Circadian Rhythms in Blood Brain Barrier Permeability and Increased Efficacy of Chemotherapy for Brain Metastases

血脑屏障通透性的昼夜节律和脑转移化疗疗效的提高

• 批准号: 10663717
• 负责人: William Harry Walker
• 金额: $ 11.45万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10663717
• 关键词: ABCG2 gene; Adverse effects; Affect; Anxiety; Autoradiography; Award; Behavior; Behavioral; Biology; Bioluminescence; Blood - brain barrier anatomy; Brain Death; Breast cancer metastasis; Cancer Patient; Cell Death; Circadian Rhythms; Clustered Regularly Interspaced Short Palindromic Repeats; Cyclophosphamide; Darkness; Data; Development; Diagnosis; Disease; Doxorubicin; Equilibrium; Goals; Grant; Hour; Image; Immunohistochemistry; Impaired cognition; Incidence; Inferior; Injections; Label; Location; Malignant Neoplasms; Medicine; Mental Depression; Mentors; Metastatic malignant neoplasm to brain; Mus; Neuropsychology; Neurosciences; Nonmetastatic; Outcome; Paclitaxel; Patients; Permeability; Pharmaceutical Preparations; Phase; Physiological Processes; Quantitative Reverse Transcriptase PCR; Research; Research Personnel; Research Support; Sleep; Survival Rate; Techniques; Therapeutic; Time; Training; Treatment Efficacy; Tumor Burden; United States; Woman; Writing; anxiety-like behavior; blood-brain barrier crossing; blood-brain barrier permeabilization; blood-brain tumor barrier; cancer diagnosis; cancer type; career development; chemotherapeutic agent; chemotherapy; circadian; circadian biology; circadian regulation; clinically relevant; cognitive function; depressive symptoms; genetic approach; improved; inhibitor; intravenous injection; laboratory experience; malignant breast neoplasm; mouse model; multidisciplinary; neuroinflammation; novel; optimal treatments; pharmacologic; side effect; treatment strategy; trend; tumor; tumor growth

Project Summary Breast cancer is a devastating disease that affects large numbers of women annually; it is estimated that 1 in 8 women in the United States will be diagnosed with this disease during their lifetime. The five-year survival rate for women diagnosed with localized or regional breast cancer is greater than 90 percent. However, the presence of brain metastases reduces five-year survival rates to less than 10 percent. Chemotherapy treatment of brain metastases is challenging and has yielded inferior results compared to tumors in the periphery, likely reflecting the inability of chemotherapy to cross the blood brain barrier (BBB) and/or blood tumor barrier (BTB) at efficacious rates. Recent studies demonstrate circadian regulation of BBB permeability; however no study has examined whether temporal alterations in chemotherapy administration can improve the efficacy of treatment of brain metastases. This project aims to take advantage of circadian control of BBB permeability by optimally timing chemotherapy administration to increase anti-tumor efficacy and reduce adverse side effects of brain metastases. Specifically, I hypothesize that circadian control of efflux transporter expression at the BBB underlies the fluctuations in BBB/BTB permeability to chemotherapeutic agents. Permeability of two of the most commonly prescribed chemotherapeutic drugs for breast cancer, doxorubicin (A) and paclitaxel (P), will be assessed via phosphor autoradiography imaging by using 14C labeled chemotherapeutic drugs. Additionally, pharmacological inhibition and genetic approaches (CRISPR) will be utilized to determine both the type and location (BBB or BTB) of efflux transporters that underlie altered permeability. Mice harboring brain metastases of breast cancer will receive intravenous injections of doxorubicin/cyclophosphamide cocktail or paclitaxel every 2 weeks during either the peak or trough of BBB permeability. Anti-tumor efficacy will be assessed via bioluminescence and immunohistochemistry. Adverse behavioral effects of chemotherapy will be assessed via multiple behavioral tasks and sleep assessment. I predict that optimal timing of chemotherapy administration will increase anti-tumor efficacy and minimizes adverse side effects. Indeed, preliminary data demonstrate that altering only the timing of injection increased the amount of chemotherapy within brain metastases of breast cancer by approximately 50%. Thus, chrono-chemotherapy represents a viable and novel treatment strategy. Together, these studies will provide essential information with a high potential for clinical relevance to better treat patients with breast cancer. This career development training award will enable me to become an independent investigator by allowing training in emerging techniques (i.e., CRISPR and blood-brain barrier/blood-tumor barrier biology), professional development, grant writing, guest lab training, mentor training, and highly focused research support. To help accomplish my goals, I have assembled a multidisciplinary mentoring team that has extensive expertise in the fields of circadian biology, cancer, and neuroscience.

项目摘要 乳腺癌是一种毁灭性的疾病，每年都会影响大量女性。据估计，有1分之一 美国的妇女将在其一生中被诊断出患有这种疾病。五年生存率 对于诊断患有局部乳腺癌或区域性乳腺癌的妇女，大于90％。但是，存在 脑转移的五年生存率降低到不到10％。大脑的化学治疗 与周围的肿瘤相比，转移具有挑战性，结果较低，可能反映 化学疗法无法穿越血脑屏障（BBB）和/或血液肿瘤屏障（BTB） 有效的费率。最近的研究表明，昼夜节律对BBB渗透性的调节。但是没有研究 检查化疗给药的时间改变是否可以提高治疗的疗效 脑转移。该项目旨在通过最佳地利用昼夜节律控制BBB渗透率 定时化学疗法给药以提高抗肿瘤功效并降低大脑的不良副作用 转移。具体而言，我假设昼夜节律控制在BBB底部的外排转运蛋白表达 BBB/BTB渗透性对化学治疗剂的波动。两个最常见的渗透性 针对乳腺癌，阿霉素（A）和紫杉醇（P）的规定化学治疗药物将通过 通过使用14C标记的化学治疗药物的磷光自显影成像。另外，药理 抑制和遗传方法（CRISPR）将用于确定类型和位置（BBB或BTB） 渗透率改变的外排转运蛋白。拥有乳腺癌脑转移的小鼠将 每两周，一次接受阿霉素/环磷酰胺鸡尾酒或紫杉醇的静脉注射一次 BBB渗透性的峰值或谷。抗肿瘤功效将通过生物发光和 免疫组织化学。化学疗法的不利行为影响将通过多种行为评估 任务和睡眠评估。我预测，化学疗法给药的最佳时机将增加抗肿瘤 功效并最小化不良副作用。确实，初步数据表明仅更改时间安排 注射的注射量增加了乳腺癌脑转移量的化学疗法量大约 50％。因此，计时化学疗法代表了一种可行且新颖的治疗策略。这些研究将在一起 提供具有临床相关性高潜力的基本信息，以更好地治疗乳腺癌患者。 这个职业发展培训奖将使我能够通过允许 新兴技术培训（即CRISPR和血脑屏障/血肿瘤屏障生物学），专业 开发，赠款写作，来宾实验室培训，导师培训以及高度重点的研究支持。提供帮助 完成我的目标，我组建了一个多学科指导团队，该团队在该领域拥有广泛的专业知识 昼夜节律生物学，癌症和神经科学领域。

项目成果

Chronotherapeutics for Solid Tumors.

• DOI: 10.3390/pharmaceutics15082023
• 发表时间: 2023-07-26
• 期刊: PHARMACEUTICS
• 影响因子: 5.4
• 作者: Kisamore, Claire O.;Elliott, Brittany D.;Devries, A. Courtney;Nelson, Randy J.;Walker II, William H.
• 通讯作者: Walker II, William H.