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(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：
8843753
负责人：
Matthew Petroski
金额：
$ 10.9万
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 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8843753
关键词：
2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole 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 cancer therapy design drug development drugged driving enzyme activity in vivo innovation novel pre-clinical pressure prevent public health relevance resistance mechanism response 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（由申请方提供）：我们将使用NEDD 8激活酶（NAE）抑制剂MLN 4924检测调节耐药性出现和演变的新型靶向策略。目的1侧重于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。将设计用于控制已知MLN 4924耐药机制的类型和频率的离体策略与体内治疗相关复发进行比较，以描述强单靶向药物的选择性压力如何驱动癌细胞进化。目的2检测了一种策略，该策略使用选择性较低的NAE抑制剂，通过提供低水平的次级选择性压力来短暂抑制MLN 4924耐药性。目的3确定在NAE的已知耐药热点提供不同的选择性压力如何影响MLN 4924治疗后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MLN 4924的研究将为靶向治疗建立新的合理范例，这些靶向治疗旨在抑制和潜在逆转治疗后出现的耐药性。