Targeting the MICAL2 signaling axis in pancreatic cancer

靶向胰腺癌中的 MICAL2 信号轴

基本信息

批准号：
10676946
负责人：
ANDREW M LOWY
金额：
$ 21.72万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-04 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10676946
关键词：
3-Dimensional Acetylation Actins Acute Affect American Benign Binding Biological Models Biology CDKN2A gene Cancer cell line Cell Cycle Cell Cycle Progression Cell model Cells Chemoresistance Combination Drug Therapy Combined Modality Therapy Cyclins Cytotoxic Chemotherapy Data Data Set Development Disease Dominant Genes Down-Regulation Enhancers Enzymes Epigenetic Process Excision Flavins Gene Mutation Genes Genetic Genetic Transcription Genetically Engineered Mouse Genome Goals Growth Histones Human In Vitro Invaded Ionizing radiation KRAS2 gene Knockout Mice Lesion Libraries Link Liver Lung Lysine MADH4 gene Malignant neoplasm of pancreas Maps Mitosis Mixed Function Oxygenases Modeling Mus Neoplasm Metastasis Nuclear Nucleic Acid Regulatory Sequences Operative Surgical Procedures Organoids Outcome Pancreas Pancreatic Ductal Adenocarcinoma Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Phenotype Play Pre-Clinical Model Primary Neoplasm Prognosis Proliferating Regimen Research Resected Resistance Role Serum Response Factor Signal Transduction Slice Stromal Cells Systemic Therapy TP53 gene Testing Therapeutic Time Tissues Toxic effect Transcriptional Regulation advanced disease cancer cell cancer survival cancer therapy cell motility chemotherapeutic agent chemotherapy cofactor disorder control experimental study gain of function gemcitabine human disease human tissue improved in vivo in vivo Model loss of function mouse genetics mouse model myocardin neoplastic cell new therapeutic target novel novel drug combination novel therapeutic intervention optimal treatments overexpression pancreas development pancreatic cancer cells pancreatic cancer model pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model pre-clinical programs recombinase response targeted treatment therapeutically effective therapy resistant transcription factor transcriptome sequencing tumor tumor growth

项目摘要

PROJECT SUMMARY/ABSTRACT There is a critical need for novel therapeutic approaches for pancreatic ductal adenocarcinoma (PDAC) as the current chemotherapeutic regimens fail to control the disease for a majority of patients. To identify novel regulators of PDAC we compared the epigenetic landscape of surgically resected tumors to normal pancreas using histone-3 lysine-27 acetylation (H3K27ac). This analysis revealed super-enhancer regions which are “hot- spots” for transcription factor binding. Super-enhancer profiling of PDAC tissue revealed a distinctive landscape compared to that of normal pancreas. Amongst the most highly acetylated enhancers mapped to the MICAL2 gene. The MICAL2 enzyme is a flavin monooxygenase that regulates nuclear actin dynamics resulting in downstream modulation of transcription by myocardin-related transcription factor-A and serum response factor. As an enzyme whose class has been successfully inhibited in human disease, we believe MICAL2 represents an exciting and potentially tractable target for pancreatic cancer therapy. We examined human and murine pancreatic cancer cell lines and organoids as well as several independent datasets and confirmed that MICAL2 is overexpressed in PDAC and that its overexpression confers a poor prognosis. In addition, we have generated robust preliminary data demonstrating that loss of MICAL2 results in downregulation of key cell cycle regulators which slows proliferation and causes stalling in G1 and G2/M phases. Furthermore, silencing of MICAL2 inhibits colony formation and cell migration in vitro which are key phenotypes of advanced disease. Importantly, these phenotypes are conserved in vivo, where the loss of MICAL2 in either mouse or human PDAC cells markedly inhibits tumor growth, as well as metastatic spread to both liver and lung. Finally, MICAL2 appears to promote chemoresistance to gemcitabine, a common PDAC chemotherapeutic. The evidence we have gathered strongly suggests that targeting the MICAL2 program in PDAC will be therapeutically effective. To validate our hypothesis, our goals are to determine how inhibition of MICAL2 impacts PDAC response to cytotoxic therapies and to define the cell extrinsic effects of MICAL2 inhibition in PDAC models. To accomplish this, we will use orthogonal approaches to define the potential benefits and outcomes of MICAL2 targeting. We will leverage our extensive pre-clinical modeling expertise to assess cell intrinsic and extrinsic effects of MICAL2 inhibition. We will define MICAL2 dependent programs that promote chemoresistance and assess novel drug combinations to overcome these programs. Importantly, we will thoroughly investigate the potential toxicity of our therapeutic approach. The findings from these studies will enhance our understanding of MICAL2 biology and thereby serve to inform the development and testing of MICAL2-directed therapies in pancreatic cancer.

项目概要/摘要胰腺导管腺癌 (PDAC) 迫切需要新的治疗方法目前的化疗方案无法控制大多数患者的疾病。我们将手术切除的肿瘤与正常胰腺的表观遗传景观进行了比较使用组蛋白 3 赖氨酸 27 乙酰化 (H3K27ac) 该分析揭示了“热增强子”区域。 PDAC 组织的超级增强子分析揭示了独特的景观。与正常胰腺相比，MICAL2 乙酰化程度最高的增强子之一。 MICAL2 酶是一种黄素单加氧酶，可调节核肌动蛋白动力学，从而产生心肌素相关转录因子 A 和血清反应因子对转录的下游调节。作为一种在人类疾病中已被成功抑制的酶，我们相信 MICAL2 代表了胰腺癌治疗的一个令人兴奋且可能易于处理的目标。我们检查了人类和小鼠胰腺癌细胞系和类器官以及几个独立的细胞系数据集并证实 MICAL2 在 PDAC 中过度表达，并且其过度表达赋予了较差的此外，我们已经生成了可靠的初步数据，证明 MICAL2 的缺失会导致预后不良。关键细胞周期调节因子的下调，减缓增殖并导致 G1 和 G2/M 期停滞。此外，MICAL2 的沉默会抑制体外集落形成和细胞迁移，这是关键的表型重要的是，这些表型在体内是保守的，其中任何一个中 MICAL2 的缺失。小鼠或人类 PDAC 细胞显着抑制肿瘤生长以及向肝脏和肺部的转移扩散。最后，MICAL2 似乎可以促进对吉西他滨（一种常见的 PDAC 化疗药物）的化疗耐药性。我们收集的证据强烈表明，针对 PDAC 中的 MICAL2 计划将是为了验证我们的假设治疗，我们的目标是确定 MICAL2 的抑制如何影响。 PDAC 对细胞毒性疗法的反应并定义 PDAC 中 MICAL2 抑制的细胞外在效应为了实现这一目标，我们将使用正交方法来定义潜在的好处和结果。我们将利用我们的广泛临床建模专业知识来评估细胞内在和我们将定义促进化疗耐药的 MICAL2 依赖性程序。并评估新的药物组合以克服这些计划。重要的是，我们将彻底调查。这些研究的结果将增强我们对治疗方法的潜在毒性的理解。 MICAL2 生物学的研究，从而为 MICAL2 导向疗法的开发和测试提供信息胰腺癌。