Evaluation of voltage-gated calcium ion channels as a therapeutic target in intrahepatic cholangiocarcinoma

电压门控钙离子通道作为肝内胆管癌治疗靶点的评估

• 批准号: 10634505
• 负责人: Annie Liu
• 金额: $ 8.31万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10634505
• 关键词: Antihypertensive Agents; Antipsychotic Agents; Apoptosis; Basic Science; Benign; CACNA1G gene; CRISPR screen; Calcium; Calcium Channel; Calcium Channel Blockers; Cancer cell line; Cell Line; Cell physiology; Cells; Cytotoxic Chemotherapy; Data; Databases; Dependence; Development; Disease; Drug Targeting; Endoplasmic Reticulum; Evaluation; Exhibits; FDA approved; Foundations; Genes; Genetic; Homeostasis; In Vitro; Individual; Institution; Intrahepatic Cholangiocarcinoma; Ion Channel Gating; Laboratories; Liver; Malignant Neoplasms; Modeling; Neoplasms; Operative Surgical Procedures; Organelles; Organoids; P-Q type voltage-dependent calcium channel; Patients; Pre-Clinical Model; Primary Malignant Neoplasm of Liver; Primary carcinoma of the liver cells; Proliferating; Research; Role; Sampling; Signal Pathway; Surgical Oncologist; Systemic Therapy; Testing; Therapeutic; Tissues; Training; Unresectable; Work; Xenograft Model; antagonist; antitumor effect; cancer survival; cancer therapy; career; cell type; chemotherapeutic agent; chemotherapy; endoplasmic reticulum stress; experimental study; genome-wide; improved; in vivo; in vivo Model; knock-down; melanoma; migration; new therapeutic target; novel; novel therapeutics; pharmacologic; therapeutic target; translational impact; translational potential; tumor; voltage

Project Summary/Abstract Intrahepatic cholangiocarcinoma (ICC) is an aggressive primary liver cancer with a median overall survival of 11.7 months. The majority of patients present with unresectable disease, demonstrating a significant need for improved systemic therapies. Here, we use CRISPR/Cas9 screens to identify genes essential to ICC survival that could serve as novel therapeutic targets. We demonstrate that CACNA1A and CACNA1G, which encode the main pore-forming subunits of two voltage-gated calcium ion channels (VGCCs), are two genes of essentiality in five ICC cell lines. We hypothesize that aberrant expression of voltage-gated ion channels is essential to ICC survival and propose that existing FDA-approved calcium channel blockers could be repurposed to treat ICC. Our preliminary data demonstrate that not only are these two genes essential to ICC proliferation, but also that both antihypertensives and antipsychotics may be effective in decreasing ICC viability in vitro. To test our central hypothesis, we propose the following aims: 1) determine the effect of VGCC genetic knockdown and pharmacologic blockade on ICC cells in vitro, 2) investigate the mechanisms by which blockade of these calcium channels decreases ICC viability, and 3) determine whether calcium channel blockers can be used individually or to augment the effects of chemotherapy both in vivo and in novel patient- derived models.

项目总结/摘要 肝内胆管细胞癌（ICC）是一种侵袭性原发性肝癌， 11.7个月大多数患者存在不可切除的疾病，这表明对 改善系统治疗。在这里，我们使用CRISPR/Cas9筛选来识别ICC生存所必需的基因。 可以作为新的治疗靶点。我们证明了CACNA 1A和CACNA 1G，它们编码 两个电压门控钙离子通道（VGCC）的主要成孔亚单位是两个基因， 在五种ICC细胞系中的必要性。我们假设电压门控离子通道的异常表达是 对于ICC存活至关重要，并建议现有FDA批准的钙通道阻滞剂可以 重新用于治疗ICC。我们的初步数据表明，不仅这两个基因是必要的ICC 抗高血压药和抗精神病药都可能有效降低ICC 体外活力。为了验证我们的中心假设，我们提出了以下目标：1）确定VGCC的效果 体外对ICC细胞的基因敲低和药物阻断，2）研究其机制， 这些钙通道的阻断降低了ICC的活力，以及3）确定钙通道是否 阻断剂可以单独使用或用于增强体内和新患者的化疗效果， 衍生模型。