Oncogenic Roles and Therapeutic Potential of MCL1 Addiction in Primary Effusion Lymphoma

MCL1 成瘾在原发性渗出性淋巴瘤中的致癌作用和治疗潜力

基本信息

批准号：
10469489
负责人：
Mark Manzano
金额：
$ 15.84万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-04 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10469489
关键词：
Acquired Immunodeficiency Syndrome Affect Apoptosis Apoptotic Area Award B lymphoid malignancy B-Cell Lymphomas BAX gene BCL-2 Protein BCL2 gene Biology CRISPR screen Cancer Etiology Cell Death Cell Line Cells Collaborations DNA Tumor Viruses Dependence Disease Dose Drug Targeting Engineering Environment Exhibits Family Family member Genes Genetic Genetic Transcription Hematologic Neoplasms Hematopoietic Neoplasms Human Human Herpesvirus 8 Immune system Individual Inhibition of Apoptosis Knock-out Knowledge Lead Left Lymphoma Lymphoma cell MCL1 gene Malignant Neoplasms Mitochondria Modeling Mutation Oncogenes Oncogenic Pathway interactions Patient Care Patients Pharmacology Play Proteins Proto-Oncogenes Recurrence Reporting Research Research Personnel Role Sampling Stress TP53 gene Testing Therapeutic Time Treatment Protocols Tumor-Derived Viral Viral Oncogene Work Xenograft Model Xenograft procedure addiction base career clinically relevant design effective therapy efficacy testing functional genomics gene interaction genome-wide genome-wide analysis in vivo inhibitor insight mouse model neoplastic cell new therapeutic target novel oncogene addiction patient derived xenograft model prevent primary effusion lymphoma programs small molecule therapeutic evaluation transcriptome treatment strategy tumor tumor xenograft

项目摘要

Project Summary Primary effusion lymphoma (PEL) is an aggressive B cell lymphoma caused by the DNA tumor virus Kaposi’s sarcoma-associated herpesvirus (KSHV). PEL is an unusual cancer in that no recurrent mutations have been reported in tumors. Instead, PEL requires the continued expression of virally encoded oncogenes to alter the cellular transcriptome in latently infected cells. Candidate approaches have left us with a limited view of what cellular oncogenes are required by the viral lymphoma. It is not surprising that no effective and specific therapy is available to treat this disease. We have recently identified 210 human genes, called PEL-specific oncogenic dependencies (PSODs), that are critically important for the survival of these tumor-derived cell lines using genome-wide CRISPR/Cas9 screens. We have shown that PEL cell lines exhibit a specialized requirement for the anti-apoptotic protein MCL1 despite having high levels of other related BCL2 proteins. New functions of MCL1 have started to emerge independent of its canonical role in preventing apoptosis. It is not clear whether this selective requirement for MCL1 over the other BCL2 proteins is due to a need to block a specific apoptotic stress or whether MCL1 plays a non-canonical function in PEL. Nevertheless we have shown that we can leverage this dependency by pharmacologically inhibiting MCL1 using the small molecule compound S63845. In Aim 1, I will test the therapeutic potential of S63845 for treating PEL in a xenograft mouse model. In Aim 2, I will investigate why PEL is addicted to MCL1. Specifically in Aim 2A, I will study the role of MCL1 in blocking the activities of the p53 tumor suppressor family. In Aim 2B, I will take an unbiased approach and perform CRISPR screens to identify genetic interactions of MCL1. Together, I expect that this study will uncover new insights into the biology of MCL1 in general, answer why MCL1 is important in PEL, and develop MCL1 as a new therapeutic target for this cancer. Completion of this award will open new research areas for my career as an independent investigator in viral lymphomas.

项目概要原发性渗出性淋巴瘤 (PEL) 是一种侵袭性 B 细胞淋巴瘤，由 DNA 肿瘤病毒卡波西氏病毒引起肉瘤相关疱疹病毒（KSHV）是一种不寻常的癌症，没有复发性突变。相反，PEL 需要病毒编码的癌基因的持续表达来改变潜在感染细胞中的细胞转录组的候选方法使我们对什么的了解有限。病毒性淋巴瘤需要细胞癌基因，因此没有有效且特异性的治疗方法并不奇怪。我们最近发现了 210 个人类基因，称为 PEL 特异性致癌基因。依赖性（PSOD），对于这些肿瘤衍生细胞系的生存至关重要我们已经证明 PEL 细胞系对全基因组 CRISPR/Cas9 表现出特殊的要求。尽管具有高水平的其他相关 BCL2 蛋白，但抗凋亡蛋白 MCL1 的新功能。 MCL1 已开始独立于其预防细胞凋亡的典型作用而出现，目前尚不清楚。相对于其他 BCL2 蛋白，MCL1 的这种选择性需求是由于需要阻断特定的细胞凋亡压力或 MCL1 是否在 PEL 中发挥非规范功能，但我们已经证明我们可以。使用小分子化合物 S63845 通过药理学抑制 MCL1 来利用这种依赖性。在目标 1 中，我将测试 S63845 在异种移植小鼠模型中治疗 PEL 的治疗潜力。将研究为什么 PEL 对 MCL1 上瘾，具体来说，在目标 2A 中，我将研究 MCL1 在阻断中的作用。在目标 2B 中，我将采取公正的方法并执行 p53 肿瘤抑制因子家族的活动。通过 CRISPR 筛选来鉴定 MCL1 的遗传相互作用，我预计这项研究将揭示新的内容。深入了解 MCL1 的生物学特性，回答为什么 MCL1 在 PEL 中很重要，并将 MCL1 开发为这种癌症的新治疗目标的完成将为我的职业生涯开辟新的研究领域。病毒性淋巴瘤的独立研究者。