Targeting therapeutic resistance in glioblastoma

靶向胶质母细胞瘤的治疗耐药性

• 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
• 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

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.

胶质母细胞瘤多形（GBM）是一种高度侵略性的脑肿瘤，与极度差的预后相关 和生存。尽管在美国一般人口相对较少，但GBM是第三大最常见的原因 美国现役军人的癌症死亡。临床对当前的临床反应的相对瞬态性质 可用的疗法强调了制定其他治疗策略的紧迫性。多种的 研究表明，GBM和 表征了它们对GBM进展，热阻力和复发的贡献；但是，努力 迄今为止，消除或在功能上调节了这些疗法 - 不战士的亚群已经有限 成功。 ATP结合盒，子家庭B（MDR/TAP），成员5（ABCB5），一种积分的质膜 蛋白质首先由申请人克隆和特征（Frank等人J BiolChem。2003），由 包括GBM在内的几种恶性肿瘤中的正常组织特异性干细胞和CSC。 ABCB5在 原发性GBM肿瘤，其中其表达与CSC标记CD133显着相关，并且与 总体生存率较差（Lee等人J BiolChem。2020）。在GBM-CSC中，已显示ABCB5介导 临床上相关的对替莫唑胺（TMZ）的耐药性。 ABCB5封锁抑制CD133阳性GBM- CSC自我更新和废除了TMZ诱导的G2/m逮捕。最近，适用的确定了一个新颖的关键 正常干细胞维持所需的ABCB5的抗凋亡功能（Ksander等，Nature 2014）和 作为推论，用于CSC驱动的肿瘤生长，侵袭和热耐药性，部分涉及ABCB5- RTK AXL信号转移的依赖调节（Guo等，J BiolChem。2018）。重要的是， 申请人的最新初步研究进一步表明，ABCB5是一种新颖的受体 磷脂酰肌醇4,5-双磷酸（PIP2），abcb5/pip2结合是PIP3所需的 磷酸化。 PIP2衍生的PIP3充当受体酪氨酸激酶（RTK）信号传导的关键介体 因此激活下游PI3K/AKT信号级联。值得注意的是，抑制ABCB5-PIP2 通过ABCB5单克隆抗体阻断或ABCB5基因敲除（KO）抑制PIP2的结合2 磷酸化，阻断PIP3的产生并中断PI3K/PAKT的下游PAKT激活 信号通路，损害ABCB5阳性GBM-CSC上的RTK信号转移。基于这个新的 确定的中心机制，我们假设ABCB5至关重要 在人类GBM中的功能，包括干细胞中的自我更新，抗凋亡，促血管生成和侵入性 能力以及干细胞驱动的表观遗传进化和治疗性抗性相关细胞周期停滞 （Lee等人J BiolChem。2020）。拟议的研究将进一步支持ABCB5作为新颖的发展 GBM中的治疗靶标，应该为成功消除ABCB5_PS阳性GBM STEM铺平道路 人类患者的细胞可改善临床治疗。