MSK SPORE in Lymphoma

描述（由申请人提供）：MSK孢子在淋巴瘤中的目标是通过三家纽约市机构的合作努力，提高弥漫性大B细胞淋巴瘤患者的治愈率：1)纪念斯隆凯特琳癌症中心（MSK）， 2)威尔康奈尔医学院（WCMC）和3)哥伦比亚大学赫伯特欧文综合癌症中心（HICCC）。该淋巴瘤孢子的总体方法旨在通过引入、开发和应用新的概念、方法和技术来改变当前的治疗范式和临床实践，以解决几个明显未满足医疗需求的DLBCL亚群。我们的总体目标是：研究针对导致肿瘤发生过程的特定基因和分子改变的DLBCL的新治疗方法。具体目标2。利用在SPORE开展的四项临床试验中登记的患者的组织标本，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、遗传学和临床生物标志物来选择DLBCL患者的新治疗方法。在Project 1中，我们将针对Myc和Bcl2之间的致癌合作开发新的治疗方法。随后，可以使用标准免疫组织化学方法对DLBCL中Myc+/Bcl2+高表达的患者进行评估。在项目2中，我们将研究基因修饰T细胞表达靶向CD19的嵌合抗原受体（car）在不适合干细胞移植的老年复发DLBCL患者中的安全性和临床疗效这些患者预后不佳，中位总生存期很少超过1年在项目3中，我们将研究首个肿瘤富集- HSP90 （TE-Hsp90）抑制剂PU-H71在复发性dlbcl患者中的安全性和有效性21,22。使用放射性标记I-124 PU-H71的新型pet分子成像将用于检查PU-H71对HSP90的体内靶向性，并指导给药和患者选择23由于c-Myc和内在凋亡途径蛋白是TE-Hsp90的客户蛋白，因此将对Myc+/Bcl2+ DLBCL患者的治疗效果进行回顾性评估。最后，在Project 4中，我们将阐明CBP和p300在B细胞中的正常和病理作用，建立其治疗靶向的临床前模型，并在II期临床试验中测试新型HDAC抑制剂moceinostat的活性。我们将使用靶向测序策略来选择携带CBP/p300组蛋白乙酰转移酶（HAT）基因突变的DLBCL患者，并用新型HDAC抑制剂进行治疗。7-12我们的目标是在生物标志物定义的复发性DLBCL患者中找到安全有效的新药。

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.