Optimizing the therapeutic index for pediatric medulloblastomas by targeting apoptosis

通过靶向细胞凋亡优化儿童髓母细胞瘤的治疗指数

• 批准号: 10316157
• 负责人: Stacey Jessica Yu
• 金额: $ 3.49万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10316157
• 关键词: Accounting; Affect; Aftercare; Age; Animals; Apoptosis; Apoptotic; Automobile Driving; BAX gene; BCL2 gene; Beds; Behavioral; Biological; Brain; Bromodomain; Cancer Patient; Cancerous; Cell Death; Cells; Child; Childhood; Childhood Brain Neoplasm; Childhood Medulloblastomas; Clinical; Clinical Trials; DNA Damage; Development; Diagnosis; Dose; Excision; Exhibits; Exposure to; Flow Cytometry; Functional disorder; Genetic; Genetic Transcription; Genetically Engineered Mouse; Growth; Health; Human; Image; Immunofluorescence Immunologic; Impaired cognition; In Vitro; Ionizing radiation; Lead; Longevity; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of central nervous system; Measurement; Measures; Modeling; Molecular; Motor; Mus; Neuraxis; Neurocognitive Deficit; Neurons; Neurosecretory Systems; Normal tissue morphology; Oncogenes; Operative Surgical Procedures; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Performance; Pharmacology; Photons; Postoperative Period; Pre-Clinical Model; Protein Family; Proteins; Protocols documentation; Proton Radiation; Protons; Quality of life; Radiation; Radiation Dose Unit; Radiation Tolerance; Radiation induced damage; Radiation therapy; Recurrence; Signal Transduction; Stress; Therapeutic; Therapeutic Index; Tissues; Treatment Protocols; United States; Weight; cell growth; cell type; childhood cancer survivor; cognitive function; dosage; experimental study; genotoxicity; improved; inhibitor/antagonist; irradiation; medulloblastoma; medulloblastoma cell line; mouse model; neuroprotection; neurotoxicity; prevent; proton therapy; radiation response; response; standard care; tumor

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.

项目摘要/摘要 髓母细胞瘤是影响儿童的最常见的恶性脑肿瘤，占所有肿瘤的20%。 儿童脑瘤。目前的治疗方法包括手术切除和术后放射治疗。 横穿颅脊轴线，肿瘤床上再加高剂量。这种治疗方案，虽然 对消除髓母细胞瘤有效，也会使健康组织暴露在有害水平的辐射下，导致 细胞发生凋亡，或细胞程序性死亡。这种神经细胞的丧失可能会导致终生的负面影响， 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 放射治疗防止这些治疗造成的永久性损害，导致迫切需要改进 治疗。因此，质子放射治疗正越来越多地在临床上使用，因为它减少了进入和离开 剂量与更常见的光子疗法相比，同时仍允许足够的靶向覆盖， 消除了对正常组织施加的大约一半不必要的辐射。今天, 美国约50%的儿童髓母细胞瘤患者术后接受质子治疗 放射疗法。即便如此，仍有大量健康组织暴露在辐射中，如髓母细胞瘤。 患者接受肿瘤床和整个颅脊神经轴的放射治疗。尽管有明显的重要性 为了最大限度地提高儿科癌症幸存者的治疗后生活质量，我们对其机制的理解 驾驶辐射引起的神经毒性是有限的，目前还不存在临床上有用的减压剂。上一首 研究表明，基因抑制Bax，一种细胞凋亡所必需的蛋白质，可以保护神经细胞免受 辐射诱导细胞凋亡。虽然目前还没有得到充分验证的直接药理Bax抑制剂， 已有研究表明，MYC可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信号转导的抑制剂， 包括以Myc自身转录为靶点的溴域和末端外基序(BET)抑制剂，以及 目前正在进行临床试验评估。这些最新的发现和发展创造了一个潜在的 调整Myc以改善患者预后的机会。因此，我们假设以Myc为目标的BET 抑制剂将保护健康的神经细胞免受辐射诱导的凋亡，同时增敏 髓母细胞瘤转变为放射治疗，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抑制剂有效地保护原代小鼠神经元免受辐射诱导的细胞凋亡 诱导髓母细胞瘤细胞凋亡。因此，我们建议扩大我们的研究范围，以阐明 将BET抑制剂与光子和质子治疗相结合的方式，并揭示分子 它们对健康细胞和癌细胞的不同作用机制。