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.

抽象的我们的首要目标是评估表观遗传的治疗潜力和作用机制肺腺癌 (LUAD) 中的调节因子 NSD2。肺癌是最常见的癌症原因—— 美国和全世界的相关死亡率，每年导致超过 180 万人死亡。 LUAD是它的最常见的肺癌组织学类型。虽然新的靶向疗法和免疫疗法已经改善了中位不幸的是，过去 20 年来 LUAD 患者的生存率一直在改善增量。因此，人们对识别可能与规范合作的新因素非常感兴趣。驱动 LUAD 的致癌途径的概念是，打击多种途径的治疗策略将通过降低每种药物所需的总剂量和并行战斗来减轻潜在的药物毒性抵抗力的发展。这里要测试的一个中心假设是临床上可操作的组蛋白赖氨酸 36（H3K36）二甲基转移酶NSD2就是这样一个因子。在前期工作中我们发现 NSD2 在经典 LUAD 小鼠模型中促进侵袭性恶性肿瘤进展和快速致死。在我们的提案中，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使用一流的 NSD2 抑制剂和状态直接测试 NSD2 靶向治疗的功效最先进的 LUAD 临床前模型。在目标 1 中，我们研究了 NSD2 在肺癌发病机制中的作用。我们开发了 KRASG12C- 驱动NSD2可调小鼠肺癌模型，研究升高的功能和作用机制或在 LUAD 起始、进展、转移和瘤内异质性中 NSD2 活性耗尽。目标 2 我们使用一流的 NSD2 强效抑制剂评估 NSD2 抑制的治疗效果。我们将利用基因模型，例如由 KRASG12C 突变驱动的 LUAD 和多个患者衍生的 LUAD 异种移植物测试 NSD2 抑制作为单一药物和联合疗法的一部分的抗肿瘤功效。在一起，这个这项工作将是第一个评估 NSD2 在 LUAD 中的治疗潜力和作用机制的工作。