Targeted Molecular Nano-Irradiation Against a Malignant Glioma Biomarker

描述（由申请人提供）：高级别恶性胶质瘤是原发性脑癌死亡的主要原因，仅在美国每年就有近20，000名患者受到折磨。靶向肿瘤特异性分子生物标志物提供了将大量治疗辐射特异性地递送到浸润肿瘤细胞而不是周围正常脑组织的可能性。恶性胶质瘤的细胞毒性放射性分子递送最近显示出巨大的治疗潜力。然而，这种方法的一个缺点是当使用长距离β发射体（例如131碘）或短距离α发射体时，对正常脑组织发生广泛的放射毒性。相比之下，俄歇发射的放射性同位素只有纳米范围，因此只有当它们能够进入细胞核并与DNA密切相互作用时才能杀死细胞。尽管射程极短，俄歇发射同位素仍具有非常高的线性能量转移（LET）系数，这就是为什么它们主要产生双链DNA断裂，而这些断裂不太可能被肿瘤细胞修复。因此，本提案的目的是创建靶向分子支架，其可以有效且精确地将大量分子靶向纳米辐射递送到浸润性胶质瘤细胞，而不伤害邻近的正常脑。拟议研究背后的中心假设是，我们可以将细胞毒性量的111铟（原型俄歇发射器）仅传递给表达肿瘤生物标志物的恶性细胞，我们发现该肿瘤生物标志物在恶性胶质瘤中高度表达，但不是正常脑组织。具有重要意义的是，我们的肿瘤相关生物标志物在成人和儿童浸润性脑干胶质瘤和髓母细胞瘤中表达的比例很高。 我们的期望是，在拟议的工作结束时，我们将创造出一种临床相关的抗肿瘤药物，具有根除浸润性肿瘤细胞的潜力，从而防止复发，同时不会对正常大脑造成附带损害。此外，我们预计我们的系统将是一个理想的支架，以安全地提供其他治疗的浸润性恶性胶质瘤细胞，目前的标准治疗范围之外，负责恶性高级别胶质瘤的不可避免的复发。 公共卫生相关性：高级别恶性神经胶质瘤是原发性脑癌死亡的主要原因，仅在美国每年就有近20，000名患者受到折磨。我们建议创造一种临床相关的抗肿瘤药物，具有根除浸润性肿瘤细胞和预防脑肿瘤复发的潜力，同时不会对正常大脑造成附带损害。我们的方法有望为成人和儿童恶性脑癌的治疗增加一种新型的分子靶向治疗。

DESCRIPTION (provided by applicant): High grade malignant gliomas are the leading cause of primary brain cancer deaths, afflicting close to 20,000 patients annually in the United States alone. Targeting tumor-specific molecular biomarkers offers the potential to deliver large amounts of therapeutic radiation specifically to infiltrating tumor cells but not to the surrounding normal brain tissue. Molecular delivery of cytotoxic radioactivity to malignant gliomas has recently shown great therapeutic potential. However, one shortcoming of this approach has been the extensive radiotoxicity that occurs to the normal brain tissue when using long range beta emitters (such as 131Iodine) or shorter range alpha emitters. In contrast, Auger emitting radioisotopes only have nanometer reach and therefore can only kill cells if they can access the nucleus and intimately interact with DNA. Despite the ultra short reach, Auger emitting isotopes have a very high linear energy transfer (LET) coefficient, which is why they produce predominantly double stranded DNA breaks that are unlikely to be repaired by tumor cells. Therefore, the objective of this proposal is create a targeted molecular scaffolding that can effectively and precisely deliver large amounts of molecular targeted nano-irradiation to infiltrating glioma cells without harming adjacent normal brain. The central hypothesis behind the proposed research is that we can deliver cytotoxic quantities of 111Indium (a prototype Auger emitter) only to malignant cells expressing a tumor biomarker that we discovered to be highly expressed in malignant gliomas, but not normal brain tissue. Of great significance, our tumor associated biomarker is expressed by a significant percentage of both adult and pediatric infiltrative brainstem gliomas and medulloblastomas. Our expectations are that at the conclusion of the proposed work, we will have created a clinically relevant anti-tumor agent with potential to eradicate infiltrating tumor cells and hence prevent recurrence while causing no collateral damage to normal brain. In addition, we anticipate our system will be an ideal scaffolding to safely deliver other therapeutics to the infiltrative malignant glioma cells that are currently outside the reach of standard therapy and responsible for the inevitable recurrence of malignant high grade gliomas. PUBLIC HEALTH RELEVANCE: High grade malignant gliomas are the leading cause of primary brain cancer deaths, afflicting close to 20,000 patients annually in the United States alone. We are proposing to create a clinically relevant anti-tumor agent with potential to eradicate infiltrating tumor cells and prevent brain tumor recurrence while causing no collateral damage to normal brain. Our approach promises to add a new type of molecular targeted therapy to the arsenal against malignant brain cancers in both adults and children.