MSK SPORE in Lymphoma

MSK SPORE 治疗淋巴瘤

基本信息

批准号：
9753960
负责人：
Riccardo Dalla-Favera
金额：
$ 209.4万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-30 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9753960
关键词：
Academic Medical Centers Address Adriamycin PFS Apoptosis Area B-Lymphocytes BCL2 gene Biological Biological Markers CD19 gene Cells Client Clinical Clinical Trials Collaborations Comprehensive Cancer Center Cyclophosphamide Dose EP300 gene Enrollment Ensure Event Future Gene Expression Profiling Genetic Genetic Markers Goals Heat-Shock Proteins 90 Herbert Irving Comprehensive Cancer Center Histologic Histone Deacetylase Inhibitor Immunohistochemistry Institution Knowledge Lymphoma Mediastinal Mediating Medical Memorial Sloan-Kettering Cancer Center Methods Molecular Mutation New Agents New York City Non-Hodgkin&apos s Lymphoma Oncogenic Pathologic Patient Selection Patients Phase II Clinical Trials Positron-Emission Tomography Pre-Clinical Model Prednisone Process Proteins Radiolabeled Reaction Reagent Regimen Relapse Reproduction spores Resistance Resource Sharing Role Safety Science Scientist Site Specimen Stem cell transplant Structure of germinal center of lymph node Subgroup T-Lymphocyte Technology Testing Time Tissues Translating Translations Treatment Efficacy Universities Vincristine base c-myc Genes chemotherapy chimeric antigen receptor clinical biomarkers clinical efficacy clinical practice curative treatments data sharing disease heterogeneity drug development gene therapy improved in vivo inhibitor/antagonist innovation large cell Diffuse non-Hodgkin&apos s lymphoma medical schools molecular imaging novel novel therapeutic intervention older patient outcome forecast potential biomarker public health relevance rituximab success targeted sequencing therapeutic target translational physician treatment strategy tumor

项目摘要

DESCRIPTION (provided by applicant): The goal of the MSK SPORE in Lymphoma is to improve the cure rate of patients with diffuse large B cell lymphoma, through a collaborative effort between three New York City institutions: 1) Memorial Sloan Kettering Cancer Center (MSK), 2) Weill Cornell Medical College (WCMC), and 3) Herbert Irving Comprehensive Cancer Center (HICCC) of Columbia University. The overall approach for this SPORE in Lymphoma seeks to shift current treatment paradigms and clinical practice by introducing, developing, and applying new concepts, methods, and technologies to address several DLBCL subgroups with a clear unmet medical need. Our overall broad aims are: Specific Aim 1. To develop novel treatments for DLBCL based on targeting specific genetic and molecular alterations that contribute to the oncogenic process. Specific Aim 2. Identify potential biomarkers of antitumor efficacy using tissue specimens from patients enrolled on four clinical trials developed in the SPORE. We plan to identify and utilize biologic, genetic, and clinical biomarkers to select patients with DLBCL for novel therapeutic approaches. In Project 1, we will develop novel treatments to target the oncogenic cooperation between Myc and Bcl2. Such therapy can subsequently be evaluated in patients enriched for high Myc+/Bcl2+ expression in DLBCL using standard immunohistochemistry methods. These patients have a clear unmet medical need, as they have a poor prognosis with standard chemotherapy In Project 2, we will investigate the safety and clinical efficacy of genetically modified T cells to express chimeric antigen receptors (CARs) targeting CD19 in elderly patients with relapsed DLBCL who are not candidates for stem cell transplant.19 These patients have a dismal prognosis, with a median overall survival rarely exceeding one year.20 In Project 3, we will investigate the safety and efficacy of the first Tumor Enriched-Hsp90 (TE-Hsp90) inhibitor PU-H71 in patients with relapsed DLBCL.21,22 A novel PET-based molecular imaging using radiolabeled I-124 PU-H71 will be used to examine in vivo targeting of HSP90 by PU-H71, and to guide dosing and patients selection.23 Because c-Myc and intrinsic apoptosis pathway proteins are client proteins of TE-Hsp90, the efficacy of this treatment will be retrospectively assessed in patients with Myc+/Bcl2+ DLBCL. Finally, in Project 4, we will elucidate the normal and pathologic role of CBP and p300 in B cells, establish pre-clinical models for their therapeutic targeting, and test the activity of the novel HDAC inhibitor mocetinostat in a phase II clinical trial. we will use targeted sequencing strategies to select patients with DLBCL that carry mutations in the CBP/p300 histone acetyltransferase (HAT) genes for therapy with novel HDAC inhibitors.7-12 Our goal is to identify safe and active new agents in biomarker-defined patients with relapsed DLBCL.

DESCRIPTION (provided by applicant): The goal of the MSK SPORE in Lymphoma is to improve the cure rate of patients with diffuse large B cell lymphoma, through a collaborative effort between three New York City institutions: 1) Memorial Sloan Kettering Cancer Center (MSK), 2) Weill Cornell Medical College (WCMC), and 3) Herbert Irving Comprehensive Cancer Center (HICCC) of Columbia University.该孢子在淋巴瘤中的总体方法试图通过引入，开发和应用新的概念，方法和技术来解决目前的治疗范式和临床实践，以解决明显未满足医疗需求的几个DLBCL亚组。我们的总体广泛目的是：特定目标1。基于针对有助于致癌过程的特定遗传和分子改变开发DLBCL的新型治疗方法。具体目标2。使用参加孢子中四项临床试验的患者的组织标本来确定抗肿瘤功效的潜在生物标志物。我们计划识别和利用生物学，遗传和临床生物标志物来选择DLBCL的患者进行新型治疗方法。在项目1中，我们将开发新的治疗方法，以针对MYC和BCL2之间的致癌合作。随后，可以使用标准的免疫组织化学方法对DLBCL中高MYC+/BCl2+表达的富含的患者进行评估。这些患者的医疗需求明显，因为在项目2中，他们对标准化学疗法的预后不良，我们将研究靶向CD19的遗传修饰的T细胞的安全性和临床功效，该嵌合抗原受体（CARS）在老年人中对患者的复发性DLBCL的一年级候选人的态度超过一位，这些疾病是diss tem diss them diss them diss to dism n disal them disal n a disal n a disal n a s and s n promistive。 In Project 3, we will investigate the safety and efficacy of the first Tumor Enriched-Hsp90 (TE-Hsp90) inhibitor PU-H71 in patients with relapsed DLBCL.21,22 A novel PET-based molecular imaging using radiolabeled I-124 PU-H71 will be used to examine in vivo targeting of HSP90 by PU-H71, and to guide dosing and patients selection.23 Because c-Myc and内在凋亡途径蛋白是TE-HSP90的客户蛋白，该治疗的功效将在MYC+/BCL2+ DLBCL患者中进行回顾性评估。最后，在项目4中，我们将阐明CBP和P300在B细胞中的正常和病理作用，为其治疗靶向建立临床前模型，并在II期临床试验中测试新型HDAC抑制剂Mocetinostat的活性。我们将使用有针对性的测序策略来选择DLBCL患者在CBP/P300组蛋白乙酰基转移酶（HAT）基因中携带突变的患者，以对新型HDAC抑制剂进行治疗。7-12我们的目标是识别带有复发DLBCL的生物标志物定义患者的安全且活跃的新药物。