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: 10599170
• 负责人: Yibin Yang
• 金额: $ 39.56万
• 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/10599170
• 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; Cytology; Data; Development; Disease; Exhibits; FDA approved; Gene Expression; Genes; Genetic; Goals; Growth; Human; IL1R Signaling Pathway; IL1R1 gene; 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; Lesion; Libraries; Lymphoma cell; Lymphoproliferative Disorders; Malignant - descriptor; Malignant Neoplasms; Malignant lymphoid neoplasm; Mature T-Lymphocyte; Mediator; 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 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; 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; 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 那型大细胞淋巴瘤（ALCL）包括一组成熟的T细胞肿瘤，共享升高 CD30和变性细胞学的表达。 ALCL子类型根据状态分为两个类 变性淋巴瘤激酶（ALK），ALK+和ALK-。而Alk+ Alcl相对均匀，Alk-Alcl 代表一个完成全身性ALK负和原发性皮肤ALCL（PC-ALCL）的异质组。 最近在血清腔周围产生的最近认识的乳腺植入物相关（BIA）ALCL 乳房被公认为是一个独特的临床和病理实体，具有形态学特征 与Alk-Alcl。 ALCL的当前治疗策略主要基于侵略性的B细胞淋巴瘤 方案。但是，ALK-ALCL患者的结局通常要比ALK+的患者差得多 ALCL。这是有必要开发出新颖的，优先的小分子的靶向疗法 淋巴性恶性肿瘤，尤其是在ALK和BIA ALCL病例中。这个目标的主要障碍是缺乏 对ALK和BIA ALCL的深层分子特征的系统和全面理解 病理学，显然需要这是为了识别关键治疗漏洞。解决差距 知识，我们在ALCL中应用了公正的高通量CRISPR筛选，并确定了出乎意料的 IL-1R-MYD88途径在支持ALK-和BIA ALCL中的作用。 IL-1R信号通路是键 免疫和炎症的介体已被证明在许多实体瘤中起着至关重要的作用。然而， 它在淋巴恶性肿瘤中的作用尚未确定。确实，我们的初步研究提供了第一个 明确的证据表明IL-1R1途径在支持ALK和BIA ALCL细胞存活中起着至关重要的作用。 在临床上，我们发现IL-1受体和IL-1α表达在原发性ALK-病例中始终升高，并且 这与主要样品中的IL-1R信号激活（P-IRAK4水平）相关。此外，使用RNA-Seq 分析，我们确定了一组IL-1R途径在ALK-ALCL中调节的基因，该基因与 反映JAK-STAT3活性和Th17/Th1表型的特征。最后，高度特异的IRAK4抑制剂 在体外和小鼠的Xenographic模型中显示出对ALK和BIA ALCL的有希望的活性。这些，这些 发现为我们的假设提供了强有力的支持，即IL-1R途径促进了ALK和BIA ALCL 发病机理，靶向这种途径可能是这些疾病中的一种新型治疗策略。在这个 研究，我们将通过以下目的检验我们的假设：1）阐明IL-1R途径在 Alk-和Bia Alcl，2）理解调查这一途径及其与经常性关系的机制 ALCL中的遗传病变和3）验证IL-1R途径是这些新型热目标 恶性肿瘤。拟议的研究应提供对驱动这些分子电路的关键见解 ALCL的类型，因此导致为这些新型有针对性的治疗策略发展 不同的淋巴增生剂疾病。