Engineering Knotted Peptide Therapeutics for Pediatric Brain Tumor Patients

脑瘤导致的儿童死亡比任何其他形式的癌症都要多。大多数儿童脑肿瘤患者 接受手术和放射治疗作为治疗的关键要素。帮助外科医生最大限度地、安全地取出 脑瘤，我们之前发现并开发了肿瘤涂料，它向大脑传递荧光信号 儿科临床试验中的肿瘤细胞。氯毒素(CTX)，蝎子来源的肿瘤靶向肽，交叉 血脑屏障(BBB)，并与癌细胞特异性结合。因为氯毒素可以传递荧光 分子进入脑瘤细胞的细胞质，我们假设它可以携带治疗分子作为 井。随着我们专注于开发使用CTX或CTX药物载体的治疗候选药物，它变得 对了解血脑屏障穿透机制至关重要。 除了研究以环磷酰胺为基础的脑瘤疗法(例如，将化疗或免疫疗法提供给 脑瘤)，我们在一种候选药物上取得了重大进展，这种药物可能会帮助每一个孩子 他正在接受脑瘤的放射治疗。因为脑辐射会导致严重且不可逆转的 儿童的神经认知损害，我们渴望设计一种治疗药物来阻断有毒的呼吸道 放射后正常脑组织中的小胶质细胞爆裂。Kv1.3钾离子通道对小胶质细胞的阻断作用 已被证明可以阻止辐射对小鼠正常大脑的损害。我们设计了一个选项(优化 多肽)，它专门阻断Kv1.3，但不幸的是，在目前的形式下，它不能通过BBB。 我们想要解决的知识差距是环磷酰胺和其他一些药物 穿透血脑屏障是未知的。因为CTX的Lys27面上受到一个荧光团的立体阻碍。 肿瘤涂料临床候选跨血脑屏障在儿童，我们假设药效团 负责血脑屏障穿透的面孔与含有Lys27的面孔不同。 阻止临床开发阻断Kv1.3以减轻辐射诱导的OPT的关键障碍 大脑损伤是因为它没有穿过血脑屏障，因此无法到达目标。我们假设我们 能够以促进血脑屏障渗透的方式设计候选Kv1.3拦截剂。 我们的具体目标是： 目的1：确定与血脑屏障穿透有关的氯毒素的药效团 目标2：确定负责穿透血脑屏障的转运体 目标3：创建一种具有治疗性药效团和穿透血脑屏障药效团的抗菌肽 这项工作的意义在于，我们将产生一种临床开发候选方案，可以减轻 辐射对儿童造成的严重脑损伤。基础知识可以应用于一种新的 治疗许多脑部疾病的药物的产生。

Brain tumors cause more deaths in children than any other form of cancer. Most pediatric brain tumor patients receive surgery and radiation as key elements of treatment. To help surgeons maximally and safely remove brain tumors, we previously discovered and developed Tumor Paint, which delivers fluorescent signal to brain tumor cells in pediatric clinical trials. Chlorotoxin (CTX), the scorpion-derived tumor targeting peptide, crosses the blood brain barrier (BBB) and specifically binds to cancer cells. Because chlorotoxin can deliver fluorescent molecules to the cytoplasm of brain tumor cells, we hypothesized that it could carry therapeutic molecules as well. As we focus on developing therapeutic candidates that use CTX or CTX pharmacophores, it becomes essential to understand the mechanism of BBB penetration. In addition to work on CTX-based brain tumor therapies (e.g., delivery of chemotherapy or immunotherapy to brain tumors), we have made significant progress on a candidate drug that could potentially help every child who undergoes radiation therapy for brain tumors. Because brain irradiation causes severe and irreversible neurocognitive damage in children, we aspire to engineer a therapeutic agent that blocks the toxic respiratory burst of microglia in normal brain following radiation. Blockade of the Kv1.3 potassium ion channel on microglia has been shown to block radiation damage to normal brain in mice. We have engineered an optide (optimized peptide) that specifically blocks Kv1.3 but unfortunately does not, in its current form, cross the BBB. The gap in knowledge that we intend to address is that the mechanism by which CTX and some other optides penetrate the BBB is unknown. Because the Lys27 face of CTX is sterically hindered by a fluorophore in the Tumor Paint clinical candidate that crosses the BBB in children, we hypothesize that the pharmacophore responsible for BBB penetration lies on a different face than the face that contains Lys27. The key hurdle that prevents clinical development of an optide that blocks Kv1.3 to alleviate radiation-induced brain damage is that it does not cross the BBB and therefore fails to reach its target. We hypothesize that we can engineer the candidate Kv1.3 blocker in a manner that fosters BBB penetration. Our Specific Aims are: Aim 1: To identify the pharmacophore of chlorotoxin responsible for BBB penetration Aim 2: To identify the transporter responsible for optide penetration of the BBB Aim 3: To create an optide that has a therapeutic pharmacophore and a BBB-penetrating pharmacophore The significance of this work is that we will produce a clinical development candidate that could alleviate severe brain damage caused by irradiation in children. The foundational knowledge could be applied to a new generation of drugs for many brain disorders.