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：
9765023
负责人：
Thomas J Kipps
金额：
$ 63.51万
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/9765023
关键词：
Address Adult Affect Antigens 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 Receptors, Antigen, B-Cell Resistance development Role Sampling Signal Pathway Signal Transduction Structure Structure-Activity Relationship System Technology Therapeutic Tissues Transgenic Mice WNT Signaling Pathway beta catenin calmodulin-dependent protein kinase II cancer therapy cell growth cell motility chronic lymphocytic leukemia cell clinically relevant in vivo indexing inhibitor/antagonist 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，可诱导非经典 Wnt 信号传导、激活 Rho GTP 酶，并增强白血病细胞的迁移、增殖和存活。ROR1 的高水平表达可以加速白血病细胞的迁移、增殖和存活。转基因小鼠模型中白血病的发生和进展并与更具侵袭性相关 CLL 细胞的疾病和较短的生存期也表达其他发育限制。 Wnt5a 受体，即 ROR2 和 RYK，可促进 CLL 中的非典型 Wnt 信号传导。阐明了 ROR1、ROR2 和 ROR1、ROR2 信号传导所涉及的结构功能关系 RYK 将定义非典型 Wnt 信号传导的临床相关生物标志物，并确定新的靶标此外，非经典 Wnt 信号传导的抑制可能具有治疗应用，无论是单独使用。或与其他新开发的抑制 B 细胞受体信号传导或 BCL2 的靶向疗法联合使用。为此，我们有以下具体目标：（目标 1）询问非规范信号通路 CLL 中的 Wnt 受体 - 我们将定义响应 Wnt5a 而招募至 ROR1/2 的蛋白质，并确定我们将研究 RYK 对 Wnt5a 信号传导的贡献。 CLL，确定 SH3 结合蛋白、14-3-3ze 或 Ca2+/钙调蛋白 (CaM) 依赖性蛋白激酶的作用 II (CaMKII) 参与 ROR1 依赖性信号传导，并检查 ROR1 激酶对非规范 Wnt 信号转导 (AIM 2) 检查 CLL 细胞的非规范 Wnt 受体的共表达。并确定 Wnt 信号传导的相对水平 - 我们将检查 CLL 患者的血液样本血浆 Wnt5a 的 ROR1 表达高、低或可忽略不计的细胞，白血病细胞表达 ROR2 和 RYK，以及白血病细胞激活经典和非经典 Wnt 信号传导。检查所选 CLL 样本和细胞系的转录组以获得新描述的干性指数，这取决于 ROR1 信号传导，我们还将检查经典 β-连环蛋白之间的串扰。依赖的 Wnt 信号通路和非经典的、不依赖 β-catenin 的通路，这可能是受 ROR1、ROR2 或 RYK 相对表达或新生成的 mAb 处理的影响特定于 ROR2 或 RYK (AIM 3) 检查 ROR1 信号传导对发展的贡献。 CLL 对靶向治疗的耐药性 - 我们将检查 ROR1、ROR2 的表达水平和功能，和 RYK 在一系列 CLL 样本中，从出现耐药性之前、期间和之后的患者收集靶向治疗并评估 cirmtuzumab 和 BCL2 拮抗剂之间的协同潜力，维奈托克。