Developing novel therapy to improve outcomes in MCL

项目摘要 套细胞淋巴瘤（MCL）是一种无法治愈的非霍奇金淋巴瘤，尽管加强治疗， 在这些方法中，一线治疗后的中位无进展生存期为4年。的出现 化疗耐药是迅速的，对二线和三线治疗的持久反应是罕见的，复发几乎是不可能的。 在MCL中普遍存在。主要通过E2F1靶基因上调的细胞周期失调是MCL的标志。 我们发现成纤维细胞生长因子受体1（FGFR 1）在MCL存活和调节细胞增殖中的新作用， 主要通过抑制E2F1介导的反式激活来抑制细胞周期依赖性过程。我们发现FGFR1，而不是 其它同源物在MCL患者中过表达，并且其表达与不良预后相关。 FGFR 1的功能性、遗传性消融或Erdafitinib（一种选择性小分子）的药理学靶向作用 靶向FGFR，诱导细胞周期停滞，体外细胞死亡，减少肿瘤形成，并改善总体 体内存活率。从机制上讲，我们发现FGFR1正调控E2F1介导的转录激活， 通过cMYC/EZH2/CDKN1C轴靶向基因，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因子，是一种新的有吸引力的候选信号通路 用于复发性MCL患者的靶向治疗。在本提案中，我们将剖析 FGFR1影响MCL生存期，并使用erdafitinib作为预防和治疗药物进行临床前研究 MCL通过以下具体目标：SA 1：表征FGFR1在体外和体内MCL存活中的作用 MCL的体内小鼠模型。在这个目标中，我们将研究a）FGFR 1在调节E2F1介导的细胞凋亡中的作用。 B）CDKN1C在调节E2F1依赖性细胞因子中的作用， 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 构成反馈回路，以及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。SA 2：使用患者进行FGFR 1抑制的临床前研究- 衍生的异种移植物（PDX）鼠模型和MCL的原代遗传鼠模型。我们将进行 使用PDX和MCL鼠模型进行的erdafitinib临床前试验，以确定a） 诱导FGFR 1信号传导和下游靶基因表达有效抑制， 毒性和B）单独使用Erdafitinib可产生最大临床疗效的最佳剂量和给药方案和c） 与伊鲁替尼的组合。SA3：我们将对复发性乳腺癌患者的组织活检进行回顾性分析。 a）分析FGFR 1蛋白的作用及其相关的临床结果，和B）分析MCL患者的免疫应答。 复发性/难治性乳腺癌患者中FGFR 1蛋白及其活化、下游效应物之间的相关性 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 计划在MCL，并提供了一个强大的临床前评估，通过评价毒性，暴露和疗效 Erdafitnib在MCL临床前模型中的作用，以将FGFR 1抑制剂Erdafitinib转化为临床治疗MCL。

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.