Non-canonical Wnt-Receptor Signaling and Targeted Therapies

非经典 Wnt 受体信号转导和靶向治疗

基本信息

批准号：
10375514
负责人：
Thomas J Kipps
金额：
$ 62.51万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10375514
关键词：
Address Adult Affect Antigens B-Cell Antigen Receptor BCL2 gene BLNK gene Binding Binding Proteins Biological Markers Biological Models Biology Blood specimen CD19 gene Cell Line Cell Survival Cell model Cells Chronic Lymphocytic Leukemia Clinical Clinical Research Development Disease Enzymes Failure Immunoglobulins In complete remission Left Leukemic Cell Lymphocyte Monitor Monoclonal Antibodies Mutate Oncogenic Pathway interactions Patients Phenotype Phosphotransferases Plasma Play Postpartum Period Proteins Proto-Oncogene Proteins c-akt ROR1 gene Receptor Signaling Resistance development Role Sampling Signal Pathway Signal Transduction Structure-Activity Relationship System Technology Therapeutic Tissues Transgenic Mice WNT Signaling Pathway antagonist beta catenin calmodulin-dependent protein kinase II cancer therapy cell growth cell motility chronic lymphocytic leukemia cell clinically relevant in vivo indexing inhibitor leukemia mouse model neoplastic new therapeutic target novel preclinical study receptor recruit response rho GTP-Binding Proteins stemness synergism targeted treatment therapy development transcriptome tumor microenvironment

项目摘要

ROR1 is a receptor for Wnt5a, which can induce non-canonical Wnt-signaling, activate Rho GTPases, and enhance leukemia-cell migration, proliferation, and survival. High-level expression of ROR1 can accelerate development and progression of leukemia in transgenic mouse models and associates with more aggressive disease and shorter survival of patients (pts) with CLL. CLL cells also express other developmentally-restricted Wnt5a-receptors, namely ROR2 and RYK, which can contribute to non-canonical Wnt-signaling in CLL. We hypothesize that elucidation of the structure-function-relationships involved in signaling by ROR1, ROR2, and RYK will define clinically relevant biomarkers for non-canonical Wnt-signaling and identify novel targets for therapy. Moreover, inhibition of non-canonical Wnt-signaling could have therapeutic applications, either alone or in combination with other newly developed targeted therapies that inhibit B-cell-receptor-signaling or BCL2. For this, we have the following specific aims: (AIM 1) Interrogate the signaling-pathways of non-canonical Wnt receptors in CLL - We will define the proteins recruited to ROR1/2 in response to Wnt5a and determine the structural domains required for signaling. We will examine the contribution of RYK to Wnt5a-signaling in CLL, determine the role of SH3-binding proteins, 14-3-3ζ, or Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) in ROR1-dependent signaling, and examine the contribution and function of ROR1 kinase to non- canonical Wnt-signaling. (AIM 2) Examine CLL cells for co-expression of non-canonical Wnt-receptors and determine the relative levels of Wnt-signaling - We will examine the blood samples of pts with CLL cells that have high, low, or negligible expression of ROR1 for plasma Wnt5a, leukemia-cell expression of ROR2 and RYK, and for leukemia-cell activation of canonical and non-canonical Wnt signaling. We also will examine the transcriptomes of selected CLL samples and cell lines for the newly described stemness index, which is dependent on ROR1-signaling. We also will examine for cross-talk between the canonical β-catenin- dependent Wnt-signaling pathway and the non-canonical, β-catenin-independent pathway, which may be influenced by the relative expression of ROR1, ROR2, or RYK, or by treatment with newly generated mAbs specific for ROR2 or RYK. (AIM 3) Examine the contribution of ROR1-signaling to the development of resistance to targeted therapies in CLL - We will examine expression-levels and function of ROR1, ROR2, and RYK in serial CLL samples collected from pts before, during, and after development of resistance to targeted therapies and evaluate the potential for synergy between cirmtuzumab and the BCL2 antagonist, venetoclax.

ROR1是Wnt5a的受体，它可以诱导非典型的Wnt信号，激活Rho GTPase，并且增强白血病细胞的迁移，增殖和生存。 ROR1的高级表达可以加速在转基因小鼠模型和伴侣中，白血病的开发和进展与更具侵略性患者（PTS）与CLL的疾病和短期生存期。 CLL细胞还表达其他发育限制的 Wnt5a受体，即ROR2和RYK，这可以在CLL中有助于非典型的WNT信号。我们假设阐明ROR1，ROR2和 RYK将定义非典型Wnt信号的临床相关生物标志物，并确定新的目标治疗。此外，抑制非经典Wnt信号可以具有治疗应用，或者单独使用或结合其他抑制B受体信号或BCL2的其他新开发的靶向疗法。为此，我们具有以下特定目的：（目标1）询问非典型的信号通道 CLL中的Wnt接收器 - 我们将根据Wnt5a定义募集到ROR1/2的蛋白质并确定信号所需的结构域。我们将研究RYK对Wnt5a信号的贡献 CLL，确定SH3结合蛋白，14-3-3ζ或Ca2+/钙调蛋白（CAM）依赖性蛋白激酶的作用 II（CAMKII）在ROR1依赖性信号中，并检查ROR1激酶对非 - 的贡献和功能典型的Wnt信号。（AIM 2）检查CLL细胞是否共表达了非经典WNT受体并确定Wnt信号的相对水平 - 我们将检查使用CLL的PT的血液样本对于血浆Wnt5a的ROR1表达高，低或可以忽略的细胞，白血病 - 细胞表达的表达 ROR2和RYK，以及用于典型和非典型Wnt信号的白血病细胞激活。我们也会检查选定的CLL样品的转录组和细胞系的转录组，以了解新描述的Stemness指数，这取决于ROR1信号。我们还将检查规范β-catenin-之间的串扰依赖的Wnt信号途径和非典型的β-catenin独立途径，这可能是受ROR1，ROR2或RYK的相对表达的影响，或受到新产生的mAb处理的影响针对ROR2或RYK。（目标3）检查ROR1信号对发展的贡献 CLL中对靶向疗法的抗性 - 我们将检查ROR1，ROR2，和RYK中的串行CLL样品从PT中收集的串行CLL样品，此前，期间和之后的耐药性有针对性的疗法并评估CenturyTuzumab和Bcl2拮抗剂之间协同作用的潜力 Venetoclax。