Targeting novel therapeutic vulnerabilities in LKB1 mutant tumors.

针对 LKB1 突变肿瘤的新治疗漏洞。

基本信息

批准号：
10443802
负责人：
NABEEL El-BARDEESY
金额：
$ 66.39万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-11 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10443802
关键词：
3-Dimensional Antigen Presentation Biological Assay Biopsy Blood Cancer Patient Carbon Cell Death Cell Line Cell Survival Cells Cellular Metabolic Process Clinical Trials Combined Modality Therapy Coupled DNA Methylation DNA Methyltransferase Inhibitor DNA Modification Methylases Data Development Elements Enrollment Epithelial Cells Gene Expression Generations Genes Genetic Genetic Transcription Genetically Engineered Mouse Glucose Glycine Human Hypersensitivity Immune Immune checkpoint inhibitor Immune response Immunologic Markers Immunologic Surveillance Immunologics Immunotherapy Interferon Type I Interferons KRAS2 gene Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Mediating Metabolism Microfluidics Modeling Molecular Mus Mutate Mutation Non-Small-Cell Lung Carcinoma Nucleic Acids Nutrient Oncogenic Outcome PDL1 inhibitors Pancreatic Ductal Adenocarcinoma Patients Peripheral Blood Mononuclear Cell Phenotype Point Mutation Production Protein-Serine-Threonine Kinases Research Personnel Retrotransposon Role S-Adenosylmethionine STK11 gene Sampling Science Serine Signal Transduction Specimen System T cell response Testing Therapeutic Tissues Transcript Tumor Suppressor Proteins Tumor-infiltrating immune cells Viral Vulnerable Populations Xenograft procedure anti-PD-L1 antibodies behavioral response cancer type cell growth checkpoint inhibition clinical translation cohort cytokine cytotoxic demethylation detection of nutrient epigenetic regulation in vivo inhibitor molecular marker mutant neoplastic cell new therapeutic target novel novel therapeutics pancreatic ductal adenocarcinoma cell phase 1 study preclinical study programmed cell death ligand 1 programmed cell death protein 1 programs response single-cell RNA sequencing standard of care synergism translational approach treatment strategy tumor tumor behavior tumor microenvironment tumor-immune system interactions tumorigenesis

项目摘要

KRAS is the most frequently mutated gene in human cancers. Unfortunately, KRAS inhibitors have been elusive and attempts to target downstream signaling have had limited benefit. KRAS mutations are particularly common in two especially deadly cancers: non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDA). The basis for this multiple investigator R01 is our recent identification of a distinct molecular program in a genetically defined subset of KRAS mutant tumors—specifically those with concurrent KRAS/LKB1 mutations— that points to a novel therapeutic vulnerability. The LKB1/STK11 tumor suppressor encodes a serine-threonine kinase that integrates nutrient availability, cell metabolism, and cell growth. We recently discovered that KRAS activation and LKB1 loss synergize to drive tumorigenesis associated with pronounced rewiring of metabolism that is coupled to changes in epigenetic regulation. In particular, we find that oncogenic cooperation between these mutations is fueled by pronounced induction of the serine-glycine- one carbon network coupled to generation of the methyl donor S-adenosylmethionine. In concert, DNA methyltransferases (DNMTs) are upregulated, leading to increased DNA methylation, with particular enrichment at retrotransposon elements, which are consequently silenced. Accordingly, KRAS-LKB1 mutant NSCLC and PDA cell lines, xenografts, and GEMMs are highly sensitive to DNMT inhibitors (DNMTi), compared to equivalent cancers lacking LKB1 mutations. Importantly, we show that this sensitivity is associated with pronounced activation of retrotransposons and induction of the interferon (IFN)-mediated cytotoxic response. IFN signaling also alters immune surveillance, both positively by increasing antigen presentation, and negatively by upregulating PD-L1. Thus, combined immune checkpoint inhibition and DNMTi represents a novel translational strategy for this vulnerable group of patients. Our proposal seeks to dissect the differences in immune microenvironment and molecular circuitry of genetically defined NSCLC and PDA subsets and to investigate the efficacy and mechanisms of response to combination therapy. These studies will utilize both human tumors and GEMMs to further define the role of discrete genetic alterations in conferring this therapeutic vulnerability. Importantly, our data has also led to the development of an investigator-initiated Phase I study of a DNMTi and an immune checkpoint inhibitor in KRAS/LKB1 NSCLC with expansion planned for PDA. Assessment of on-study specimens will be integrated with other analyses described here to further extend the clinical translation of this therapeutic approach for patients whose options are otherwise limited.

KRAS是人类癌症中最常见的基因。不幸的是，KRAS抑制剂已经难以捉摸的和针对下游信号的尝试的好处有限。 KRAS突变特别是在两种特别致命的癌症中常见：非小细胞肺癌（NSCLC）和胰腺导管腺癌（PDA）。该多个研究者R01的基础是我们最近对一个独特的识别在KRAS突变肿瘤的一般定义子集中的分子程序 - 特别是同时发生的 KRAS/LKB1突变 - 指出了一种新型的治疗脆弱性。 LKB1/STK11肿瘤抑制剂编码一种丝氨酸 - 硫代激酶，该丝氨酸激酶整合营养素的可利用性，细胞代谢和细胞生长。我们最近发现，KRAS激活和LKB1损失协同驱动与肿瘤发生相关的肿瘤。代谢的明显重新布线与表观遗传调节的变化耦合。特别是，我们发现这些突变之间的致癌合作是通过明显诱导丝氨酸 - 甘氨酸 - 一个碳网络与甲基供体S-腺苷甲硫氨酸的产生结合。在音乐会上，DNA 甲基转移酶（DNMT）上调，导致DNA甲基化增加，特定逆转座子元素的富集，因此被沉默。根据以下内容，KRAS-LKB1突变体 NSCLC和PDA细胞系，Xenographtics和GEMM对DNMT抑制剂（DNMTI）高度敏感，与缺乏LKB1突变的同等癌症相比。重要的是，我们表明这种敏感性是与逆转座子的明显激活和干扰素（IFN）介导的诱导有关细胞毒性反应。 IFN信号传导也会改变免疫监视，均通过增加抗原积极呈现，并通过上调PD-L1来负面。那是联合免疫检查点抑制和DNMTI 代表了这一脆弱患者组的新型翻译策略。我们的建议旨在剖析一般定义的NSCLC和PDA的免疫微环境和分子电路的差异子集并研究组合疗法反应的效率和机制。这些研究会利用人类肿瘤和宝石进一步定义了会议中离散遗传改变的作用治疗脆弱性。重要的是，我们的数据还导致了研究人员发起的 INMTI和IMNOCHECKECKPOINT抑制剂在KRAS/LKB1 NSCLC中进行的I期研究，并计划了扩展对于PDA。研究标本的评估将与此处描述的其他分析集成扩展这种治疗方法的临床翻译，以否则选择有限的患者。