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MALT1 Targeted Therapy for B-Cell Lymphoma

B细胞淋巴瘤的MALT1靶向治疗

基本信息

批准号：
8897310
负责人：
ARI M. MELNICK
金额：
$ 35.17万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8897310
关键词：
B-Cell Lymphomas B-Lymphocytes BCL10 gene BCL2 gene BCL6 gene Binding Biological Markers Caspase Cell Line Cell Proliferation Cell Survival Cells Chronic Lymphocytic Leukemia Clinic Clinical Trials Combined Modality Therapy Complex Correlative Study Data Disease Disease Resistance Down-Regulation Drug Combinations Drug Targeting Enzymes Exhibits Follicular Lymphoma Gene Targeting Genetic Gold Growth Human In Vitro Kinetics Knowledge Lead Lymphoma Mantle Cell Lymphoma Mus Mutation Nuclear Pathway interactions Patients Peptide Hydrolases Peptides Protein Tyrosine Kinase Proteins Receptor Signaling Receptors, Antigen, B-Cell Reporting Resistance Sampling Scaffolding Protein Signal Pathway Signal Transduction Somatic Mutation Structure Testing Time Translating Translations Xenograft Model base clinical practice design high throughput screening holistic approach in vivo inhibitor/antagonist killings large cell Diffuse non-Hodgkin&apos s lymphoma leukemia/lymphoma novel strategies outcome forecast prevent public health relevance resistance mechanism response screening small molecule targeted treatment therapeutic target tumor

项目摘要

DESCRIPTION (provided by applicant): Recent studies have identified small molecule inhibitors of the paracaspase activity of MALT1, a protease and scaffolding protein involved in the B-cell receptor (BCR) signaling pathway, that are effective killing lymphomas in vitro and in vivo in xenograft models of Activated B-cell like Diffuse Large B-cell Lymphoma (ABC-DLBCL). DLBCL is the most common lymphoma and ABC-DLBCL its most chemoresistant subtype. Moreover, the BCR pathway is involved in cell proliferation and survival of several lymphoma subtypes, including follicular lymphoma, mantle cell lymphoma and chronic lymphocytic leukemia/lymphoma. However, not all ABC-DLBCL cell lines and primary patient samples were equally sensitive to MALT1 inhibitors in vitro. Thus, we hypothesize that response to MALT1 inhibitors will be dependent on the genetic background of ABC-DLBCLs, being those holding mutations downstream of MALT1 more likely to be resistant. Likewise, as already reported for other targeted therapies, acquired resistance mechanisms could arise that prevent response to MALT1 inhibitors by either mutation in MALT1 or its downstream targets or by activation of alternative survival pathways. Moreover, lymphoma therapy with drug combinations is the gold standard for the disease and has been proven most effective, thus we hypothesize that MALT1 inhibition will be most valuable in combination with other chemotherapeutic or targeted therapy agents. Consequently, in order to effectively translate MALT1 inhibitors to the clinical practice, our specific aims are: 1) To determine the genetic background of responders to MALT1 inhibition; 2) To define possible resistance mechanisms that tumors will deploy to escape therapy and 3) To design and test combination therapies using a holistic approach (rational combination based on actual knowledge of the disease, resistance mechanisms found in Aims 1 and 2 and, unbiased high throughput screening).

描述（由申请人提供）：最近的研究已经确定了MALT 1的paracaspase活性的小分子抑制剂，MALT 1是一种参与B细胞受体（BCR）信号传导途径的蛋白酶和支架蛋白，在活化B细胞样弥漫性大B细胞淋巴瘤（ABC-DLBCL）的异种移植模型中，其在体外和体内有效杀死淋巴瘤。DLBCL是最常见的淋巴瘤，ABC-DLBCL是其最耐化疗的亚型。此外，BCR途径涉及几种淋巴瘤亚型的细胞增殖和存活，包括滤泡性淋巴瘤、套细胞淋巴瘤和慢性淋巴细胞性白血病/淋巴瘤。然而，并非所有ABC-DLBCL细胞系和原代患者样品在体外对MALT 1抑制剂同样敏感。因此，我们假设对MALT 1抑制剂的反应将取决于ABC-DLBCL的遗传背景，即那些在MALT 1下游具有突变的人更有可能耐药。同样，正如其他靶向治疗已经报道的那样，可能出现获得性耐药机制，通过MALT 1或其下游靶点突变或通过激活替代生存途径来阻止对MALT 1抑制剂的反应。此外，淋巴瘤联合药物治疗是该疾病的金标准，并且已被证明是最有效的，因此我们假设MALT 1抑制与其他化疗或靶向治疗药物联合使用最有价值。因此，为了有效地将MALT 1抑制剂应用于临床实践，我们的具体目标是：1）确定MALT 1抑制剂应答者的遗传背景; 2）确定肿瘤将部署以逃避治疗的可能的耐药机制和3）使用整体方法设计和测试组合疗法（基于疾病的实际知识、目的1和2中发现的抗性机制以及无偏高通量筛选的合理组合）。