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.

项目摘要/摘要胰腺导管腺癌（PDAC）的新型热方法至关重要当前的化学治疗方案无法控制大多数患者的疾病。识别小说 PDAC的调节剂我们将手术切除的肿瘤的表观遗传景观与正常胰腺进行了比较使用组蛋白-3赖氨酸-27乙酰化（H3K27AC）。该分析揭示了超级增强剂区域，“ 转录因子结合的斑点。PDAC组织的超增强剂分析显示出独特的景观与正常胰腺相比。在映射到mical2的最高乙酰化增强器中基因。 mical2酶是一种黄素单加氧酶，可调节核肌动蛋白动力学，导致核肌动蛋白动力学通过心肌相关转录因子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成功抑制类的酶，我们认为mical2代表一个令人兴奋的胰腺癌治疗靶标。我们检查了人和鼠胰腺癌细胞系和类器官以及几个独立的数据集并确认mical2在PDAC中过表达，并且其过表达供认了差预后。此外，我们产生了强大的初步数据，表明Mical2的丢失导致关键细胞周期调节剂的下调会减慢增殖并导致G1和G2/M相停滞。此外，麦克拉2的沉默抑制了菌落形成和细胞迁移的体外，这是关键表型晚期疾病。重要的是，这些表型在体内是保守的，其中任何一个mical2的损失小鼠或人PDAC细胞显着抑制肿瘤的生长，并转移到肝脏和肺部。最后，Mical2似乎促进了吉西他滨的化学抗性，吉西他滨是一种常见的PDAC化学治疗性。我们收集的证据强烈表明，针对PDAC的Mical2计划将是治疗上有效。为了验证我们的假设，我们的目标是确定对Mical2的抑制如何影响 PDAC对细胞毒性疗法的反应，并定义MICAL2抑制在PDAC中的外在效应型号。为此，我们将使用正交方法来定义 mical2靶向。我们将利用广泛的临床前建模专业知识来评估细胞的固有和 Mical2抑制的外在作用。我们将定义促进化学抗性的MICAL2依赖性程序并评估新的药物组合以克服这些程序。重要的是，我们将彻底调查我们理论方法的潜在毒性。这些研究的发现将增强我们的理解 Mical2 Biology的研究，从而为Mical2定向疗法的开发和测试提供了信息胰腺癌。