Optimizing the therapeutic index for pediatric medulloblastomas by targeting apoptosis

项目总结/摘要 髓母细胞瘤是影响儿童的最常见的恶性脑肿瘤，占所有恶性脑肿瘤的20 儿童脑肿瘤目前的治疗方法包括手术切除，术后放疗 穿过颅脊髓轴，并向肿瘤床施加额外的更高剂量。这种治疗方法，虽然 有效地消除髓母细胞瘤，也暴露健康组织的有害水平的辐射，造成 细胞发生凋亡或程序性细胞死亡。这种神经细胞的损失会导致终身的负面影响， 例如神经认知缺陷和神经内分泌功能障碍。目前，临床医生必须权衡 放射治疗对这些治疗的永久性损伤，导致迫切需要改善 治疗因此，质子放射治疗在临床上越来越多地使用，因为它减少了进入和退出。 与更普通的光子治疗相比的剂量同时仍然允许足够的目标覆盖， 消除了对正常组织施加的大约一半的不必要的辐射。今天， 在美国，大约50%的儿童髓母细胞瘤患者接受术后质子治疗， 放射治疗即便如此，仍有大量健康组织暴露在辐射下，如髓母细胞瘤 患者接受对肿瘤床以及整个颅脊髓轴的放射。尽管很明显 最大限度地提高儿童癌症幸存者的治疗后生活质量，我们对机制的理解 驱动辐射诱导的神经毒性是有限的，并且目前不存在临床上有用的缓解剂。先前 研究表明，对凋亡所必需的蛋白BAX的遗传抑制，可以保护神经细胞， 辐射诱导细胞凋亡。虽然目前没有经过充分验证的直接药理学BAX抑制剂， Myc已被证明直接促进发育中大脑中BAX的表达。重要的是，Myc还 已被证明是髓母细胞瘤生长的关键驱动因素，靶向这种致癌基因会促进压力- 诱导髓母细胞瘤细胞凋亡。已经开发了许多Myc信号传导的抑制剂， 包括靶向Myc自身转录的溴结构域和额外末端基序（BET）抑制剂，和 目前正在临床试验中进行评估。这些最新的发现和发展， 有机会调节Myc以改善患者结局。因此，我们假设用BET靶向Myc 抑制剂将保护健康的神经细胞免受辐射诱导的凋亡，同时敏化 髓母细胞瘤的放射治疗，从而扩大了放射治疗的治疗窗口。我们迄今为止的研究 显示BET抑制剂保护原代鼠神经元免于辐射诱导凋亡，同时有效地 诱导髓母细胞瘤细胞凋亡。因此，我们建议扩大我们的研究，以阐明最佳的 将联合收割机BET抑制剂与光子和质子治疗相结合的方式， 它们对健康细胞和癌细胞的不同作用的机制。

Project Summary/Abstract Medulloblastomas are the most prevalent malignant brain tumor affecting children, accounting for 20% of all childhood brain tumors. Current therapies include surgical resection followed by postoperative radiotherapy across the craniospinal axis, with an additional higher dose to the tumor bed. This treatment regimen, while effective in eliminating medulloblastomas, also exposes healthy tissue to harmful levels of radiation, causing the cells to undergo apoptosis, or programmed cell death. This loss of neural cells can lead to lifelong negative effects, such as neurocognitive deficits and neuroendocrine dysfunction. Currently, clinicians must weigh the benefits of radiation therapy against the permanent damage from these treatments, leading to a critical need for improved therapies. As such, proton radiotherapy is being increasingly used clinically, as it reduces the entrance and exit doses compared to more commonplace photon therapy while still allowing for adequate target coverage, eliminating approximately half of the unnecessary radiation administered to normal tissue. Today, approximately 50% of pediatric medulloblastoma patients in the United States receive post-surgery proton radiation therapy. Even so, there is substantial healthy tissue being exposed to radiation, as medulloblastoma patients receive radiation to the tumor bed as well as the entire craniospinal axis. Despite the clear importance of maximizing post-treatment quality of life for pediatric cancer survivors, our understanding of the mechanisms driving radiation induced neurotoxicity is limited, and no clinically-useful mitigators currently exist. Previous studies have shown that genetic inhibition of BAX, a protein necessary for apoptosis, protects neural cells from radiation induced apoptosis. While there are currently no well validated direct pharmacological BAX inhibitors, Myc has been shown to directly promote the expression of BAX in the developing brain. Importantly, Myc also has been shown to be a critical driver of medulloblastoma growth, and targeting this oncogene promotes stress- induced apoptosis in medulloblastoma cells. Numerous inhibitors of Myc signaling have been developed, including bromodomain and extra-terminal motif (BET) inhibitors that target the transcription of Myc itself, and are currently being evaluated in clinical trials. These recent discoveries and developments create a potential opportunity to modulate Myc to improve patient outcomes. We thus hypothesize that targeting Myc with BET inhibitors will protect healthy neural cells from radiation induced apoptosis while simultaneously sensitizing medulloblastomas to radiotherapy, thus widening the therapeutic window for radiotherapy. Our studies to date show that BET inhibitors protect primary murine neurons from radiation induced apoptosis while potently inducing apoptosis in medulloblastomas cells. As such, we propose to expand our studies to elucidate the optimal manner in which to combine BET inhibitors with photon and proton therapy, and uncover the molecular mechanisms responsible for their divergent effects on healthy and cancerous cells.