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，每年影响大量妇女;据估计， 在美国，女性在一生中都会被诊断出患有这种疾病。五年生存率 对于被诊断为局部或区域性乳腺癌的妇女，然而， 脑转移瘤的死亡率将五年生存率降低到10%以下。脑化疗 转移是具有挑战性的，并且与周围肿瘤相比，结果较差，可能反映了 化疗不能穿过血脑屏障（BBB）和/或血肿瘤屏障（BTB）， 有效利率。最近的研究表明，血脑屏障通透性的昼夜节律调节，但没有研究表明， 研究了化疗给药的时间改变是否可以提高化疗的疗效。 脑转移该项目旨在通过最佳方式利用血脑屏障通透性的昼夜节律控制 定时化疗给药以增加抗肿瘤疗效并减少脑的不良副作用 转移具体来说，我假设在血脑屏障外排转运蛋白表达的昼夜节律控制， BBB/BTB对化疗剂的渗透性的波动。两种最常见的渗透性 用于乳腺癌的处方化疗药物多柔比星（A）和紫杉醇（P）将通过 荧光放射自显影成像，使用14 C标记的化疗药物。此外，药理学 抑制和遗传方法（CRISPR）将用于确定类型和位置（BBB或BTB） 外排转运蛋白的作用。携带乳腺癌脑转移的小鼠将 接受静脉注射阿霉素/环磷酰胺鸡尾酒或紫杉醇，每2周一次， 血脑屏障通透性的峰值或谷值。将通过生物发光评估抗肿瘤疗效， 免疫组化化疗的不良行为影响将通过多项行为评估来评估。 任务和睡眠评估。我预测化疗的最佳时机将增加抗肿瘤 疗效和最大限度地减少不良副作用。事实上，初步数据表明， 注射的剂量增加了乳腺癌脑转移瘤的化疗剂量， 百分之五十因此，时辰化疗是一种可行的和新的治疗策略。这些研究将 提供具有高度临床相关性的基本信息，以更好地治疗乳腺癌患者。 这个职业发展培训奖将使我成为一个独立的调查员， 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，客座实验室培训，导师培训和高度集中的研究支持。帮助 为了实现我的目标，我组建了一个多学科的指导团队，在以下方面拥有广泛的专业知识： 生理节律生物学、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.