Unlocking the Potential of PI3K Inhibition in CLL

释放 PI3K 抑制在 CLL 中的潜力

• 批准号: 9883758
• 负责人: Jennifer R Brown
• 金额: $ 57.11万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9883758
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affect; Apoptosis; Autoimmune Process; Autoimmunity; B-Lymphocytes; Biochemical; Biological Assay; Biology; Bone Marrow; CD4 Positive T Lymphocytes; Catalytic Domain; Cell physiology; Cells; Characteristics; Clinic; Clinical; Clinical Trials; Colitis; Combined Modality Therapy; Data; Development; Disease; Disease remission; Drug usage; Enrollment; Evaluation; Evolution; Exposure to; FDA approved; Generations; Genetic; Genetic Models; Genomics; Goals; Grant; Hepatitis; Human; Immune; Immune system; Immuno-Chemotherapy; Immunologics; In Vitro; Individual; Lead; Malignant Neoplasms; Mediating; Mus; North America; Oral; Pathway interactions; Patient Care; Patient Selection; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Phosphotransferases; Protein Isoforms; Pulmonary Inflammation; Receptors, Antigen, B-Cell; Refractory; Regimen; Regulatory T-Lymphocyte; Relapse; Resistance; Risk; Role; Safety; Selection for Treatments; Signal Pathway; Signal Transduction; Solid; Solid Neoplasm; Stimulus; T-Lymphocyte; Time; Toxic effect; Up-Regulation; Work; adult leukemia; anti-cancer; base; cohort; design; effector T cell; experimental study; high risk; immune activation; immune function; immunoregulation; inhibitor/antagonist; kinase inhibitor; knock-down; leukemia; mouse model; new therapeutic target; next generation; novel therapeutics; patient population; phosphatidylinositol 3-kinase gamma; pre-clinical; prospective; randomized trial; relapse patients; resistance mechanism; response; targeted treatment; transcriptomics

Project Summary CLL is the most common leukemia of adults in North America and remains incurable. Recent discovery of targeted oral kinase inhibitors of the B cell receptor signaling pathway is transforming the therapy of CLL, but challenges remain. Individually none of these drugs is curative, and approximately 30% of patients discontinue for toxicity despite good disease response. The PI3K p110δ inhibitors include the first generation FDA approved drug idelalisib, as well as duvelisib, a PI3K γ and δ inhibitor currently in registration trials. The PI3Kδ inhibitors have a pattern of toxicity that includes hepatitis, colitis and pneumonitis. We have two ongoing clinical trials in CLL patients, one idelalisib based and one duvelisib based, in which we have described these toxicities to be immune-mediated. We have further shown that this toxicity associates with a decrease in T regulatory cells, which could also enhance efficacy and decrease risk of solid tumors in these patients. In this grant in Specific Aim 1 we propose to deepen these observations, characterizing the T regulatory and T effector landscape of CLL during therapy with PI3Kδ inhibitors in relation to observed toxicities, with the goal of identifying clinical and immunologic predictors of toxicity and efficacy. We will further perform in vitro functional assays to assess the impact of PI3Kδ inhibition on the suppressive function of T regulatory cells, the activation capacity of T effector cells and the in vitro differentiation potential of naïve CD4+ T cells. In Specific Aim 2 we will assess the impact of PI3Kδ knockdown on the Eμ-TCL1 mouse model of CLL in terms of disease development, autoimmune toxicity and T cell milieu. These experiments will focus on the mouse kinase dead genetic model but will also assess pharmacologic inhibitors. Aims 1 and 2 will therefore elucidate the fundamental biology of PI3Kδ selective inhibition in humans and mice and enable us to identify predictors of toxicity and efficacy that will optimize patient selection for these drugs. In Specific Aim 3, we will characterize the mechanisms of sensitivity and resistance to PI3Kδ inhibition. Our preliminary data implicate genetic and/or biochemical upregulation of the ERK pathway in patients who are or become resistant to PI3Kδ inhibition. We therefore propose to perform direct mechanistic studies of the impact of ERK pathway activation on PI3Kδ resistance in vitro. We will also perform additional discovery by studying patients enrolled on these two prospective clinical trials at baseline, during remission and at time of acquired resistance, including genomic, transcriptomic and signaling evaluation. This previously untreated uniform patient population represents an ideal homogeneous cohort that will allow us to understand these mechanisms much more effectively than a heterogeneous relapsed cohort. This project will therefore represent a major advance in the understanding of the biology of PI3Kδ inhibition in humans, in terms of its significant immunologic effects and mechanisms of resistance, all of which will allow optimal patient selection for this therapy and may even lead to expanded use of PI3Kδ inhibition in other cancers, based on its immunoregulatory function.

项目摘要 CLL是北美成年人最常见的白血病，仍然无法治愈。最近发现 B细胞受体信号通路的靶向口服激酶抑制剂正在转化CLL的治疗，但 仍然存在挑战。这些药物都没有治愈，大约30％的患者中断 为了毒性任务良好的疾病反应。 PI3KP110Δ抑制剂包括第一代FDA 批准的药物Idelalisib以及Duvelisib，目前正在注册试验中的PI3Kγ和δ抑制剂。 PI3Kδ 抑制剂具有毒性模式，包括肝炎，结肠炎和肺炎。我们有两个正在进行的 CLL患者的临床试验，一名基于idelalisib和一个基于Duvelisib的临床试验，其中我们已经描述了这些试验 免疫介导的毒性。我们进一步表明，这种毒性关联随t的降低 调节细胞也可以提高这些患者实体瘤的效率并降低效率。在这个 在特定目的1中的授予1我们建议加深这些观察结果，表征调节和T 使用PI3Kδ抑制剂治疗期间，CLL的效应子景观与观察到的策略有关，目的是 确定毒性和效率的临床和免疫学预测指标。我们将进一步执行体外功能 评估PI3Kδ抑制对T调节细胞抑制功能的影响，激活 T效应细胞的能力和CD4+ T细胞的体外分化潜力。在特定目标2中我们 将评估PI3Kδ敲低对疾病的Eμ-TCL1小鼠模型的影响 开发，自身免疫性毒性和T细胞环境。这些实验将集中于鼠标激酶死亡 遗传模型，但还将评估药理抑制剂。因此，目标1和2将阐明 PI3KΔ选择性抑制的基本生物学，使我们能够识别预测因子 毒性和效率将优化这些药物的患者选择。在特定目标3中，我们将描述 灵敏度和对PI3Kδ抑制的抗性机制。我们的初步数据暗示遗传和/或 ERK途径的生化上调在对PI3KΔ抑制具有抗性的患者中。我们 因此，提出直接的机械研究，以了解ERK途径激活对PI3Kδ的影响 体外抗性。我们还将通过研究这两个招募的患者来进行其他发现 基线，缓解和获得抗性时的前瞻性临床试验，包括基因组， 转录组和信号评估。以前未经治疗的统一患者人群代表 理想的同质队列将使我们能够更有效地理解这些机制 异构接力队的队列。因此，该项目将代表理解的重大进步 PI3Kδ抑制人类的生物学，就其显着的免疫作用和机制而言 阻力，所有这些都将使该疗法的最佳患者选择，甚至可能导致使用扩大 基于其免疫调节功能，其他癌症中PI3Kδ的抑制作用。