Targeted Molecular Nano-Irradiation Against a Malignant Glioma Biomarker

描述（由申请人提供）：高度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2万名患者遭受折磨。靶向肿瘤特异性分子生物标志物提供了提供大量治疗辐射的潜力，特别是浸润性肿瘤细胞，而不是周围的正常脑组织。细胞毒性放射性分子递送到恶性胶质瘤最近显示出巨大的治疗潜力。然而，这种方法的一个缺点是，当使用长程发射体（如131碘）或短程发射体时，会对正常脑组织产生广泛的放射性毒性。相比之下，俄歇释放的放射性同位素只能达到纳米级，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。尽管距离极短，但俄歇发射的同位素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，不太可能被肿瘤细胞修复。因此，本提案的目标是创建一个靶向分子支架，可以有效和精确地向浸润的胶质瘤细胞提供大量的分子靶向纳米辐射，而不会伤害邻近的正常大脑。这项研究提出的核心假设是，我们可以将具有细胞毒性的111铟（一种原型俄格发射物）仅递送到表达肿瘤生物标志物的恶性细胞中，我们发现这种肿瘤生物标志物在恶性胶质瘤中高度表达，而在正常脑组织中则没有。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均有显著比例的表达。我们的期望是，在提出的工作结束时，我们将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成为一个理想的支架，以安全地向浸润性恶性胶质瘤细胞提供其他治疗方法，这些细胞目前在标准治疗范围之外，并且负责恶性高级别胶质瘤的不可避免的复发。

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.