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

机构的子组件

• 批准号: 10493966
• 负责人: Waldemar Debinski
• 金额: $ 14.18万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-17 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10493966
• 关键词: Sub; component; Institution; 16; 01848

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 患者过度表达白细胞介素 13 受体 α2 (IL-13RA2) 和 EphA2 受体，而正常大脑中不存在这些受体。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 GBM 肿瘤的各个区室中。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中表达，而 EphA2 在肿瘤新血管系统中也过度表达。此外，IL-13RA2、EphA2 和 EphA3 与神经胶质瘤干样细胞 (GSC) 的病理学相关，并在其中发挥关键作用。 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、肿瘤相关巨噬细胞 (TAM) 中轻松检测到。因此，总的来说，IL-13RA2、EphA2 和 EphA3 在主要 GBM 区室中表达，显示参与肿瘤进展和/或对治疗的抵抗。 Eph 受体配体之一 ephrinA5 (eA5) 可结合 EphA2 和 EphA3，并且还独特地结合 EphB2 受体；后者也特异地表达于 GBM 细胞上。在当前的项目中，我们将追求用一种药物化合物靶向所有四种受体的新想法。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促进其生长的肿瘤环境细胞。我们还分离出一种小肽Pep-1L，它特异性识别IL-13RA2，诱导受体内化，并与小鼠颅内肿瘤结合。这些和其他特性使肽成为增加药物/标记进入肿瘤的理想载体。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，我们将生产一种有效的二价细胞毒素 QUAD-CTX，同时靶向 IL-13RA2、EphA2、EphA3 和 EphB2 受体。我们将用改良的化疗药物生成一种化学共轭物，它可以自行通过血脑屏障（BBB），称为 WP1244。该药物缀合物将在 GBM 不同区室的体外模型和体内进行测试。在第二个目标中，我们将利用与 IL-13RA2 结合的肽进行有效的靶向全身或局部化疗，以监测 BBB 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 模型中对其进行测试，以验证缀合物穿透 BBB 和/或血液的能力。脑肿瘤屏障。我们还将生成基于肽的成像探针。我们预计，这种对 GBM 的全面攻击将转化为患者明确持久的反应。