Tumor Immunity; Tumor Suppressor Proteins; Tumor Tissue; United States; Xenograft procedure; anti-PD-1; cancer cell; cancer therapy; chemoproteomics; drug testing; efficacy evaluation; immune checkpoint blockade; improved; in vivo; inhibition of autophagy; inhibitor; innovation; mouse model; mutant; neoplastic cell; novel; pancreatic cancer cells; pancreatic cancer model; pancreatic cancer patients; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; pancreatic neoplasm; pancreatic stellate cell; pharmacologic; pre-clinical; preclinical development; side effect; small molecule inhibitor; synergism; targeted agent; therapy resistant; tumor; tumor growth; tumor hypoxia; tumor microenvironment; tumor progression

PROJECT SUMMARY Pancreatic cancer is responsible for the third most cancer-related deaths in the United States, and >60,000 Americans will be diagnosed in 2022. Further, patients with pancreatic ductal adenocarcinoma (PDAC) face a 5-year survival rate of less than 5%. Although the genetic drivers of PDAC have been well established, these cancers remain largely refractory to treatment. To survive, PDACs depend on autophagy, an intracellular nutrient recycling process. Autophagy provides an internal nutrient pool for tumor cell survival, and pancreatic stellate cells also use autophagy to support their metabolic demands. Further, autophagy contributes to immune evasion, a well-known therapeutic challenge in PDAC. Consistent with these roles, genetic autophagy inhibition has been shown to reduce PDAC tumor growth; however, the translation of these discoveries is limited by a lack of pharmacologic autophagy inhibitors available for preclinical use. To address this problem, our lab developed a potent and selective small molecule inhibitor of ULK1 (ULK-101), a protein kinase that controls autophagy induction. Importantly, we have shown that starved cancer cells are highly sensitive to ULK1 inhibition, consistent with autophagy-dependent survival during stress. While several ULK1 inhibitors exist, we have demonstrated that ULK-101 is the most potent and selective to date and the ideal candidate for preclinical investigations. Therefore, we propose to evaluate the effects of ULK-101 in mouse models of pancreatic cancer. We hypothesize that ULK-101 will suppress autophagy through ULK1 inhibition and thereby reduce pancreatic tumor growth and improve therapeutic efficacy. Aim 1 will use an orthotopic tumor model using human pancreatic cancer cell lines (MIA PaCa-2 and PANC-1) to test whether ULK-101 treatment reduces tumor progression in vivo. We will then use these orthotopic models to assess target engagement and ULK-101 selectivity by measuring ULK1 inhibition using chemoproteomics. These orthotopic models will also be used to evaluate the effect of ULK-101 on tumor progression, which we will benchmark against hydroxychloroquine, an approved lysosomal inhibitor. For Aim 2, we will use a syngeneic orthotopic tumor model with 7940b murine cells and the established pancreatic KPC mouse (LSL-KrasG12D/+, LSL-Trp53R172H/+, Pdx1-cre model) to test whether ULK-101 will decrease tumor burden. Because autophagy inhibition sensitizes PDACs to immunotherapy, we will also evaluate ULK-101 in combination with dual immune checkpoint blockade (anti-CTL4 and anti-PD-1). The genetically engineered mouse model in Aim 2 features a functional immune system, tumors at the appropriate site, and disease progression that parallels human pancreatic cancer. Through these thorough in vivo studies, we will examine ULK1 inhibition as a strategy for treating pancreatic cancer and may provide evidence for further development of ULK-101 and novel autophagy inhibitors.

项目摘要 胰腺癌是美国第三大癌症相关死亡原因， 美国人将在2022年被确诊。此外，患有胰腺导管腺癌（PDAC）的患者面临着 5-年生存率低于5%。虽然PDAC的遗传驱动因素已经很好地建立，但这些 癌症在很大程度上仍然难以治疗。为了生存，PDAC依赖于自噬，一种细胞内营养素 回收过程。自噬为肿瘤细胞存活提供了内部营养库， 细胞还利用自噬来支持它们的代谢需求。此外，自噬有助于免疫逃避， 这是PDAC中众所周知的治疗挑战。与这些作用相一致，遗传自噬抑制已经被证明是有效的。 显示减少PDAC肿瘤生长;然而，这些发现的转化受到缺乏 可用于临床前使用的药理学自噬抑制剂。 为了解决这个问题，我们的实验室开发了一种有效的选择性ULK 1小分子抑制剂（ULK-101）， 一种控制自噬诱导的蛋白激酶重要的是，我们已经证明饥饿的癌细胞是 对ULK 1抑制高度敏感，与应激期间的自噬依赖性存活一致。虽然若干 ULK-101抑制剂存在，我们已经证明ULK-101是迄今为止最有效和最具选择性的， 临床前研究的候选人。因此，我们建议评估ULK-101在小鼠中的作用， 胰腺癌的模型。我们假设ULK-101将通过抑制ULK 1抑制自噬， 从而减少胰腺肿瘤生长并提高治疗效果。 目标1将使用人胰腺癌细胞系（MIA PaCa-2和PANC-1）的原位肿瘤模型 以测试ULK-101治疗是否在体内减少肿瘤进展。然后我们将使用这些原位模型 通过使用化学蛋白质组学测量ULK 1抑制来评估靶标接合和ULK-101选择性。 这些原位模型也将用于评估ULK-101对肿瘤进展的影响，我们将 与羟氯喹（一种已批准的溶酶体抑制剂）相比，对于目标2，我们将使用同基因的 用7940 b鼠细胞和建立的胰腺KPC小鼠（LSL-KrasG 12 D/+， LSL-Trp 53 R172 H/+，Pdx 1-cre模型），以测试ULK-101是否会降低肿瘤负荷。因为自噬 抑制使PDAC对免疫疗法敏感，我们还将评估ULK-101与双重免疫疗法的组合。 检查点阻断（抗CTL 4和抗PD-1）。Aim 2中的基因工程小鼠模型具有以下特征： 功能性免疫系统，适当部位的肿瘤，以及与人类相似的疾病进展 胰腺癌 通过这些彻底的体内研究，我们将检查ULK 1抑制作为治疗胰腺癌的策略， 并可能为进一步开发ULK-101和新型自噬抑制剂提供证据。