MSK SPORE in Lymphoma

描述（由申请人提供）：淋巴瘤MSK SPORE的目标是通过以下三个纽约市机构之间的合作提高弥漫性大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）哥伦比亚大学的赫伯特欧文综合癌症中心（EICC）。该淋巴瘤SPORE的总体方法旨在通过引入，开发和应用新概念，方法和技术来改变当前的治疗模式和临床实践，以解决具有明确未满足医疗需求的几个DLBCL亚组。我们的总体目标是：具体目标1。基于靶向导致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。使用来自SPORE开发的四项临床试验中入组患者的组织标本，确定抗肿瘤疗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患者进行新的治疗方法。在项目1中，我们将开发新的治疗方法来靶向Myc和Bcl 2之间的致癌合作。随后可以使用标准免疫组织化学方法在富集DLBCL中的高Myc+/Bcl 2+表达的患者中评价这种疗法。这些患者有明确的未满足的医疗需求，因为他们在标准化疗中预后不良。在项目2中，我们将研究遗传修饰的T细胞表达靶向CD 19的嵌合抗原受体（汽车）在不适合干细胞移植的复发性DLBCL老年患者中的安全性和临床疗效。19这些患者预后不良，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Hsp 90的安全性和有效性。（TE-Hsp 90）抑制剂PU-H71在复发性DLBCL患者中的作用。21，22使用放射性标记的I-124 PU-H71的新型基于PET的分子成像将用于检查PU-H71对HSP 90的体内靶向，并指导剂量和患者选择。23因为c-Myc和内在凋亡途径蛋白是TE-Hsp 90的客户蛋白，将在Myc+/Bcl 2 + DLBCL患者中回顾性评估该治疗的功效。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mocetinostat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，以用新型HDAC激动剂进行治疗。7 -12我们的目标是在生物标志物确定的复发DLBCL患者中鉴定安全且有效的新药。

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.