Targeting the heat shock response for the therapy of DLBCL

靶向热休克反应治疗 DLBCL

基本信息

批准号：
8444649
负责人：
GABRIELA CHIOSIS
金额：
$ 47.49万
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：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8444649
关键词：
17-(Allylamino)-17-demethoxygeldanamycin 17-(Dimethylaminoethylamino)-17-Demethoxygeldanamycin Affect Animals Attenuated B-Cell Lymphomas BCL6 gene Benzoquinones Binding Biochemical Bioinformatics Biological Biological Assay Biological Markers Cell Line Cells Characteristics Chemicals Client Clinical Clinical Data Clinical Trials Combined Modality Therapy Complex Coupled Critical Pathways Data Development Disease Dose Drug Formulations Drug Kinetics Drug Targeting Exhibits Future Genes Heat-Shock Proteins 90 Heat-Shock Response Hour Human In Vitro Laboratories Lead Letters Lymphoma Malignant Neoplasms Molecular Molecular Chaperones Molecular Profiling Mus National Cancer Institute Non-Hodgkin&apos s Lymphoma Normal Cell Normal tissue morphology Oncogenes Oncogenic Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Phenotype Principal Investigator Production Property Proteins Proteomics Purines Regimen Reporting Research Role Schedule Signal Transduction Testing Therapeutic Time Toxic effect Transcription Repressor/Corepressor Translations Treatment Protocols United States base cancer diagnosis cancer therapy chemotherapy combinatorial design disorder subtype functional genomics improved in vivo inhibitor/antagonist interest killings large cell Diffuse non-Hodgkin&apos s lymphoma malignant breast neoplasm neoplastic cell novel novel therapeutics pre-clinical programs public health relevance purine research study response scaffold therapeutic development therapeutic target tool tumor validation studies

项目摘要

DESCRIPTION (provided by applicant): Our proposal explores the molecular pathogenesis and therapeutic targeting of diffuse large B-cell lymphomas (DLBCL), which are the most common form of non-Hodgkin's lymphoma. Since these tumors are markedly heterogeneous, we are interested in identifying mechanisms relevant to the broadest cross-section possible of DLBCL patients. A recent report suggested that heat shock protein 90 (Hsp90) is widely expressed in DLBCL. We independently confirmed and validated this result and showed that Hsp90 binds and protects from degradation the BCL6 transcriptional repressor and the NEMO subunit of the IKK complex, both of which are components of oncogenic pathways in DLBCL. Several groups have developed Hsp90 inhibitors. However, most of these molecules have a relatively narrow therapeutic window that makes it impossible to fully suppress tumor Hsp90 in vivo. The Chiosis laboratory developed a purine scaffold inhibitor of Hsp90 called PUH71. PUH71 more potently and specifically binds the fraction of Hsp90 that chaperones oncogenic client proteins within tumor cells vs. other Hsp90 inhibitors and readily kills DLBCL cells in vitro and in vivo. A single dose of PUH71 administered to mice remained in lymphomas for over 48 hours at therapeutic levels, but rapidly cleared from normal tissues in just a few hours. Accordingly, PUH71 exhibited a wider therapeutic window and thus greater anti-DLBCL efficacy than other Hsp90 inhibitors. Given these promising results, the National Cancer Institute Division of Cancer Treatment and Diagnosis is sponsoring the translation of PUH71 for use in clinical trials. Altogether, our preliminary mechanistic and pre-clinical data lead us to hypothesize that Hsp90 is a critical therapeutic target in a broad cross-section of DLBCLs and that DLBCLs become addicted to Hsp90 since it protects from degradation components of multiple pathways involved in the survival of DLBCL across its various subtypes. Given its superior pharmacologic properties, we predict that PUH71 will be a highly active in primary human DLBCL and will synergize with anti-lymphoma drugs that target complementary biological pathways. The current proposal will take advantage of the unique biochemical properties of PUH71 and use it as a bait to identify oncogenic Hsp90 client proteins in DLBCL in proteomics assays, coupled with functional validation studies. A second approach will explore the response of a spectrum of primary human DLBCLs to PUH71 and use expression profiling and bio-informatic tools to identify gene pathways that contribute to making DLBCLs biologically dependent on Hsp90. We will then use this information to design combinatorial-targeted therapy regimens for the treatment of DLBCL. This proposal will deliver mechanistic information concerning the functions of Hsp90 in lymphomas, and also will deliver new therapeutic regimens and biomarkers for testing in DLBCL patients.

描述（由申请人提供）：我们的建议探讨了弥漫性大B细胞淋巴瘤（DLBCL）的分子发病机理和治疗靶向，这是非霍奇金淋巴瘤的最常见形式。由于这些肿瘤明显异质，因此我们有兴趣识别与DLBCL患者可能最广泛的横截面相关的机制。最近的一份报告表明，热休克蛋白90（HSP90）在DLBCL中广泛表达。我们独立证实并验证了这一结果，并表明HSP90结合并保护了IKK复合物的Bcl6转录阻遏物和NEMO亚基的降解，这两者都是DLBCL中致癌途径的组成部分。几个小组已经开发了HSP90抑制剂。但是，这些分子中的大多数具有相对狭窄的治疗窗口，这使得无法完全抑制体内肿瘤HSP90。 Chiosis实验室开发了一种称为PUH71的HSP90的嘌呤支架抑制剂。 PUH71更有效，专门结合Hsp90的比例，即肿瘤细胞中的致癌型客户蛋白与其他HSP90抑制剂，并且很容易在体外和体内杀死DLBCL细胞。在淋巴瘤中施用的单剂量PUH71在治疗水平上保持超过48小时，但仅几个小时就可以从正常组织中迅速清除。因此，与其他HSP90抑制剂相比，PUH71表现出更宽的治疗窗口，因此具有更大的抗DLBCL功效。鉴于这些有希望的结果，国家癌症治疗和诊断部门正在赞助PUH71在临床试验中的翻译。总之，我们的初步机械和临床前数据使我们假设HSP90是DLBCLS广泛的横截面中的关键治疗靶标，并且DLBCLs会上瘾HSP90，因为它可以保护它免受涉及多个降级组件的降级组件的降低， DLBCL的各种亚型。鉴于其出色的药理特性，我们预测PUH71将是原代人DLBCL的高度活跃，并将与靶向互补生物学途径的抗淋巴瘤药物协同作用。当前的建议将利用PUH71的独特生化特性，并将其用作诱饵，以鉴定DLBCL中蛋白质组学测定中的致癌HSP90客户端蛋白，再加上功能验证研究。第二种方法将探索一系列原代人DLBCL对PUH71的响应，并使用表达分析和生物形式的工具来识别有助于使DLBCLS生物学上依赖HSP90的基因途径。然后，我们将使用此信息来设计靶向组合的治疗方案，以治疗DLBCL。该提案将提供有关HSP90在淋巴瘤中功能的机械信息，并且还将提供新的治疗方案和生物标志物，用于在DLBCL患者中进行测试。