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Exploring Collateral Lethality for Development of Cancer Therapeutics

探索癌症治疗开发的附带致死率

基本信息

批准号：
10365970
负责人：
RONALD ANTHONY DEPINHO
金额：
$ 46.43万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-09 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10365970
关键词：
3-Dimensional Allosteric Site Animal Model Applications Grants Attention Biological Assay Branched-Chain Amino Acids CDKN2A gene CRISPR/Cas technology Cancer Etiology Carbonic Acid Cell Line Cell Proliferation Cells Cessation of life Clinical Clustered Regularly Interspaced Short Palindromic Repeats DNA Sequence Alteration Data Development Diagnostic Dimerization Disease Documentation Engineering Enzymes Event Extinction (Psychology)Financial compensation Generations Genes Genetic Genomics Goals Housekeeping Human Hypersensitivity Immunologic Markers In Vitro KRAS2 gene Knock-out MADH4 gene Maintenance Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Measures Metabolic Metabolic Marker Mitochondria Modeling Molecular Target Morphology Mutate Mutation Nature Neoplasm Metastasis Oncogenes Onset of illness Pancreatic Ductal Adenocarcinoma Patients Pharmaceutical Preparations Plasma Play Proteins Proteomics Role Route Site Structure System TP53 gene Therapeutic Therapeutic Agents Time Toxic effect Translating Tumor Suppressor Genes Tumor Suppressor Proteins Validation amino acid metabolism base cancer cell design early detection biomarkers enzyme deficiency gain of function mutation genomic signature in silico in vivo inhibitor innovation knock-down malic enzyme metabolomics molecular targeted therapies mutant new therapeutic target novel pancreatic cancer cells pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model patient derived xenograft model pre-clinical precision medicine prostate cancer model siRNA delivery small molecule inhibitor therapeutic target therapeutically effective tool transcriptomics tumor tumor progression uptake virtual screening

项目摘要

Project Summary Pancreatic cancer remains the most lethal disease with no effective therapeutics. We have recently made conceptual advances in targeting signature genomic deletions, a hallmark of human cancers. We demonstrated earlier that passenger deletions could confer cancer cell specific vulnerabilities, which we termed “Collateral Lethality”. We deployed this concept in targeting the SMAD4 deletion, which occurs frequently in pancreatic cancer, and have identified malic enzyme (ME) 3 as a target for collateral lethality in SMAD4-deleted pancreatic tumor cells harboring adjacent deletion of malic enzyme 2. We unexpectedly discovered that mitochondrial malic enzymes are required for the uptake of branched chain amino acids (BCAAs) in pancreatic cancer, which has been implicated as a diagnostic plasma marker for early detection of pancreatic cancer. Our overall goals are: to validate ME3 as a therapeutic target for pancreatic cancer in vitro and in PDX models (Aim 1) and in vivo using chimeric PDAC model (Aim 2); and to identify useful therapeutic agents that specifically target ME2 deleted cells (Aim 3). Our goals align well with the NCI directive on “Scientific Framework for Pancreatic Ductal Adenocarcinoma.”

项目摘要胰腺癌仍然是最致命的疾病，没有有效的治疗方法。我们最近做出了靶向特征基因组缺失的概念进展，这是人类癌症的标志。我们早些时候证明，乘客删除可以赋予癌细胞特异性的脆弱性，我们被称为“附带致死”我们将这一概念应用于SMAD 4删除，经常在胰腺癌中，并已确定苹果酸酶（ME）3作为靶点的附带致死性， SMAD 4缺失的胰腺肿瘤细胞携带苹果酸酶2的相邻缺失。我们出乎意料地发现线粒体苹果酸酶是摄取支链氨基酸所必需的（支链氨基酸）在胰腺癌中的作用，它已被认为是早期检测胰腺癌的诊断性血浆标志物。胰腺癌我们的总体目标是：在体外验证ME 3作为胰腺癌的治疗靶点以及在PDX模型中（目的1）和在体内使用嵌合PDAC模型（目的2）;并鉴定有用的治疗性药物特异性靶向ME 2缺失细胞的药剂（Aim 3）。我们的目标与NCI指令一致，胰腺导管腺癌的科学框架。