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。 B细胞受体信号途径的靶向口服激酶抑制剂正在转化CLL的尿道疗法 挑战仍然存在。 尽管疾病反应良好，但PI3Kp110Δ抑制剂包括第一代 批准的Idelalisib以及Duvelisib，PI3Kγ和δ抑制剂当前注册试验 抑制剂具有包括肝炎，结肠炎和肺炎的毒性模式。 CLL患者的临床试验，一名基于idelalisib和一个基于Duvelisib的临床试验，我们将其描述为这些 免疫介导的毒性。 调节性细胞可增强这些患者的实体瘤的风险。 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tet 与观察到的毒性相关的PI3KΔ侵蚀剂治疗期间，CLL的效应子景观与目的是 识别毒和功效的临床和免疫学预测指标。 评估pI3KΔ击中对Tregulatoration细胞抑制功能的影响，激活 T效细胞的Capace和幼稚的CD4+ T细胞的体外分化潜力。 将评估PI3KΔ敲低对疾病的Eμ-TCL1小鼠模型的影响 开发，自身免疫性毒物和t -cell Milieu。 遗传模型，但会Alsess药理抑制剂。 PI3Kδ选择性侵入人类和小鼠的基本生物学，使我们能够识别预测 毒性和功效将优化这些药物的患者选择。 灵敏度和对PI3Kδ抑制的抗性机制。 ERK途径的生化上调或对PI3Kδ具有抗性的患者 因此，建议对RRK途径激活对PI3Kδ的影响进行直接的机械研究 在体外，我们还将通过研究这两个患者进行额外的发现 基线时的前瞻性临床，缓解和获得抗药性时，倾斜基因组， 转录组和信号传导评估。 理想的同质队列将使这些机制比一个更有效 因此，异质复发了该项目。 PI3Kδ抑制人类的生物学，就其显着的免疫作用和机制而言 耐药性，所有柳树最佳patimal patiemal患者选择治疗甚至会增加使用 基于其免疫调节功能，其他癌症中PI3Kδ的抑制作用。