Targeting autophagy to increase the sensitivity of LKB1-deficient lung tumors to angiogenesis inhibitor

靶向自噬提高 LKB1 缺陷型肺部肿瘤对血管生成抑制剂的敏感性

基本信息

批准号：
10669269
负责人：
Yanxiang Guo
金额：
$ 17.98万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10669269
关键词：
Ablation Accounting Amino Acids Angiogenesis Inhibitors Autophagocytosis Blood Blood Vessels Cancer Etiology Cancer Patient Cell physiology Cells Cessation of life Clinical Research Clinical Trials Combined Modality Therapy Compensation Data Eating Fatty Acids Frequencies Growth Homeostasis Hydroxychloroquine Hypoxia Isotopes K-ras mouse model KRAS2 gene Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Malnutrition Mediating Metabolic Metabolic stress Metabolism Mitochondria Mutation Mutation Detection Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Nucleotides Nutrient Nutrient Depletion Nutrient availability Oxidation-Reduction Patients Play Proliferating Property Recycling Reporting Resistance Role STK11 gene Solid Neoplasm Source Starvation Symbiosis TP53 gene Testing Therapeutic Translating Tumor Angiogenesis angiogenesis antitumor effect bevacizumab cancer cell cancer therapy chemotherapy clinical translation extracellular in vivo inhibition of autophagy inhibitor innovation lung tumorigenesis metabolomics mitochondrial metabolism mouse model mutant neoplastic cell novel novel therapeutic intervention novel therapeutics nutrient deprivation patient derived xenograft model pre-clinical predictive marker programs resistance mechanism resistance mutation response stem tumor tumor growth tumor metabolism tumorigenesis uptake wasting

项目摘要

ABSTRACT Lung cancer is the leading cancer killer worldwide, with non-small cell lung cancer (NSCLC) accounting for more than 85% of these cases. KRAS and LKB1 are the two most frequent mutations detected in lung cancer patients. Lung cancer patients bearing co-mutations of KRAS and LKB1 show increased aggressiveness, a high frequency of metastases, and resistance to all standard therapies. Cancer cells acquire nutrients from circulating blood. Angiogenesis inhibitors, which block the growth of blood vessels, have been used for lung cancer treatment. However, multiple preclinical as well as clinical studies have reported that LKB1 depletion confers resistance to angiogenesis inhibitors, regardless of whether or not receiving chemotherapy. One of acquired resistance to antiangiogenics stems from tumor adaptations by induction of metabolic symbiosis. Autophagy is a process that cell eats itself to generate building blocks, energy, and redox homeostasis, and for elimination of waste in response to metabolic stress, such as nutrient depletion. Many studies including our group have proved that in response to extracellular nutrient deprivation, cancer cells can scavenge nutrients through autophagy- mediated intracellular recycling for tumor growth, proliferation, survival, and malignancy. Therefore, simultaneously eliminating nutrient availability from both intracellular and extracellular sources could be an innovative strategy for a successful cancer treatment. In particular, we recently demonstrated that autophagy is upregulated in Kras-mutant Lkb1-deficient (KL) lung tumor and autophagy inhibition is synthetically lethal in KL- mediated tumorigenesis. Moreover, anti-tumor effect by autophagy ablation is much more profound in Lkb1- deficient KL lung tumor than Lkb1 wild type (WT) KP (Kras-mutant p53-deficient) lung tumor. Based on above rationale and preliminary studies, we formed central hypothesis: autophagy-mediated intracellular recycling compensates for nutrient deprivation caused by angiogenesis inhibitor to support the survival and growth of KL lung tumor. We will: 1) determine the role and mechanism of cell-autonomous autophagy in conferring resistance of KL lung tumor to angiogenesis inhibitor; and 2) Determine if targeting autophagy can sensitize Lkb1-deficient KL lung tumor, but not Lkb1-WT KP lung tumor, to angiogenesis inhibitor. Our study will determine if LKB1 mutations could be explored as a predictive biomarker for precision lung cancer therapy using the combination of autophagy inhibitor and angiogenesis inhibitor. Once our hypothesis is confirmed in preclinical mouse models, the novel therapy of autophagy inhibitor hydroxychloroquine combined with angiogenesis inhibitor Bevacizumab can be naturally and immediately translated into clinical trials for treating lung cancer patients harboring co- mutations of KRAS and LKB1.

抽象的肺癌是全球头号癌症杀手，其中非小细胞肺癌（NSCLC）占比更高超过这些案例的 85%。 KRAS 和 LKB1 是肺癌患者中最常见的两种突变。携带 KRAS 和 LKB1 共突变的肺癌患者表现出攻击性增加，转移的频率以及对所有标准疗法的耐药性。癌细胞从循环中获取营养血。血管生成抑制剂可阻止血管生长，已用于治疗肺癌治疗。然而，多项临床前和临床研究表明，LKB1 缺失会导致对血管生成抑制剂的耐药性，无论是否接受化疗。获得的其中之一对抗血管生成药物的耐药性源于肿瘤通过诱导代谢共生的适应。自噬是细胞吞噬自身以产生构建模块、能量和氧化还原稳态的过程，并消除因代谢压力（例如营养耗尽）而产生的废物。包括我们小组在内的许多研究都证明为了应对细胞外营养缺乏，癌细胞可以通过自噬清除营养介导肿瘤生长、增殖、存活和恶性肿瘤的细胞内循环。所以，同时消除细胞内和细胞外来源的营养供应可能是一种成功癌症治疗的创新策略。特别是，我们最近证明自噬是在 Kras 突变型 Lkb1 缺陷 (KL) 肺肿瘤中表达上调，并且自噬抑制在 KL- 中是综合致死的介导的肿瘤发生。此外，自噬消融的抗肿瘤作用在 Lkb1- 中更为深远。 KL 缺陷型肺肿瘤优于 Lkb1 野生型 (WT) KP（Kras 突变型 p53 缺陷型）肺肿瘤。基于以上基本原理和初步研究，我们形成了中心假设：自噬介导的细胞内循环补偿血管生成抑制剂引起的营养缺乏，以支持 KL 的生存和生长肺部肿瘤。我们将：1）确定细胞自主自噬在赋予耐药性中的作用和机制 KL肺肿瘤对血管生成抑制剂的影响； 2) 确定靶向自噬是否可以使 Lkb1 缺陷敏感 KL肺肿瘤，但不是Lkb1-WT KP肺肿瘤，为血管生成抑制剂。我们的研究将确定 LKB1 是否使用该组合可以探索突变作为精准肺癌治疗的预测生物标志物自噬抑制剂和血管生成抑制剂。一旦我们的假设在临床前小鼠模型中得到证实，自噬抑制剂羟氯喹联合血管生成抑制剂贝伐珠单抗的新疗法可以自然地立即转化为治疗患有共病的肺癌患者的临床试验 KRAS 和 LKB1 突变。