Sub-component for Institution # 16-01848 Novel moleculary targeted therapy of GBM

机构的子组件

基本信息

批准号：
10220881
负责人：
Waldemar Debinski
金额：
$ 39.98万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-17 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10220881
关键词：
Abnormal Cell Adult Antitumor Response Binding Blood - brain barrier anatomy Brain Canis familiaris Catheters Cells Clinic Convection Cyclophosphamide Cytotoxin Development Disease Management Dose Drug Delivery Systems EPHA3 gene Engineering Environment EphA2 Receptor EphB2 Receptor Ephrin-A1 Ephrin-A5 Ephrins Exhibits Generations Glioblastoma Glioma Growth Home Human IL13RA1 gene IgG1 Institution Interleukin-13 Intracranial Neoplasms Label Laboratories Ligands Measurement Modality Modeling Molecular Target Monitor Mus Patients Pattern Peptides Pharmaceutical Preparations Pharmacologic Substance Pharmacotherapy Phase I Clinical Trials Play Primary Brain Neoplasms Prognosis Property Protocols documentation Recurrence Reflux Regional Chemotherapy Research Resistance Rodent Model Role System Testing Therapeutic Translating Treatment Efficacy Tumor-associated macrophages Tumorigenicity Variant Work assault base biophysical properties blood-brain barrier disruption blood-brain barrier permeabilization blood-brain tumor barrier cancer therapy catalyst chemical conjugate chemotherapy clinical efficacy drug candidate drug distribution imaging probe in vitro Model in vivo innovation interest monocyte neoplastic cell neovasculature novel overexpression peptide A preclinical evaluation receptor receptor internalization response scaffold self-renewal stem cells stem-like cell targeted treatment therapeutically effective therapy resistant translational model treatment response tumor tumor progression

项目摘要

Patients with glioblastoma (GBM) have a dismal prognosis. We found that over 90% of patients with GBM over-express both interleukin 13 receptor alpha 2 (IL-13RA2) and EphA2 receptor that are absent in normal brain. More recently, we have demonstrated that the EphA3 receptor is also over-expressed in GBM, and its pattern of expression differs from that of EphA2. IL-13RA2, EphA2, and EphA3 are present in various compartments of GBM tumors. All three receptors are expressed in tumor cells of the core of tumor and in locally-infiltrating tumor cells, while EphA2 is also over-expressed in tumor neovasculature. Further, IL-13RA2, EphA2, and EphA3 are associated with, and play crucial roles in, the pathobiology of glioma stem-like cells (GSC). IL-13RA2 contributes to GSC properties and EphA2 and EphA3 both drive their self-renewal and tumorigenicity. Finally, the EphA3 receptor can be readily detected in GBM-infiltrating cells of monocytic origin, tumor-associated macrophages (TAM). Thus, collectively, IL-13RA2, EphA2, and EphA3 are expressed in principal GBM compartments shown to be involved in tumor progression and/or resistance to therapies. One of the Eph receptor ligands, ephrinA5 (eA5), binds EphA2 and EphA3 and also uniquely the EphB2 receptor; the latter also is expressed specifically on GBM cells. In the current project, we will pursue the novel idea of targeting all four receptors with one pharmaceutical compound. This bi-valent compound will recognize IL- 13RA2, EphA2, EphA3, and EphB2 and deliver a drug to GBM tumors, specifically killing tumor cells and cells of the tumor environment promoting its growth. We have also isolated a small peptide, Pep-1L, which specifically recognizes IL-13RA2, induces receptor's internalization and it is bound by intracranial tumors in mice. These and other properties make the peptide a desirable vehicle to augment access of drugs/labels to tumors. We will continue this exciting line of research through two Specific Aims. In the first Aim, we will produce a potent bi-valent cytotoxin, QUAD-CTX, simultaneously targeting the IL-13RA2, EphA2, EphA3, and EphB2 receptors. We will generate a chemical conjugate with a modified chemotherapeutic which can pass the blood-brain barrier (BBB) on its own, termed WP1244. The drug conjugate will be tested in in vitro models of various compartments of GBM and in vivo. In the second Aim, we will exploit a peptide binding to IL-13RA2 for effective targeted systemic or loco-regional chemotherapy, for monitoring of the disruption of the BBB and responses to treatment. We will exploit internalized peptide Pep-1L, which homes to intracranial tumors, for conjugation to WP1244 (Pep-1L-CTX) and test it in GBM models expressing IL-13RA2 to verify the conjugate's ability to penetrate the BBB and/or blood-brain tumor barrier. We will also generate imaging probes based on the peptide. We expect that this comprehensive assault on GBM will translate into clear-cut durable responses in patients.

胶质母细胞瘤（GBM）患者的预后很差。我们发现超过 90% 的 GBM 患者过度表达正常细胞中不存在的白细胞介素 13 受体 α2 (IL-13RA2) 和 EphA2 受体脑。最近，我们证明 EphA3 受体在 GBM 中也过度表达，并且其表达模式与 EphA2 不同。 IL-13RA2、EphA2 和 EphA3 存在于多种 GBM 肿瘤的区室。所有三种受体均在肿瘤核心的肿瘤细胞和局部浸润的肿瘤细胞，而 EphA2 在肿瘤新血管系统中也过度表达。 [0103] 此外，IL-13RA2， EphA2 和 EphA3 与神经胶质瘤干样细胞的病理学相关，并在其中发挥关键作用（全球供应链）。 IL-13RA2 有助于 GSC 特性，EphA2 和 EphA3 均驱动其自我更新和致瘤性。最后，EphA3 受体可以在单核细胞来源的 GBM 浸润细胞中轻松检测到，肿瘤相关巨噬细胞（TAM）。因此，IL-13RA2、EphA2 和 EphA3 共同表达于主要的 GBM 区室被证明与肿瘤进展和/或治疗耐药有关。之一 Eph 受体配体 ephrinA5 (eA5) 结合 EphA2 和 EphA3，并且还独特地结合 EphB2 受体；这后者也在 GBM 细胞上特异性表达。在当前的项目中，我们将追求新的想法用一种药物化合物靶向所有四种受体。这种二价化合物将识别 IL- 13RA2、EphA2、EphA3 和 EphB2 并向 GBM 肿瘤递送药物，特异性杀死肿瘤细胞和细胞肿瘤环境促进其生长。我们还分离出了一种小肽 Pep-1L，特异性识别IL-13RA2，诱导受体内化，并与颅内肿瘤结合老鼠。这些和其他特性使肽成为增加药物/标签获取的理想载体。肿瘤。我们将通过两个具体目标继续这一令人兴奋的研究。在第一个目标中，我们将产生有效的二价细胞毒素 QUAD-CTX，同时靶向 IL-13RA2、EphA2、EphA3 和 EphB2 受体。我们将生成一种带有改良化疗药物的化学共轭物，它可以通过血脑屏障 (BBB) 本身，称为 WP1244。该药物结合物将在体外模型中进行测试 GBM 和体内的各个隔室。在第二个目标中，我们将利用与 IL-13RA2 结合的肽有效的靶向全身或局部化疗，用于监测血脑屏障的破坏和对治疗的反应。我们将利用颅内肿瘤的内化肽 Pep-1L，与 WP1244 (Pep-1L-CTX) 缀合，并在表达 IL-13RA2 的 GBM 模型中进行测试，以验证缀合物的穿透血脑屏障和/或血脑肿瘤屏障的能力。我们还将基于以下内容生成成像探针肽。我们预计，对 GBM 的全面攻击将转化为明确持久的反应在患者中。