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：
8606439
负责人：
GABRIELA CHIOSIS
金额：
$ 48.16万
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/8606439
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. PUBLIC HEALTH RELEVANCE: B-cell lymphomas are the fourth most common form of cancer in the United States and several subtypes of this disease are incurable; and although these tumors are markedly heterogeneous from the molecular standpoint, many of them appear to express and require the presence of the Hsp90 chaperone protein. We recently developed an Hsp90 inhibitor called PUH71 with superior pharmacologic and biochemical properties. This proposal will identify the oncogenic client proteins of Hsp90, determine the spectrum of lymphomas that respond to PUH71, identify the functional genomics characteristics of tumors that are Hsp90 dependent, and then use this information to develop rationally designed combinatorial therapy regimens for B-cell lymphomas centered around the use of PUH71.

描述（由申请人提供）：我们的提案探讨了弥漫性大 B 细胞淋巴瘤 (DLBCL) 的分子发病机制和治疗靶向，DLBCL 是最常见的非霍奇金淋巴瘤形式。由于这些肿瘤具有明显的异质性，我们有兴趣确定与 DLBCL 患者可能的最广泛横截面相关的机制。最近的一份报告表明，热休克蛋白 90 (Hsp90) 在 DLBCL 中广泛表达。我们独立证实和验证了这一结果，并表明 Hsp90 结合 BCL6 转录阻遏蛋白和 IKK 复合物的 NEMO 亚基并防止其降解，这两者都是 DLBCL 致癌途径的组成部分。多个研究小组已开发出 Hsp90 抑制剂。然而，这些分子中的大多数具有相对狭窄的治疗窗，使得不可能在体内完全抑制肿瘤Hsp90。 Chiosis 实验室开发了一种 Hsp90 的嘌呤支架抑制剂，称为 PUH71。与其他 Hsp90 抑制剂相比，PUH71 能更有效、更特异地结合 Hsp90 部分，从而在肿瘤细胞内陪伴致癌客户蛋白，并在体外和体内轻松杀死 DLBCL 细胞。给小鼠注射单剂量的 PUH71 在治疗水平下在淋巴瘤中保留超过 48 小时，但在短短几个小时内就迅速从正常组织中清除。因此，PUH71 表现出比其他 Hsp90 抑制剂更宽的治疗窗，因此具有更强的抗 DLBCL 功效。鉴于这些有希望的结果，美国国家癌症研究所癌症治疗和诊断部门正在赞助 PUH71 的翻译以用于临床试验。总而言之，我们的初步机制和临床前数据使我们假设 Hsp90 是广泛的 DLBCL 中的关键治疗靶点，并且 DLBCL 会对 Hsp90 上瘾，因为它可以保护与 DLBCL 存活相关的多种途径的降解成分。 DLBCL 涵盖其各种亚型。鉴于其优越的药理学特性，我们预测 PUH71 将在原发性人类 DLBCL 中具有高度活性，并将与针对互补生物途径的抗淋巴瘤药物产生协同作用。目前的提案将利用 PUH71 独特的生化特性，并用其作为诱饵，在蛋白质组学测定中识别 DLBCL 中的致癌 Hsp90 客户蛋白，并结合功能验证研究。第二种方法将探索一系列原发性人类 DLBCL 对 PUH71 的反应，并使用表达谱和生物信息学工具来识别有助于使 DLBCL 在生物学上依赖于 Hsp90 的基因途径。然后，我们将利用这些信息来设计治疗 DLBCL 的组合靶向治疗方案。该提案将提供有关 Hsp90 在淋巴瘤中功能的机制信息，并将提供新的治疗方案和生物标志物用于 DLBCL 患者的测试。公共卫生相关性： B 细胞淋巴瘤是美国第四大常见癌症，这种疾病的几种亚型是无法治愈的；尽管从分子角度来看这些肿瘤明显异质，但其中许多似乎表达并需要 Hsp90 伴侣蛋白的存在。我们最近开发了一种名为 PUH71 的 Hsp90 抑制剂，具有优异的药理和生化特性。该提案将鉴定Hsp90的致癌客户蛋白，确定对PUH71有反应的淋巴瘤谱，鉴定Hsp90依赖性肿瘤的功能基因组学特征，然后利用这些信息开发合理设计的B细胞淋巴瘤组合治疗方案以 PUH71 的使用为中心。