Proximal Differentiation Therapy for K-Ras-Induced Lung Adenocarcinoma

K-Ras 诱导的肺腺癌的近端分化治疗

• 批准号: 10045952
• 负责人: Mark Onaitis
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-10-01 至 2021-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10045952
• 关键词: Adenocarcinoma; Alleles; Biological Assay; Cancer Patient; Cell Communication; Cells; Characteristics; Clinical; Complex; Data; Development; Differentiation Therapy; Distal; EZH2 gene; Epidermal Growth Factor Receptor; Epithelial Cells; Event; Genes; Genetic; Genetic Recombination; Genetic Transcription; Glare; Goals; Heterogeneity; Human; Human Cell Line; In Vitro; Interruption; KRAS2 gene; Knock-out; Lead; Lesion; Light; LoxP-flanked allele; Lung; Lung Adenocarcinoma; Maintenance; Malignant neoplasm of lung; Mus; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenes; Pathway interactions; Patients; Peripheral; Phenotype; Prognostic Factor; Proliferating; Publishing; Signal Pathway; Smoking; Structure of respiratory epithelium; TP53 gene; Testing; Therapeutic; Transgenic Mice; Tumor Suppression; Type II Epithelial Receptor Cell; Up-Regulation; Validation; Veterans; cell transformation; chemosensitizing agent; efficacy testing; experimental study; genetic approach; high throughput screening; in vitro Assay; in vivo; individualized medicine; inhibitor/antagonist; military veteran; mimetics; mortality; mouse genetics; mutant; notch protein; novel; novel strategies; novel therapeutic intervention; novel therapeutics; progenitor; programs; response; stem cells; therapeutic target; transcription factor; treatment strategy; tumor; tumor initiation; tumor xenograft

ABSTRACT Individualized therapeutics for K-RAS mutant lung adenocarcinoma are nonexistent. Recently, we have described a unique interaction between activated K-Ras and the Type II cell that explains the unique ability of the Type II cell to proliferate in response to K-Ras activation. The absence of the transcription factor Sox2 allows Notch to be upregulated when K-Ras is activated. In addition, K-Ras is able to induce a transcriptional program that dedifferentiates distal lung epithelial cells into distal progenitors that are proliferative and multipotent during development. These distal stem cells express Sox9 as well as Ezh2. In this proposal, we will examine the effects of proximalizing Type II cells with Sox2 activation and Notch inhibition and Ezh2 inhibition on tumor initiation in Aim 1. This will involve inducible mouse transgenic alleles and human cell lines and human cells and tumors. We will also test the efficacy of a novel Sox2- mimetic compound, RepSox, for anti-tumor activity in K-Ras activated distal epithelial cells. In Aim 2, we will test the hypothesis that proximalization of the Type II cells suppresses progression of established K- Ras mutant adenocarcinomas. Finally, in Aim 3, we will assess the tumor suppression of Sox2 activation and Notch inhibition in more genetically complex tumors (K-Ras mutant, p53 knockout). We hypothesize that proximalization therapy will be tumor suppressive and potentially also chemosensitizing. Successful completion of these aims could help tens of thousands of patients per year. 1

摘要 K-RAS突变型肺腺癌的个体化治疗尚不存在。最近我们 描述了激活的K-Ras和II型细胞之间独特的相互作用，解释了 II型细胞响应K-Ras活化而增殖的能力。没有转录本 当K-Ras被激活时，因子Sox 2允许Notch被上调。此外，K-Ras能够诱导 将远端肺上皮细胞去分化为远端祖细胞的转录程序， 在发育过程中增殖和多能。这些远端干细胞表达Sox 9以及Ezh 2。 在这个提议中，我们将研究Sox 2激活和Notch对接近II型细胞的影响。 抑制和Ezh 2抑制对Aim 1中肿瘤起始的作用。这将涉及诱导小鼠转基因 等位基因和人类细胞系以及人类细胞和肿瘤。我们还将测试一种新的Sox 2的有效性， 模拟化合物RepSox在K-Ras活化的远端上皮细胞中的抗肿瘤活性。在目标2中， 将检验II型细胞的近端化抑制已建立的K- Ras突变型腺癌。最后，在目标3中，我们将评估Sox 2激活的肿瘤抑制作用。 和Notch抑制在更遗传复杂的肿瘤（K-Ras突变体，p53敲除）。我们假设 近端化治疗将是肿瘤抑制性的，并且还可能是化学增敏性的。成功 若能达到这些目标，每年可帮助数以万计的病人。 1

项目成果

Activation of KrasG12D in Subset of Alveolar Type II Cells Enhances Cellular Plasticity in Lung Adenocarcinoma.

• DOI: 10.1158/2767-9764.crc-22-0408
• 发表时间: 2023-11-24
• 期刊: CANCER RESEARCH COMMUNICATIONS
• 作者: Chaudhary, Priyanka;Xu, Xia;Wang, Guangfang;Hoj, Jacob P.;Rampersad, Rishi R.;Asselin-Labat, Marie-Liesse;Ting, Stephanie;Kim, William;Tamayo, Pablo;Pendergast, Ann Marie;Onaitis, Mark W.
• 通讯作者: Onaitis, Mark W.