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NSD 2在肺腺癌（LUAD）中的作用。肺癌是最常见的癌症原因- 在美国和世界范围内的相关死亡率，导致每年超过180万人死亡。LUAD是其 最常见的肺癌组织类型。虽然新的靶向和免疫疗法改善了中位数， LUAD患者的生存率，不幸的是，在过去的20年中， 增量。因此，有很大的兴趣，在确定新的因素，可能与规范合作， 驱动LUAD的致癌途径，其概念是打击多个途径的治疗策略将 通过降低每种药物所需的总剂量来减轻潜在的药物毒性， 抗性发展这里要检验的一个中心假设是， 36（H3 K36）二甲基转移酶NSD 2就是这样一种因子。在初步工作中，我们发现NSD 2 在classis 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 因此，我们将研究NSD 2-H3 K36 me 2轴在肺中的分子、表观遗传、细胞和体内作用。 癌症，并直接测试NSD 2靶向治疗的疗效，使用一流的NSD 2抑制剂和 最先进的LUAD临床前模型。 在目的1中，我们研究了NSD 2在肺癌发病机制中的作用。我们开发了KRASG 12 C- 驱动的NSD 2可调小鼠肺癌模型，以研究升高的 或在LUAD起始、进展、转移和肿瘤内异质性中缺失NSD 2活性。在目标2中 我们使用第一种有效的NSD 2抑制剂评价NSD 2抑制的治疗效果。我们将利用 遗传模型，如由KRASG 12 C突变驱动的LUAD和多个患者来源的LUAD异种移植物， 测试作为单一药剂和作为组合疗法的一部分的NSD 2抑制的抗肿瘤功效。在一起，这 这项工作将是第一次评估NSD 2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.