Targeting therapeutic resistance in glioblastoma

靶向胶质母细胞瘤的治疗耐药性

基本信息

批准号：
10588313
负责人：
NATASHA Y FRANK
金额：
--
依托单位：
VA BOSTON HEALTH CARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10588313
关键词：
Afghanistan Angiogenesis Inhibitors Apoptosis Apoptotic Binding Blood - brain barrier anatomy Brain Neoplasms Cancer Control Cancer Etiology Cell Cycle Arrest Cell Cycle Regulation Cell Maintenance Cell membrane Cell physiology Cessation of life Clinical Colon Carcinoma Colorectal Cancer DDR1 gene DNA DNA Repair Development Drug resistance Enhancers Epigenetic Process Epithelium Etiology Evolution Excision Exposure to Feedback G2/M Arrest General Population Genes Glioblastoma Heterogeneity Human Immunotherapeutic agent Impairment Incidence Interruption Invaded Iraq Laboratories Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Mediating Mediator Membrane Membrane Proteins Mesenchymal Military Personnel Modality Monoclonal Antibodies Multi-Drug Resistance Nature Neoplasm Metastasis Normal tissue morphology Operative Surgical Procedures PI3K/AKT PIK3CG gene Pathway interactions Patients Phenotype Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Phosphorylation Physiological Primary carcinoma of the liver cells Production Prognosis Quality of life Radiation Receptor Protein-Tyrosine Kinases Recurrence Refractory Regulation Repression Resistance Signal Pathway Signal Transduction Testing Therapeutic Toxicant exposure Tumor Stem Cells United States Vascular Endothelial Growth Factor Receptor-1 Veterans Vietnam active duty agent orange angiogenesis axl receptor tyrosine kinase burn pit cancer stem cell chemotherapy clinically relevant epigenetic regulation epigenome improved in vitro Model in vivo inorganic phosphate knockout gene leukemia malignant breast neoplasm malignant mouth neoplasm melanoma member neoplastic cell new therapeutic target novel novel strategies novel therapeutic intervention novel therapeutics phosphatidylinositol receptor pluripotency receptor recruit refractory cancer response self-renewal stem cell biomarkers stem cell self renewal stem cells success targeted treatment temozolomide therapy resistant tumor tumor growth tumor heterogeneity tumor progression tumor-immune system interactions

项目摘要

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor associated with extremely poor prognosis and survival. Although relatively rare in the US general population, GBM is the third most common cause of cancer death in the US active-duty military. The relatively transient nature of clinical responses to currently available therapies underlines the urgency for the development of additional therapeutic strategies. Multiple studies have demonstrated the existence of aggressive cancer stem cell (CSC) subpopulations in GBM and characterized their contribution to GBM progression, therapeutic resistance and recurrence; however, efforts to eliminate or functionally modulate these therapy-refractory subpopulations have thus far met with limited success. ATP-binding cassette, sub-family B (MDR/TAP), member 5 (ABCB5), an integral plasma membrane protein first cloned and characterized by the applicant (Frank et al. J Biol Chem. 2003), is highly expressed by normal tissue-specific stem cells and CSCs in several malignancies, including GBM. ABCB5 is expressed in primary GBM tumors, in which its expression is significantly correlated with the CSC marker CD133 and with overall poor survival (Lee et al. J Biol Chem. 2020). In GBM-CSCs, ABCB5 has been shown to mediate clinically relevant drug resistance to temozolomide (TMZ). ABCB5 blockade inhibited CD133-positive GBM- CSC self-renewal and abrogated TMZ-induced G2/M arrest. Recently, the applicant identified a novel critical anti-apoptotic function of ABCB5 required for normal stem cell maintenance (Ksander et al. Nature 2014) and, as a corollary, for CSC-driven tumor growth, invasion and therapeutic resistance, involving, in part, ABCB5- dependent regulation of signal transduction of the RTK AXL (Guo et al., J Biol Chem. 2018). Importantly, the applicant’s most recent preliminary studies further revealed that ABCB5 serves as a novel receptor for Phosphatidylinositol 4,5-bisphosphate (PIP2), with ABCB5/PIP2 binding shown to be required for PIP3 phosphorylation. PIP2-derived PIP3 serves as a critical mediator of receptor tyrosine kinase (RTK) signaling, and hence activation of the downstream PI3K/AKT signaling cascade. Remarkably, inhibition of ABCB5-PIP2 binding through ABCB5 monoclonal antibody blockade or ABCB5 gene knockout (KO) inhibits PIP2 phosphorylation, blocks PIP3 production and interrupts down-stream pAKT activation of the PI3K/pAKT signaling pathway, impairing RTK signal transduction on ABCB5-positive GBM-CSC. Based on this newly identified central mechanism, we hypothesize that ABCB5 is critically required for multiple RTK-dependent functions in human GBM, including stem cell-intrinsic self-renewal, anti-apoptotic, pro-angiogenic and invasive capacities, and stem cell-driven epigenetic evolution and therapeutic resistance associated cell cycle arrest (Lee et al. J Biol Chem. 2020). The proposed studies will further support the development of ABCB5 as a novel therapeutic target in GBM and should pave the way to successful eradication of ABCB5_positive GBM stem cells in human patients for improved clinical therapy.

多形性胶质母细胞瘤 (GBM) 是一种高度侵袭性的脑肿瘤，预后极差虽然 GBM 在美国普通人群中相对罕见，但它是第三大常见原因。美国现役军人的癌症死亡目前的临床反应相对短暂。现有的疗法强调了开发额外治疗策略的紧迫性。研究表明，GBM 和 GBM 中存在侵袭性癌症干细胞 (CSC) 亚群描述了它们对 GBM 进展、治疗耐药和复发的贡献；然而，努力迄今为止，消除或功能性调节这些难治性亚群的治疗效果有限 ATP 结合盒，B 亚家族 (MDR/TAP)，成员 5 (ABCB5)，完整的质膜。申请人首先克隆并表征的蛋白质（Frank et al. J Biol Chem. 2003），在正常组织特异性干细胞和 CSC 在多种恶性肿瘤中表达，其中包括 GBM。原发性 GBM 肿瘤，其表达与 CSC 标志物 CD133 和总体生存率较差（Lee et al. J Biol Chem. 2020），ABCB5 已被证明可以调节 GBM-CSC 的介导作用。临床相关的对替莫唑胺 (TMZ) 的耐药性可抑制 CD133 阳性 GBM-。 CSC 自我更新并废除 TMZ 引起的 G2/M 逮捕最近，申请人发现了一个新的关键点。正常干细胞维持所需的 ABCB5 的抗凋亡功能（Ksander 等人，Nature 2014），作为一种推论肿瘤，用于 CSC 驱动的生长、侵袭和治疗耐药，部分涉及 ABCB5- RTK AXL 信号转导的依赖性调节（Guo 等人，J Biol Chem. 2018）。申请人最近的初步研究进一步表明ABCB5是一种新型受体磷脂酰肌醇 4,5-二磷酸 (PIP2)，ABCB5/PIP2 结合被证明是 PIP3 所必需的 PIP2 衍生的 PIP3 是受体酪氨酸激酶 (RTK) 信号传导的关键介质，从而激活下游 PI3K/AKT 信号级联反应，尤其是抑制 ABCB5-PIP2。通过 ABCB5 单克隆抗体阻断或 ABCB5 基因敲除 (KO) 结合抑制 PIP2 磷酸化，阻断 PIP3 产生并中断 PI3K/pAKT 的下游 pAKT 激活信号通路，损害 ABCB5 阳性 GBM-CSC 上的 RTK 信号转导。确定了中心机制，我们勇敢地说 ABCB5 对于多个 RTK 依赖性至关重要人类 GBM 中的功能，包括干细胞内在的自我更新、抗凋亡、促血管生成和侵袭性能力、干细胞驱动的表观遗传进化和与细胞周期停滞相关的治疗耐药性（Lee et al. J Biol Chem. 2020）拟议的研究将进一步支持 ABCB5 作为一种新型药物的开发。 GBM 的治疗目标，应为成功根除 ABCB5 阳性 GBM 干细胞铺平道路人类患者的细胞以改善临床治疗。