Developing novel therapy to improve outcomes in MCL

项目总结 套细胞淋巴瘤(MCL)是一种不可治愈的非霍奇金淋巴瘤，尽管进行了强化治疗 一线治疗后，中位无进展生存期为四年。新技术的出现 化疗耐药迅速，对二线和三线疗法的持久反应很少，而且几乎不会复发 在MCL中通用。细胞周期失调，主要是通过上调E2F1靶基因，是MCL的一个标志。 我们发现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 依赖周期的过程主要是通过抑制E2F1介导的反式激活。我们发现FGFR1和NOT 其他同源基因在MCL患者中过度表达，其表达与预后不良有关。 从功能上讲，FGFR1的基因消融或选择性小分子厄达非替尼的药理靶向 靶向FGFRs，诱导细胞周期停滞，体外细胞死亡，减少肿瘤形成，并总体改善 活体内存活。从机制上讲，我们发现FGFR1正向调节E2F1介导的ITS的反式激活 靶基因通过cMYC/EZH2/CDKN1C轴，促进细胞存活。因此，我们假设 FGFR1信号通路是细胞存活的关键调节因子，是一个新的、有吸引力的候选信号通路 对复发的MCL患者进行靶向治疗。在这项提案中，我们将剖析 FGFR1对MCL存活率的影响及使用厄达非替尼预防和治疗的临床前研究 MCL通过以下特定目的：SA1：确定FGFR1在MCL体外和体外存活中的作用。 MCL的活体小鼠模型。为此，我们将研究a)成纤维细胞生长因子受体1‘S在调控E2F1中的作用 靶基因的反式激活与体内存活，b)CDKN1C在调节E2F1依赖中的作用 反式激活程序，c)E2F1靶基因CDK1在积极调节cMYC稳定性和 建立反馈循环和d)确定基于机制的组合策略，以最大限度地提高治疗效果 FGFR1抑制的可能性。SA2：使用患者-进行抑制FGFR1的临床前研究- 衍生异种移植(PDX)小鼠模型和MCL的原始遗传小鼠模型。我们将进行一项 使用PDX和小鼠MCL模型进行的厄达菲替尼临床前试验，以确定a)厄达菲替尼的剂量， 诱导FGFR1信号和下游靶基因表达的有效抑制，而不是不可接受的 毒性；b)单用厄达非替尼的最佳剂量和时间表；c)在 与伊布鲁替尼联合使用。SA3：我们将对复发患者的组织活检进行回顾性分析 MCL患者a)分析FGFR1蛋白的作用及其相关的临床结局，以及b)分析 复发/难治患者FGFR1蛋白与其激活及其下游效应因子的相关性 MCL。影响：我们的提案将确定FGFR1在调节E2F1依赖的反式激活中的作用 计划，并通过评估毒性、暴露和疗效提供强大的临床前评估 在MCL的临床前模型中应用Erdafitnib翻译FGFR1抑制剂Erdafitinib治疗MCL的临床应用。

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.