Developing novel therapy to improve outcomes in MCL

开发新疗法以改善 MCL 的预后

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要套细胞淋巴瘤（MCL）是一种无法治愈的非霍奇金淋巴瘤，尽管经过强化治疗方法，一线治疗后的中位无进展生存期为四年。的出现化疗耐药性很快，对二线和三线疗法的持久反应很少见，而且复发几乎是不可能的在 MCL 中通用。细胞周期失调（主要是 E2F1 靶基因的上调）是 MCL 的一个标志。我们发现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主要通过抑制 E2F1 介导的反式激活来实现周期依赖性过程。我们证明 FGFR1 而不是其他同源物在 MCL 患者中过度表达，其表达与不良预后相关。功能上，FGFR1 的基因消除或使用选择性小分子 erdafitinib 进行药物靶向靶向 FGFR，诱导细胞周期停滞、体外细胞死亡、减少肿瘤形成并改善整体体内存活。从机制上讲，我们发现 FGFR1 正向调节 E2F1 介导的其反式激活通过 cMYC/EZH2/CDKN1C 轴的靶基因，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，是一种新颖且有吸引力的候选者用于复发性 MCL 患者的靶向治疗。在本提案中，我们将剖析以下机制： FGFR1 影响 MCL 存活并使用 erdafitinib 作为预防和治疗疗法进行临床前研究 MCL 通过以下具体目标： SA1：表征 FGFR1 在 MCL 体外和体内存活中的作用 MCL 体内小鼠模型。为此，我们将研究 a) FGFR1 在调节 E2F1 介导的靶基因反式激活和体内存活，b) CDKN1C 在调节 E2F1 依赖性中的作用反式激活程序，c) E2F1 靶基因 CDK1 的作用，以正向调节 cMYC 稳定性和构成一个反馈循环，d) 确定基于机制的组合策略，以最大化治疗效果 FGFR1 抑制的潜力。 SA2：使用患者进行 FGFR1 抑制的临床前研究衍生异种移植 (PDX) 小鼠模型和 MCL 的原代遗传小鼠模型。我们将进行一次使用 PDX 和 MCL 小鼠模型对 erdafitinib 进行临床前试验，以确定 a) erdafitinib 的剂量诱导有效抑制 FGFR1 信号传导和下游靶基因表达，且不会出现不可接受的情况 b) erdafitinib 的最佳剂量和给药方案可单独产生最大临床疗效，以及 c) 与依鲁替尼联合使用。 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 蛋白的影响及其相关临床结果，b) 分析复发/难治性患者中 FGFR1 蛋白与其激活、下游效应器之间的相关性 MCL。影响：我们的提案将确定 FGFR1 在调节 E2F1 依赖性反式激活中的作用 MCL 计划，并通过评估毒性、暴露和功效来提供可靠的临床前评估 erdafitinib 在 MCL 临床前模型中的应用，将 FGFR1 抑制剂 erdafitinib 转化为临床治疗 MCL。