Developing novel therapy to improve outcomes in MCL

开发新疗法以改善 MCL 的预后

• 批准号: 10717196
• 负责人: Lalit Sehgal
• 金额: $ 40.7万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-12 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10717196
• 关键词: Ablation; Biological; Biology; Biopsy; CDC2 gene; CDKN1C gene; Cell Cycle; Cell Cycle Arrest; Cell Death; Cell Line; Cell Survival; Chemoresistance; Clinic; Clinical; Combined Modality Therapy; Data; Development; Dose; E2F transcription factors; EZH2 gene; Feedback; Fibroblast Growth Factor Receptor 1; Fibroblast Growth Factor Receptors; Gene Expression; Genes; Genetic; Genetically Engineered Mouse; Goals; Hematopoietic Neoplasms; Homologous Gene; In Vitro; Investigation; Knowledge; Lymphoma cell; Mantle Cell Lymphoma; Mediating; Membrane; Methods; Molecular; Non-Hodgkin' s Lymphoma; Outcome; Pathway interactions; Patients; Physiological; Play; Pre-Clinical Model; Process; Prognosis; Progression-Free Survivals; Proteins; Receptor Protein-Tyrosine Kinases; Refractory; Relapse; Resistance; Role; Sampling; Schedule; Signal Pathway; Signal Transduction; TK1 gene; Therapeutic; Tissues; Toxic effect; Transactivation; Translating; Up-Regulation; angiogenesis; c-myc Genes; carcinogenesis; clinical decision-making; clinical efficacy; clinically significant; cohort; improved; improved outcome; in vivo; inhibitor; migration; mouse model; novel; novel therapeutic intervention; novel therapeutics; outcome prediction; overexpression; patient derived xenograft model; patient population; pharmacologic; pre-clinical; pre-clinical assessment; preclinical study; preclinical trial; prevent; programs; response; small molecule; synergism; targeted treatment; therapeutic target; tumor; virtual

PROJECT SUMMARY Mantle cell lymphoma (MCL) is an incurable non-Hodgkin lymphoma, and despite intensive therapeutic approaches, the median progression-free survival after first-line treatment is four years. The emergence of chemoresistance is rapid, durable responses to second and third-line therapies are rare, and relapse is virtually universal in MCL. Cell cycle dysregulation, primarily by upregulation of E2F1 target genes, is a hallmark of MCL. We identified a novel role of Fibroblast growth factor receptor-1 (FGFR1) in MCL survival and regulating cell cycle-dependent processes primarily by inhibiting E2F1 mediated transactivation. We show that FGFR1 and not other homologs are overexpressed in MCL patients, and its expression is associated with a poor prognosis. Functionally, genetic ablation of FGFR1 or pharmacological targeting with erdafitinib, a selective small molecule targeting FGFRs, induced cell cycle arrest, cell death in-vitro, reduced tumor formation, and improved overall survival in-vivo. Mechanistically, we show that FGFR1 positively regulates E2F1-mediated transactivation of its target gene through cMYC/EZH2/CDKN1C axis, contributing to cell survival. Hence, we hypothesize that the FGFR1 signaling pathway is a critical modulator of cell survival and represents a novel and attractive candidate for targeted therapy for patients with relapsed MCL. In this proposal, we will dissect the mechanisms by which FGFR1 impacts MCL survival and perform preclinical studies using erdafitinib as a therapy to prevent and treat MCL through the following specific aims: SA1: To characterize the role of FGFR1 in MCL survival in-vitro and in- vivo mouse models of MCL. In this aim, we will investigate a) FGFR1's role in regulating E2F1 mediated transactivation of target genes and survival in-vivo, b) the role of CDKN1C in regulating E2F1 dependent transactivation program, c) the role of E2F1 target gene CDK1, to positively regulates cMYC stability and constitute a feedback loop and d) identify mechanism-based combination strategies to maximize the therapeutic potential of FGFR1 inhibition. SA2:To conduct a preclinical investigation of inhibition of FGFR1 using patient- derived xenograft (PDX) murine models and a primary genetic murine model of MCL. We will conduct a preclinical trial of erdafitinib using PDX and murine models of MCL to identify a) the doses of erdafitinib that induce efficient inhibtion of FGFR1 signaling and downstream target gene expression without unacceptable toxicity and b) the best dose and schedule of erdafitinib resulting in maximum clinical efficacy alone and c) in combination with an ibrutinib. SA3: We will perform a retrospective analysis on tissue biopsies from relapsed MCL patients to a) analyze the effects of FGFR1 protein and its associated clinical outcomes and b) analyze the correlation between FGFR1 protein and, its activation, downstream effectors in patients with relapsed/refractory MCL. Impact: Our proposal will establish the role of FGFR1 in regulating E2F1 dependent transactivation program in MCL and provide a robust preclinical assessment by evaluating the toxicity, exposure, and efficacy of erdafitnib in preclinical models of MCL to translate FGFR1 inhibitor erdafitinib to treat MCL in clinics.

项目摘要 地幔细胞淋巴瘤（MCL）是一种无法治愈的非霍奇金淋巴瘤，尽管进行了强化治疗 接近一线治疗后的无进展生存期为四年。出现 化学耐药性是快速，对第二线和三线疗法的持久反应，而复发实际上是 MCL中的通用。细胞周期失调主要是通过E2F1靶基因的上调，是MCL的标志。 我们确定了成纤维细胞生长因子受体1（FGFR1）在MCL存活和调节细胞中的新作用 循环依赖性过程主要是通过抑制E2F1介导的反式激活。我们证明了FGFR1而不是 其他同源物在MCL患者中过表达，其表达与预后不良有关。 在功能上，用Erdafitinib（一种选择性小分子）对FGFR1或药理靶向的遗传消融 靶向FGFR，诱导细胞周期停滞，细胞死亡 - 体外死亡，减少肿瘤形成并改善总体 存活体内。从机械上讲，我们表明FGFR1积极调节E2F1介导的其反式激活 通过CMYC/EZH2/CDKN1C轴靶基因，有助于细胞存活。因此，我们假设 FGFR1信号通路是细胞存活的关键调节剂，代表了一种新颖而有吸引力的候选者 用于复发MCL患者的靶向治疗。在此提案中，我们将剖析 FGFR1影响MCL的存活率，并使用Erdafitinib作为预防和治疗的临床前研究 MCL通过以下特定目的：SA1：表征FGFR1在MCL生存中的作用 MCL的体内鼠标模型。在此目标中，我们将研究a）FGFR1在调节E2F1介导的作用 靶基因的反式激活和体内生存，b）CDKN1C在调节E2F1依赖性方面的作用 反式激活程序，c）E2F1靶基因CDK1的作用，以积极调节CMYC稳定性和 构成反馈循环和d）确定基于机制的组合策略，以最大化治疗性 FGFR1抑制的潜力。 SA2：使用患者对FGFR1抑制进行临床前研究 - 衍生的异种移植（PDX）鼠模型和MCL的主要遗传鼠模型。我们将进行 使用MCL的PDX和鼠模型对Erdafitinib的临床前试验，以识别A）Erdafitinib的剂量 诱导有效抑制FGFR1信号传导和下游靶基因表达 毒性和b）Erdafitinib的最佳剂量和时间表，仅产生最大的临床功效，c） 结合ibrutinib。 SA3：我们将对复发的组织活检进行回顾性分析 MCL患者a）分析FGFR1蛋白及其相关临床结果的影响，b）分析 FGFR1蛋白与其激活，复发/难治患者的下游效应子之间的相关性 MCL。影响：我们的建议将确定FGFR1在调节E2F1依赖性反式激活中的作用 MCL中的计划，并通过评估毒性，暴露和功效来提供强大的临床前评估 MCL的临床前模型中的Erdafitnib的of trrance fgfr1抑制剂Erdafitinib在诊所中治疗MCL。