Therapeutic Targeting of NSD2 in Lung Adenocarcinoma

NSD2 在肺腺癌中的治疗靶向

基本信息

批准号：
10657069
负责人：
Or P. Gozani
金额：
$ 66.86万
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：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10657069
关键词：
Acceleration Adverse event Biochemical CRISPR interference Cancer Etiology Cancer Model Cells Cessation of life Chromatin Clinical Combined Modality Therapy DNA methylation profiling Disease Dose Drug Targeting Drug resistance Drug toxicity Enzymes Epigenetic Process Epitopes Evolution Future Gene Expression Genetic Models Goals Heterogeneity Histologic Histones Immunotherapy KRAS2 gene KRASG12D Lung Adenocarcinoma Lysine MAP Kinase Gene MAP2K1 gene Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Mammalian Cell Measures Medicine Methylation Methyltransferase Modeling Molecular Mus Mutation Neoplasm Metastasis Oncogenic Outcome Output Pathogenesis Pathogenicity Pathologic Pathway interactions Patients Pre-Clinical Model Prognosis Proteins Regulation Reporting Resistance development Resolution Role Signal Transduction System Technology Testing Therapeutic Treatment Efficacy Treatment outcome United States Up-Regulation Work Xenograft procedure clinical prognosis clinically actionable combat efficacy testing experimental study human model immune checkpoint blockade improved in vivo inhibitor insight interest lung cancer cell mortality mouse model multiple omics mutant nanomolar neoplastic cell novel pre-clinical programs small molecule inhibitor standard of care targeted treatment therapeutic target transcriptomic profiling translational study tumor tumor growth tumor heterogeneity tumor progression

项目摘要

ABSTRACT Our overarching goal is to evaluate the therapeutic potential and mechanism-of-action of the epigenetic regulatory factor NSD2 in lung adenocarcinoma (LUAD). Lung cancer is the most common cause of cancer- related mortality in the United States and worldwide, leading to over a 1.8 million deaths each year. LUAD is its most common histological type of lung cancer. While new targeted and immunotherapies have improved median survival for LUAD patients, unfortunately, improvement in outcomes over the past 20 years has been incremental. Thus, there is great interest in identifying novel factors that might cooperate with the canonical oncogenic pathways that drive LUAD with the notion that a therapeutic strategy hitting multiple pathways will mitigate potential drug toxicity by lowering the overall dose needed for each medicine and in parallel combat resistance development. A central hypothesis to be tested here is that the clinically actionable and histone lysine 36 (H3K36) di-methyltransferase enzyme NSD2 is such a factor. In preliminary work we found that NSD2 promotes aggressive malignant tumor progression and rapid lethality in a classis LUAD mouse model. In our proposal, we will investigate the molecular, epigenetic, cellular, and in vivo role of NSD2-H3K36me2 axis in lung cancer and directly test the efficacy of NSD2-targeted therapy using a first-in-class NSD2 inhibitor and state-of- the-art pre-clinical models of LUAD. In Aim 1 we investigate the role of NSD2 in lung cancer pathogenesis. We have developed a KRASG12C- driven NSD2 tunable mouse lung cancer model to investigate the function and mechanism of action of elevated or depleted NSD2 activity in LUAD initiation, progression, metastasis, and intratumoral heterogeneity. In Aim 2 we evaluate therapeutic efficacy of NSD2 inhibition using a first-in-class potent inhibitor of NSD2. We will utilize genetic models such as LUAD driven by KRASG12C mutations and multiple patient derived LUAD xenografts to test anti-tumor efficacy of NSD2 inhibition as a single agent and as part of combination therapies. Together, this work will be the first to evaluate the therapeutic potential and mechanism-of-action of NSD2 in LUAD.

抽象的我们的总体目标是评估表观遗传学的治疗潜力和作用机理肺腺癌（LUAD）中的调节因子NSD2。肺癌是癌症的最常见原因在美国和全球的相关死亡率，每年导致180万人死亡。 luad是它的最常见的肺癌组织学类型。虽然新的靶向和免疫疗法改善了中位数不幸的是，LUAD患者的生存期在过去20年中的结果有所改善增量。因此，识别可能与规范合作的新因素非常感兴趣驱动LUAD的致癌途径，即击中多个途径的治疗策略通过降低每种药物所需的总体剂量和并行战斗来减轻潜在的药物毒性抵抗发展。这里要测试的中心假设是临床起作用和组蛋白赖氨酸 36（H3K36）DI-甲基转移酶NSD2就是这样的因素。在初步工作中，我们发现NSD2 促进攻击性恶性肿瘤进展和快速致死性在LUAD小鼠模型中。在我们的提案，我们将研究NSD2-H3K36me2轴在肺中的分子，表观遗传，细胞和体内作用癌症并直接使用一流的NSD2抑制剂和最新的NSD2靶向治疗的疗效 LUAD的艺术前模型。在AIM 1中，我们研究了NSD2在肺癌发病机理中的作用。我们已经开发了Krasg12c- 驱动的NSD2可调小鼠肺癌模型，以研究升高的作用的功能和机理或在LUAD启动，进展，转移和肿瘤内异质性中耗尽的NSD2活性。在目标2中我们使用NSD2的第一类势抑制剂评估NSD2抑制的治疗功效。我们将利用 KRASG12C突变驱动的LUAD和多个患者衍生的LUAD异种移植物等遗传模型测试NSD2抑制作用作为单一药物的抗肿瘤功效，并作为联合疗法的一部分。一起，这个工作将是第一个评估LUAD中NSD2的治疗潜力和行动机理的工作。