权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10368053
负责人：
Aimee L Edinger
金额：
$ 10.96万
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/10368053
关键词：
Address Amino Acids Anabolism Anthracycline Antigen Presentation Antigen-Presenting Cells Antigens Antineoplastic Agents Autophagocytosis Blood Blood Vessels Breast 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 Lead Lipids Lysosomes 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 Pancreas Pathway interactions Patients Pattern Play Prevalence Process Proliferating Proteins Proto-Oncogene Proteins c-akt Publishing Recycling Research Risk Role Side Signal Transduction Solid Neoplasm Source Starvation Stream Supporting Cell Testing Therapeutic WNT Signaling Pathway Work anti-tumor immune response base cancer cell cancer therapy castration resistant prostate cancer chemotherapy combination cancer therapy defined contribution extracellular in vivo inhibitor innovation interstitial macromolecule macrophage malignant breast neoplasm neoplastic cell novel nucleotide metabolism pre-clinical preservation pressure prevent prostate cancer cell response standard of care targeted cancer therapy 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.

摘要