Defining the role of macropinocytosis in solid tumor growth and therapeutic resistance

定义巨胞饮作用在实体瘤生长和治疗耐药中的作用

基本信息

批准号：
10640820
负责人：
Aimee L Edinger
金额：
$ 44.74万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10640820
关键词：
Address Amino Acids Anabolism Anthracycline Antigen Presentation Antigen-Presenting Cells Antigens Antineoplastic Agents Autophagocytosis Bladder Blood Blood Vessels Breast Breast Cancer Cell Breast Cancer Model Breast Cancer cell line Cancer Patient Carbohydrates Cell Death Cell physiology Cells Cessation of life Chemicals Clinical Collecting Cell Colon Carcinoma Colorectal Combined Modality Therapy Consumption Data Dependence Digestion Disabled Persons Drug Targeting Drug resistance Effectiveness Epidermal Growth Factor Receptor Equilibrium Extracellular Protein FDA approved Failure Genetic Goals Growth Immune Immune checkpoint inhibitor Inflammatory Innate Immune System KRAS2 gene Knowledge Lipids Lung Lysosomes Macrophage Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Malignant neoplasm of prostate Malignant neoplasm of urinary bladder Metabolic Metabolic Pathway Metabolism Metastatic breast cancer Molecular Mutation Necrosis Neoplasms in Vascular Tissue Nucleotides Nutrient Oncogenes Oncogenic Outcome PIK3CG gene Pancreas Pathway interactions Patients Pattern Play Prevalence Process Productivity Proliferating Proteins Proto-Oncogene Proteins c-akt Publishing Recycling Research Risk Role Side Signal Transduction Solid Neoplasm Source Starvation Stream Supporting Cell Testing Therapeutic Tumor Promotion WNT Signaling Pathway Work anti-tumor immune response cancer cell cancer therapy castration resistant prostate cancer chemotherapy combination cancer therapy defined contribution extracellular in vivo inhibitor innovation interstitial macromolecule neoplastic cell novel nucleotide metabolism pre-clinical preservation pressure prevent prostate cancer cell response standard of care targeted cancer therapy therapeutic target therapy resistant tool trafficking treatment strategy triple-negative invasive breast carcinoma tumor tumor growth tumor metabolism tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

ABSTRACT Cancer cells require a steady stream of nutrients to support their oncogene-driven growth. However, the blood vessels that supply these nutrients are often tortuous and leaky. Desmoplasia can also lead to elevated interstitial pressure that collapses tumor blood vessels, further compromising nutrient delivery. Cancer cells overcome these supply-side limitations by scavenging macromolecules from the microenvironment. One scavenging strategy employed by tumors is macropinocytosis, a process by which extracellular material is non- specifically engulfed and then degraded in the lysosome to produce nutrients. Oncogenic mutations in RAS, activation of the PI3K pathway, and EGFR and WNT signaling drive macropinocytosis in pancreatic, prostate, lung, colon, bladder, and breast cancer cell lines. When provided with macropinocytic fuel, these cancer cells are able to proliferate in nutrient-limiting conditions. However, is not currently clear whether the quantity and quality of material present in the tumor microenvironment is sufficient for macropinocytosis to make a significant contribution to tumor anabolism. All published studies have depended upon EIPA for in vivo macropinocytosis inhibition. EIPA is an inhibitor of Na+/H+ exchangers that has pleiotropic anti-neoplastic effects independent of macropinocytosis inhibition. What is currently lacking is a strategy to selectively disrupt macropinocytosis in vivo. As a result, it has not been possible to accurately define the contribution of macropinocytosis to tumor growth or the potential therapeutic value of targeting this pathway. Given that nutrient recycling via autophagy plays a major role in both tumor progression and therapeutic resistance, it is likely that nutrient scavenging through macropinocytosis will play a similarly important role. Aim 1 of this proposal will assess the extent to which selective macropinocytosis inhibition limits tumor growth. Aim 2 will evaluate the role of macropinocytosis in therapeutic resistance. Aim 3 will dissect the signals that promote macropinosome formation in tumor cells. Completing these studies will fill major gaps in our knowledge and could lead to new single-agent and/or combination therapies for cancer. Because some of the most difficult to treat cancers are macropinocytic (e.g. pancreas, KRAS+ colorectal, triple-negative breast, and castration- resistant prostate cancers), these studies have the potential to make a significant impact on patient survival.

抽象的癌细胞需要稳定的营养物质来支持其癌基因驱动的生长。然而，血提供这些营养物质的血管通常是曲折且渗漏的。结缔组织增生也可导致升高间质压力使肿瘤血管塌陷，进一步损害营养输送。癌细胞通过从微环境中清除大分子来克服这些供应方的限制。一肿瘤采用的清除策略是巨胞饮作用，这是细胞外物质非特异性地被吞噬，然后在溶酶体中降解以产生营养物质。 RAS 致癌突变， PI3K 通路的激活以及 EGFR 和 WNT 信号传导驱动胰腺、前列腺、肺癌、结肠癌、膀胱癌和乳腺癌细胞系。当提供巨胞饮燃料时，这些癌细胞能够在营养限制条件下增殖。但目前尚不清楚数量和数量是否肿瘤微环境中存在的物质质量足以使巨胞饮作用产生对肿瘤合成代谢有重要贡献。所有已发表的研究均依赖于 EIPA 进行体内研究巨胞饮作用抑制。 EIPA 是一种 Na+/H+ 交换剂抑制剂，具有多效性抗肿瘤作用影响与巨胞饮抑制无关。目前缺乏的是选择性破坏的策略体内巨胞饮作用。因此，目前还无法准确定义其贡献。巨胞饮作用对肿瘤生长或针对该途径的潜在治疗价值。鉴于通过自噬的营养循环在肿瘤进展和治疗耐药性中发挥着重要作用，通过巨胞饮作用进行的营养物清除可能也将发挥同样重要的作用。这个目标1 该提案将评估选择性巨胞饮抑制限制肿瘤生长的程度。目标2将评估巨胞饮作用在治疗耐药中的作用。目标 3 将剖析促进的信号肿瘤细胞中巨脂质体的形成。完成这些研究将填补我们知识和领域的重大空白可能会导致新的癌症单药和/或联合疗法。因为有些最难治疗巨胞饮癌症（例如胰腺癌、KRAS+结直肠癌、三阴性乳腺癌和去势癌）耐药性前列腺癌），这些研究有可能对患者的生存产生重大影响。