Therapeutic Targeting of NSD2 in Lung Adenocarcinoma

摘要 我们的首要目标是评估表观遗传学的治疗潜力和作用机制。 调节因子NSD2在肺腺癌中的作用肺癌是最常见的癌症原因-- 在美国和世界范围内，每年有180多万人死于相关死亡。LUAD是其 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患者的存活率在过去20年中得到了改善 递增的。因此，人们对确定可能与规范的 推动LUAD的致癌途径，认为一种治疗策略打击多条途径将 通过降低每种药物所需的总剂量和并行作战来减轻潜在的药物毒性 抗药性的发展。这里要检验的一个中心假设是，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Classsis LUAD小鼠模型中促进侵袭性恶性肿瘤的进展和快速致死性。在我们的 建议，我们将研究NSD2-H3K36me2轴在肺中的分子、表观遗传学、细胞和体内作用 并直接测试使用一流的NSD2抑制剂和状态的NSD2靶向治疗的疗效 LUAD最先进的临床前模型。 目的1研究NSD2在肺癌发病机制中的作用。我们已经开发出KRASG12C- 驱动NSD2可调小鼠肺癌模型研究升压素的功能及作用机制 或在LUAD的启动、进展、转移和肿瘤内异质性中NSD2活性减弱。在AIM 2 我们使用一种一流的有效的NSD2抑制剂来评估抑制NSD2的治疗效果。我们将利用 遗传模型，如由KRASG12C突变驱动的LUAD和多个患者来源的LUAD异种移植 作为单一药物和联合治疗的一部分，测试NSD2抑制的抗肿瘤效果。总而言之，这 这项工作将是第一次评估NSD2在LUAD中的治疗潜力和作用机制。

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.