MSK SPORE in Lymphoma

描述(由申请人提供)：淋巴瘤MSK孢子的目标是通过纽约市三个机构的合作来提高弥漫性大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)。针对淋巴瘤中这种孢子的整体治疗方法试图通过引入、开发和应用新的概念、方法和技术来改变当前的治疗模式和临床实践，以解决几个明显未得到满足的医疗需求的DLBCL亚群。我们的总体目标是：具体目标1.基于特定的基因和分子改变，促进致癌过程，开发治疗DLBCL的新方法。具体目的2.使用在孢子中进行的四项临床试验中登记的患者的组织标本，确定潜在的抗肿瘤疗效的生物标记物。我们计划识别和利用生物、遗传和临床生物标记物来选择DLBCL患者进行新的治疗方法。在项目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。随后可以使用标准的免疫组织化学方法对DLBCL中Myc/Bcl2高表达的患者进行评估。这些患者有明显的未得到满足的医疗需求，因为他们的预后很差，在项目2中，我们将研究在不适合干细胞移植的老年复发DLBCL患者中，使用基因修饰的T细胞来表达针对CD19的嵌合抗原受体(CARS)的安全性和临床疗效。19这些患者的预后很差，中位总生存期很少超过一年。20在项目3中，我们将研究第一个肿瘤富集型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我们将使用一种新型的基于PET的分子成像技术，使用放射性标记的I-124 PU-H71来检测PU-H71对HSP90的体内靶向，并指导剂量和患者的选择。23由于c-Myc和内在的凋亡途径蛋白是TE-Hsp90的客户蛋白，这种治疗的有效性将在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，建立它们的治疗靶向的临床前模型，并在II期临床试验中测试新型HDAC抑制剂莫西替诺坦的活性。我们将使用定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，以使用新型HDAC抑制剂进行治疗。7-12我们的目标是在生物标记物定义的复发DLBCL患者中识别安全和有效的新药物。

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.