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

基本信息

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
项目类别：
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

项目摘要

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）包括成熟的T细胞肿瘤的集合，这些肿瘤升高 CD30和纳普型细胞学的表达。变性淋巴瘤激酶（ALK），ALK+和ALK-。压抑物一个异质组comp compiance全身性ALK阴性和原发性皮肤ALCL（PC-ALCL）。公认的水上植入物相关（BIA）Alclounding 乳房植入物被认为是一种具有形态特征的独特临床和病理实体 Alk-Alcl。但是，ALK-ALCL患者的结果比Alk+的患者更糟糕因此，需要为这些新颖的，基于小分子的靶向差异而开发出一种新颖的，可取的小分子的靶标。淋巴恶性肿瘤，尤其是在Alk和Bia Alclier中的淋巴恶性肿瘤，这是缺乏对碱和BIA ALCL的深层分子特征的系统和全面的理解病理学，显然需要的是要确定关键的治疗漏洞。知识，我们在藻类中应用了公正的高含量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。免疫的介质，已被证明在许多实体瘤中起着至关重要的作用）它在淋巴恶性肿瘤中的作用尚未确定。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表达是一定的原代ALK-Casses升高此外，这与IL-1R信号激活（P-IRAK4水平）相关分析，我们确定了一组由ALK-ALCL中调节基因的IL-1R途径与与之显着重叠的IL-1R途径。反映JAK-STAT3活性和Th17/Th1表型的签名。在体外和小鼠异种移植模型中显示出有希望的活性结果为IL-1R途径促进Alk and Bia Alcl的假设提供了强有力的支持发病机理，靶向这一途径可能是TESE疾病中的一种新型治疗策略研究，我们将检验我们的假设以下AMS：1）阐明IL-1R途径在 Alk-and Bia Alcl，2）了解调节途径的机制，是与经常性的关系 ALCL中的遗传病变和3）验证IL-1R途径是TESE中没有新的治疗靶标 Malignnancies。这些针对这些人的类型的Albalgaties类型的Albalgaties类型用于开发小说的发展小说发展中的小说发展中的小说。独特的淋巴结疾病。