(PQD1) Treatment-emergent resistance to NEDD8-activating enzyme inhibition

(PQD1) 治疗引起的对 NEDD8 激活酶抑制的耐药性

基本信息

批准号：
8866189
负责人：
Matthew Petroski
金额：
$ 55.83万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-12 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8866189
关键词：
Address Adverse effects Affinity Attenuated Benchmarking Biological Cancer Model Cancer Patient Chemicals Clinical Complex Complication Disease Disease Progression Disease model Drug Combinations Drug Targeting Drug resistance Effectiveness Enzyme Inhibition Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Equilibrium Evolution Frequencies Gatekeeping Genetic Gold Health Human Investigation Lymphoma Lymphomagenesis Malignant Neoplasms Modeling Molecular Mono-S Mutation Patients Perception Pharmaceutical Preparations Phase I Clinical Trials Relapse Resistance Testing Therapeutic Toxic effect Ubiquitin-Activating Enzymes Xenograft Model analog base cancer cell design drug development drugged driving enzyme activity in vivo innovation novel pre-clinical pressure prevent public health relevance resistance mechanism response targeted cancer therapy targeted treatment therapy design tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): We will test novel targeted strategies to modulate the emergence and evolution of drug resistance using the NEDD8-activating enzyme (NAE) inhibitor MLN4924. Aim 1 focuses on evaluating how treatment-associated on-target mutations influence regression and relapse in spontaneous disease models. Ex-vivo strategies designed to control the types and frequencies of known MLN4924-resistance mechanisms will be compared to in vivo treatment-associated relapse to delineate how selective pressure by a strongly mono-targeted drug drives cancer cell evolution. Aim 2 tests a strategy that uses a less selective NAE inhibitor to transiently suppress MLN4924 resistance by providing a low level, secondary selective pressure. Aim 3 determines how providing distinct selective pressures at a known drug resistance hotspot in NAE influence the type and frequency of MLN4924 treatment-emergent resistance mechanisms. Collectively, our studies using the clinical NAE inhibitor MLN4924 will establish new rational paradigms for targeted therapies designed to suppress and potentially reverse treatment-emergent drug resistance.

描述（由申请人提供）：我们将使用 NEDD8 激活酶 (NAE) 抑制剂 MLN4924 测试新的靶向策略来调节耐药性的出现和演变。目标 1 重点评估治疗相关的靶向突变如何影响自发性疾病模型的消退和复发。旨在控制已知 MLN4924 耐药机制的类型和频率的体外策略将与体内治疗相关的复发进行比较，以描述强单靶向药物的选择性压力如何驱动癌细胞进化。目标 2 测试了一种策略，该策略使用选择性较低的 NAE 抑制剂，通过提供低水平的二级选择性压力来暂时抑制 MLN4924 耐药性。目标 3 确定在 NAE 的已知耐药热点处提供不同的选择压力如何影响 MLN4924 治疗出现的耐药机制的类型和频率。总的来说，我们使用临床 NAE 抑制剂 MLN4924 的研究将为旨在抑制和潜在逆转治疗中出现的耐药性的靶向治疗建立新的合理范式。