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Characterization of circadian rhythms in Glioblastoma multiforme and investigation of chronotherapy as a novel therapy to prolong patient survival

多形性胶质母细胞瘤昼夜节律的特征以及时间疗法作为延长患者生存的新疗法的研究

基本信息

批准号：
10429921
负责人：
ANNA DAMATO
金额：
$ 1.88万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2022-12-21
项目状态：
已结题

项目摘要

Project Summary Glioblastoma multiforme (GBM) is the most common primary adult brain tumor diagnosed, with a 15-month prognosis using current standard of care treatment which includes chemotherapy with Temozolomide (Temodar, TMZ). Chronotherapy, the practice of considering time of day in treating a disease, has been shown to improve outcome in several cancers such as colorectal cancer and acute lymphoblastic leukemia, but has never been applied to GBM. Our previous work on a cultured murine mesenchymal GBM cell line showed a time-of-day dependent maximum in DNA double-strand breaks, activation of the apoptotic pathway, and cell death corresponding with the peak of Bmal1 and trough of Per2 expression, two core clock genes. Our preliminary data demonstrate that intracranial GBM tumors have circadian rhythms in gene expression in vivo that can be monitored chronically throughout disease progression. Most notably, our pilot data show that tumor rhythms in gene expression align with those of the host, leading to reversed patterns in tumor gene expression in a reversed light/dark cycle and free-running patterns that align with the host in constant darkness. This proposal will evaluate the hypothesis that GBM tumors have circadian rhythms in vivo that entrain to the host and that those daily rhythms can be leveraged using chronotherapy to improve survival. To address this hypothesis, this proposal will further assess if GBM tumors align with host daily rhythms in vivo as a function of changing light schedule, as described, and circadian genotype by implanting an arrhythmic tumor in a rhythmic mouse and a rhythmic tumor in an arrhythmic mouse and measuring changes in tumor growth rate, as well as synchrony between the host and tumor, according to circadian genotype (Aim 1). Furthermore, this proposal will determine differences in tumor cell death and host survival depending on time of day of TMZ dosing by measuring the effect of TMZ on daily rhythms in gene expression in both the host and tumor, as well as the effect of TMZ on tumor size reduction and severity of hematological toxicity (Aim 2). This proposal will improve outcome for patients with GBM for the first time in 20 years by maximizing tumor destruction while minimizing side effects by personalizing treatment based on patient sex and ideal time of day to treat. It will also serve as an important next step in achieving high-throughput screening for the optimal time to treat diseases beyond Glioblastoma.

项目摘要多形性胶质母细胞瘤（GBM）是最常见的原发性成人脑肿瘤，使用当前标准治疗（包括替莫唑胺化疗）的预后（Temodar，TMZ）.时间疗法，在治疗疾病时考虑一天中的时间的做法，已经被证明是可行的。改善几种癌症如结直肠癌和急性淋巴细胞白血病的预后，但从未应用于GBM。我们以前对培养的小鼠间充质GBM细胞系的研究显示， DNA双链断裂、凋亡途径激活和细胞凋亡的时间依赖性最大值死亡对应于两个核心时钟基因Bmal 1表达的峰值和Per 2表达的谷值。我们初步数据表明颅内GBM肿瘤在体内基因表达具有昼夜节律，可以在整个疾病进展过程中长期监测。最值得注意的是，我们的试验数据显示，基因表达的节律与宿主的节律一致，导致肿瘤基因表达的逆转模式在颠倒的亮/暗循环和自由运行的模式中，在恒定的黑暗中与主机对齐。这一项提案将评估GBM肿瘤在体内具有昼夜节律的假设，这些日常节律可以通过时间疗法来提高生存率。为了解决这个假设，该提议将进一步评估GBM肿瘤是否与体内宿主的每日节律一致，改变光照时间表，如上所述，和昼夜节律基因型，通过植入一个有节奏的肿瘤，小鼠中的节律性肿瘤，并测量肿瘤生长速率的变化，以及根据昼夜节律基因型，宿主和肿瘤之间的同步性（Aim 1）。此外，该提案将确定肿瘤细胞死亡和宿主存活的差异，这取决于TMZ给药的时间，测量TMZ对宿主和肿瘤中基因表达的每日节律的影响，以及 TMZ对肿瘤尺寸减小和血液学毒性严重程度的影响（目的2）。这一建议将改善 20年来首次通过最大限度地破坏肿瘤，同时最小化根据患者的性别和理想的治疗时间进行个性化治疗。它还将作为这是实现高通量筛选的重要下一步，胶质母细胞瘤