(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测试新的目标策略，以调节耐药性的出现和演变。 AIM 1重点是评估治疗相关的靶向突变如何影响自发疾病模型的回归和复发。旨在控制已知MLN4924抗性机制的类型和频率的前体策略将与体内治疗相关的复发进行比较，以描绘出强烈单一的靶向药物的选择性压力如何驱动癌细胞的进化。 AIM 2测试一种使用较不选择的NAE抑制剂来瞬时抑制MLN4924电阻的策略，通过提供低水平的次级选择压力。 AIM 3决定了在NAE中如何提供已知耐药性热点的不同选择性压力影响MLN4924治疗凝聚力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的研究将建立针对旨在抑制和潜在逆转治疗剂耐药性的靶向疗法的新的合理范例。