Targeting PKR-Bcl2 Signaling to Overcome Paclitaxel Resistance in Ovarian Cancer

靶向 PKR-Bcl2 信号传导以克服卵巢癌中的紫杉醇耐药性

基本信息

批准号：
10672464
负责人：
Jixin Dong
金额：
$ 40.52万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
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：
2022-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10672464
关键词：
Affect Agonist Animal Model Apoptotic BCL2 gene Biochemical Biological Biological Markers Breast Cancer Cell Cancer Cell Growth Cancer Patient Cell Death Cell Death Induction Cells Cellular Metabolic Process Cellular Stress Chemoresistance Clinic Clinical Clinical Trials DNA Damage Data Double-Stranded RNA Drug resistance Eukaryotic Initiation Factors FDA approved Family Human Immune response Immunocompetent In Vitro Innate Immune Response Interferons Knowledge Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Malignant neoplasm of pancreas Mediating Messenger RNA Metabolism Microtubules Mitosis Mitotic Molecular Molecular Target Multi-Drug Resistance Outcome Paclitaxel Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Phosphorylation Phosphorylation Site Phosphotransferases Play Prognostic Marker Prokaryotic Initiation Factor-2 Protein Kinase Proteins Recurrence Regulation Resistance Role Signal Pathway Signal Transduction Signaling Protein Stress Testing Text Therapeutic Transcriptional Regulation Translating Tubulin Validation Virus Diseases antitumor agent cancer cell cancer therapy cancer type cytokine cytotoxicity drug sensitivity improved in vivo inhibitor malignant breast neoplasm new therapeutic target novel patient response pharmacologic pre-clinical protein expression protein function protein kinase R protein profiling response therapeutic target tumor tumorigenesis

项目摘要

Abstract Text Many antitubulin agents, such as paclitaxel (Taxol), have been used extensively for treatment of several types of cancer, including ovarian, lung, pancreatic, and breast cancers. Despite their wide use in cancer treatment, however, patient response is highly variable and drug resistance remains a major clinical issue. It is therefore essential to identify prognostic markers to predict the patient response and to enhance drug sensitivity. Protein kinase R (PKR) plays significant roles in innate immune response to viral infection and tumorigenesis. The biological significance of PKR in antitubulin chemotherapeutics and underlying mechanisms have yet to be defined. Through Phos-tag-based kinome-wide biochemical screens, we identified PKR as a critical regulator in antitubulin cytotoxicity. Our preliminary data suggest that inactivation of PKR confers resistance to Taxol in ovarian and breast cancer cells. Enhanced expression of PKR potentiates taxol cytotoxicity in vitro and in vivo. We further identified novel phosphorylation sites on PKR during antitubulin-mitotic arrest and in normal mitosis. Mechanistically, our findings also suggest that PKR controls Taxol chemosensitivity through modulating Bcl2 expression. Our hypothesis is that the PKR-Bcl2 axis functions as a therapeutic target for antitubulin agent-based chemotherapeutics in treatment of drug-resistant and/or recurrent patients. We will test our central hypothesis by three specific aims. Aim 1: Examine the functional significance of PKR in antitubulin chemotherapeutics in vivo; Aim 2: Determine how antitubulin drugs regulate PKR; Aim 3: Elucidate the mechanisms and downstream signaling of PKR in antitubulin chemosensitivity. The identification of new regulators and/or signaling pathways triggered by antitubulin drugs will shed light on the mechanisms underlying chemoresistance. Our study suggests that combining kinase activators (e.g., being characterized in this application) for PKR or Bcl2 inhibitors (FDA-approved) with antitubulin agents will have enhanced efficacy in treatment of drug-resistant and/or recurrent patients. Our findings also suggest that profiling PKR-Bcl2 signaling status of tumors (mRNA/protein levels and activity) can be useful to predict the patient response to antitubulin chemotherapeutics.

抽象文本许多抗微管蛋白药物，例如紫杉醇（Taxol），已被广泛用于治疗多种癌症，包括卵巢癌、肺癌、胰腺癌和乳腺癌。尽管他们的在癌症治疗中广泛使用，然而，患者的反应变化很大并且耐药性仍然是一个主要的临床问题。因此，有必要确定预后标志物来预测患者反应并增强药物敏感性。蛋白激酶 R (PKR) 发挥重要作用对病毒感染和肿瘤发生的先天免疫反应。 PKR的生物学意义抗微管蛋白化疗药物中的作用和潜在机制尚未明确。通过基于磷酸标签的激酶组范围的生化筛选，我们确定 PKR 是抗微管蛋白细胞毒性。我们的初步数据表明 PKR 失活会产生耐药性卵巢癌细胞和乳腺癌细胞中的紫杉醇。 PKR 表达增强可增强紫杉醇体外和体内细胞毒性。我们进一步鉴定了 PKR 上的新磷酸化位点抗微管蛋白有丝分裂停滞和正常有丝分裂。从机制上讲，我们的研究结果还表明 PKR 通过调节 Bcl2 表达来控制紫杉醇的化学敏感性。我们的假设是 PKR-Bcl2 轴作为基于抗微管蛋白药物的治疗靶点用于治疗耐药和/或复发患者的化疗药物。我们将测试我们的中央三个具体目标的假设。目标 1：检查 PKR 在抗微管蛋白中的功能意义体内化疗；目标 2：确定抗微管蛋白药物如何调节 PKR；目标 3：阐明 PKR 在抗微管蛋白化学敏感性中的机制和下游信号传导。这抗微管蛋白药物触发的新调节因子和/或信号通路的鉴定将会脱落阐明化学耐药性的潜在机制。我们的研究表明结合激酶 PKR 或 Bcl2 抑制剂（FDA 批准）的激活剂（例如，在本申请中进行表征）与抗微管蛋白药物联合使用可增强治疗耐药性和/或复发性的疗效患者。我们的研究结果还表明，分析肿瘤的 PKR-Bcl2 信号状态（mRNA/蛋白质水平和活性）可用于预测患者对抗微管蛋白的反应化疗。