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.

项目总结