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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要乳腺癌是一种毁灭性的疾病，每年影响大量女性。据估计，八分之一美国女性一生中都会被诊断出患有这种疾病。五年生存率诊断患有局部或区域性乳腺癌的女性超过 90%。然而，存在脑转移的发生将五年生存率降低至不到 10%。脑部化疗治疗与周围肿瘤相比，转移瘤具有挑战性，并且产生的结果较差，这可能反映出化疗无法穿过血脑屏障（BBB）和/或血肿瘤屏障（BTB）有效率。最近的研究证明了 BBB 通透性的昼夜节律调节；然而没有研究检查化疗给药的时间改变是否可以提高治疗效果脑转移。该项目旨在通过优化血脑屏障渗透性的昼夜节律控制定时化疗可提高抗肿瘤疗效并减少脑部不良副作用转移。具体来说，我假设 BBB 外排转运蛋白表达的昼夜节律控制是其基础 BBB/BTB 对化疗药物的渗透性波动。两种最常见的渗透率乳腺癌处方化疗药物阿霉素 (A) 和紫杉醇 (P) 将通过以下方式进行评估使用 14C 标记的化疗药物进行荧光放射自显影成像。此外，药理将利用抑制和遗传方法 (CRISPR) 来确定类型和位置（BBB 或 BTB）导致渗透性改变的外排转运蛋白。携带乳腺癌脑转移的小鼠将在任一期间每两周接受静脉注射多柔比星/环磷酰胺混合物或紫杉醇 BBB 渗透性的峰值或谷值。抗肿瘤功效将通过生物发光和免疫组织化学。化疗的不良行为影响将通过多种行为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作用功效并最大限度地减少不良副作用。事实上，初步数据表明，仅改变时间注射使乳腺癌脑转移体内的化疗量增加了大约 50%。因此，计时化疗代表了一种可行且新颖的治疗策略。这些研究共同将提供具有高度临床相关性的重要信息，以更好地治疗乳腺癌患者。该职业发展培训奖将使我能够成为一名独立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、资助写作、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，他们在以下方面拥有丰富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

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Chronotherapeutics for Solid Tumors.

实体瘤的时间治疗。

DOI：
发表时间：
2023-07-26
期刊：
影响因子：
5.4
作者：
Kisamore, Claire O;Elliott, Brittany D;DeVries, A Courtney;Nelson, Randy J;Walker 2nd, William H
通讯作者：
Walker 2nd, William H