Investigating the IL-1R Pathway in Anaplastic Large Cell Lymphoma for Targeted Therapy

研究间变性大细胞淋巴瘤中的 IL-1R 通路以进行靶向治疗

• 批准号: 10385771
• 负责人: Yibin Yang
• 金额: $ 41.54万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-06 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10385771
• 关键词: Address; Aggressive Clinical Course; Anti-Inflammatory Agents; B-Cell Lymphomas; CRISPR library; CRISPR screen; Cell Line; Cell Survival; Characteristics; Clinical; Collection; Cutaneous; Cytokine Receptors; Cytology; Data; Development; Disease; Exhibits; FDA approved; Gene Expression; Genes; Genetic; Goals; Growth; Human; IRAK4 gene; Immunity; In Vitro; Inflammation; Inflammatory; Interleukin-1; Interleukin-1 Receptors; Interleukin-1 alpha; Internal Breast Prosthesis; Intervention; Janus kinase; Ki-1 Large-Cell Lymphoma; Knowledge; Large-Cell Lymphomas; Lead; Lesion; Libraries; Lymphoma cell; Lymphoproliferative Disorders; Malignant Neoplasms; Malignant lymphoid neoplasm; Mature T-Lymphocyte; Mediator of activation protein; Modeling; Molecular; Morphology; Mus; Mutation; Natural Immunity; Oncogenic; Outcome; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Phosphorylation; Play; Premalignant Cell; Proteins; Public Health; Recombinants; Recurrence; Regimen; Regulation; Role; STAT3 gene; Sampling; Seroma; Shapes; Signal Pathway; Signal Transduction; Solid Neoplasm; Subgroup; T-Cell and NK-Cell Neoplasm; TNFRSF8 gene; Testing; Therapeutic; Toxic effect; Transcription Coactivator; Validation; Xenograft Model; anakinra; anaplastic lymphoma kinase; antagonist; base; cancer cell; cell transformation; clinical efficacy; cytokine; improved; in vitro testing; inhibitor; insight; kinase inhibitor; loss of function; new therapeutic target; novel; novel strategies; novel therapeutic intervention; pre-clinical; receptor expression; small molecule; targeted treatment; transcriptome sequencing; tumor; tumor microenvironment

PROJECT SUMMARY Anaplastic large cell lymphoma (ALCL) comprises a collection of mature T-cell neoplasms that share elevated expression of CD30 and anaplastic cytology. ALCL subtypes are divided into two classes based on the status of anaplastic lymphoma kinase (ALK), ALK+ and ALK-. While ALK+ ALCL is relatively homogeneous, ALK- ALCL represents a heterogeneous group comprising systemic ALK negative and primary cutaneous ALCL (pC-ALCL). The recently recognized breast implant-associated (BIA) ALCL, which arises in the seroma cavity surrounding breast implants, was acknowledged as a distinct clinical and pathological entity that shares morphologic features with ALK- ALCL. Current therapeutic strategies for ALCL are largely based on aggressive B-cell lymphoma regimens. However, the outcomes are generally much worse in patients with ALK- ALCL than in those with ALK+ ALCL. Thus, there is a need to develop novel, preferably small molecule-based targeted therapies for these lymphoid malignancies, especially in ALK- and BIA ALCL cases. A major barrier to this goal is the lack of a systematic and comprehensive understanding of the deep molecular characteristics of ALK- and BIA ALCL pathology, which is clearly needed in order to identify critical therapeutic vulnerabilities. To address the gaps in knowledge, we applied an unbiased high throughput CRISPR screening in ALCL, and identified an unexpected role of the IL-1R-MyD88 pathway in supporting ALK- and BIA ALCL. The IL-1R signaling pathway is a key mediator of immunity and inflammation and has been shown to play a critical role in many solid tumors; however, its role in lymphoid malignancies has not been established. Indeed, our preliminary studies provide the first unequivocal evidence that IL-1R1 pathway plays an essential role in supporting ALK- and BIA ALCL cell survival. Clinically, we found that IL-1 receptor and IL-1α expression are consistently elevated in primary ALK- cases, and this is correlated with IL-1R signaling activation (p-IRAK4 level) in primary samples. Moreover, using RNA-seq analysis, we identified a set of IL-1R pathway regulated genes in ALK- ALCL that overlapped significantly with signatures reflecting JAK-STAT3 activity and TH17/TH1 phenotyping. Finally, a highly specific IRAK4 inhibitor shows promising activity against ALK- and BIA ALCL in vitro and in a mouse xenograft model. Altogether, these findings provide strong support for our hypothesis that the IL-1R pathway promotes ALK- and BIA ALCL pathogenesis, and that targeting this pathway could be a novel therapeutic strategy in these diseases. In this study, we will test our hypothesis through the following aims: 1) Elucidation of the exact role of IL-1R pathway in ALK- and BIA ALCL, 2) Understanding of mechanisms regulating this pathway and its relationship to recurrent genetic lesions in ALCL, and 3) Validation of the IL-1R pathway as a novel therapeutic target in these malignancies. The proposed studies should provide critical insights into the molecular circuitry that drives these types of ALCL and, consequently, result in the development of novel targeted therapeutic strategies for these distinct lymphoproliferative disorders.

项目摘要 间变性大细胞淋巴瘤（ALCL）包括一组成熟T细胞肿瘤， CD 30表达和间变性细胞学。ALCL亚型根据以下状态分为两类： 间变性淋巴瘤激酶（ALK），ALK+和ALK-。虽然ALK+ ALCL相对同质，但ALK-ALCL 代表包括全身性ALK阴性和原发性皮肤ALCL（pC-ALCL）的异质组。 最近认识到的乳房植入体相关（BIA）ALCL，发生在周围的血清肿腔中， 乳房植入体，被认为是一个独特的临床和病理实体，共享形态学特征 ALK-ALCL目前ALCL的治疗策略主要基于侵袭性B细胞淋巴瘤 养生法然而，ALK-ALCL患者的结局通常比ALK+患者差得多。 ALCL。因此，需要开发新的，优选基于小分子的靶向疗法用于这些疾病。 淋巴系统恶性肿瘤，尤其是ALK和BIA ALCL病例。实现这一目标的一个主要障碍是缺乏一个 系统全面地了解ALK和BIA ALCL的深层分子特征 病理学，这显然是需要的，以确定关键的治疗漏洞。为了弥补 我们在ALCL中应用了一种无偏的高通量CRISPR筛选，并发现了一种意想不到的 IL-1 R-MyD 88通路在支持ALK和BIA ALCL中的作用。IL-1 R信号通路是一个关键 免疫和炎症介质并已显示在许多实体瘤中起关键作用;然而， 其在淋巴恶性肿瘤中的作用尚未确定。事实上，我们的初步研究提供了第一个 明确的证据表明IL-1 R1途径在支持ALK和BIA ALCL细胞生存方面发挥着重要作用。 临床上，我们发现IL-1受体和IL-1α表达在原发性ALK-病例中持续升高， 这与原始样品中IL-1 R信号传导激活（p-IRAK 4水平）相关。此外，使用RNA-seq 分析中，我们确定了ALK-ALCL中一组IL-1 R通路调节基因， 反映JAK-STAT 3活性和TH 17/TH 1表型的特征。最后，高度特异性的IRAK 4抑制剂 在体外和小鼠异种移植模型中显示出对ALK和BIA ALCL的有希望的活性。总之，这些 研究结果为我们的假设提供了强有力的支持，即IL-1 R通路促进ALK和BIA ALCL 因此，研究人员认为，靶向这一途径可能是这些疾病的一种新的治疗策略。在这 本研究将通过以下目的来验证我们的假设：1）阐明IL-1 R通路在 ALK和BIA ALCL，2）了解调节该途径的机制及其与复发性 ALCL中的遗传性病变，以及3）IL-1 R通路作为这些疾病的新治疗靶点的验证 恶性肿瘤。拟议的研究应该提供关键的见解，以分子电路驱动这些 ALCL类型，并因此导致这些新的靶向治疗策略的发展 不同的淋巴组织增生性疾病