Disruptive methods for increased chemotherapy distribution into preclinical brain metastases of breast cancer leading to improved tumor kill and prolonged survival.

破坏性方法增加了乳腺癌临床前脑转移的化疗分布，从而提高了肿瘤杀灭率并延长了生存期。

• 批准号: 10065208
• 负责人: Samuel Adam Tyler Sprowls
• 金额: $ 4.7万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10065208
• 关键词: Animal Model; Animals; Astrocytes; Award; Blood - brain barrier anatomy; Blood capillaries; Brain; Breast Cancer Model; Breast Cancer Patient; Breast Cancer cell line; Breast cancer metastasis; Cancer Center; Cancer Etiology; Central Nervous System Neoplasms; Cessation of life; Chemotherapy and/or radiation; Clinical Data; Consensus; Coupled; Dependence; Diagnosis; Dose; ERBB2 gene; Endothelial Cells; Environment; Event; Faculty; Failure; Fluorescence; Focused Ultrasound; Focused Ultrasound Therapy; Foot Process; Foundations; Funding; Goals; Imaging Techniques; Institution; Ionizing radiation; Laboratory Research; Lead; Lesion; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of brain; Mentors; Mentorship; Metastatic malignant neoplasm to brain; Methods; Microbubbles; Modeling; Molecular; Monitor; Mus; Neoplasm Metastasis; Neurocognitive Deficit; Neuroimmune; Operative Surgical Procedures; Outcome; Patients; Penetration; Pericytes; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Positioning Attribute; Postdoctoral Fellow; Pre-Clinical Model; Protocols documentation; Publications; Radiation; Radiation exposure; Radiation therapy; Regulation; Reporting; Research; Research Personnel; Research Project Grants; Research Training; Science; Techniques; Testing; Therapeutic; Time; Tracer; Training; Universities; West Virginia; Woman; Work; advanced breast cancer; anticancer research; blood-brain tumor barrier; chemotherapy; clinically relevant; clinically translatable; cytotoxic; cytotoxicity; design; experimental study; foot; human model; imaging modality; improved; innovation; malignant breast neoplasm; multimodality; neurovascular unit; novel; palliative; post-doctoral training; pre-clinical; programs; radiation effect; radiation response; response; standard care; treatment strategy; tumor

Project Summary Metastatic lesions encompass approximately 80% of all CNS tumors. Of that, breast cancer brain metastasis comprises a third of all brain metastases. Treatment options are few and often only offer palliative support, but include surgery, chemotherapy, and radiation therapy. Ionizing radiation is observed to disrupt the BTB, however the mechanism and time course of molecular events following radiation exposure remains poorly understood. Gap: There is currently no consensus on the sequence of events following radiation therapy for patients with brain metastases, and whether or not chemotherapy can be effectively timed with windows of greatest disruption of the BTB. My goal during the F99 phase is to elucidate the time line, at a range of clinically relevant doses, of radiation-induced BTB openings and determine if two approved therapeutics, when given at windows of greatest disruption, lead to increased cytotoxicity when timed competently rather than at random. The training plan set forth in this application employs a wide variety of experimental techniques including animal modeling of metastatic brain cancer, multiple imaging modalities, use of radiation in small animals, design of clinically translatable experiments, and conducting science with integrity in a rigorous and competitive field. This project uses an innovative approach combining our novel brain tropic breast cancer cell lines with small animal radiation techniques. Herein, we will use our unique multimodal fluorescence and phosphorescent imaging techniques to monitor changes in BTB permeability. I will complete this research under the mentorship of Dr. Paul R. Lockman, whose lab boasts a strong publication record with excellent funding in the field of brain metastases of breast cancer. The F99 phase of this award aligns with the remaining 2 years I have of my time in the Pharmaceutical and Pharmacological Sciences graduate program at West Virginia University. Our institutional environment is more than adequately positioned to conduct the research and training described in this proposal, which more than demonstrates the quality and strength offered by the faculty at our university. In the K00 phase of this award, I will identify a postdoctoral mentor at an institution with a strong cancer center allowing me to pursue further the cellular and molecular foundation of BBB/BTB regulation in brain metastases from a different, but complementary avenue. Combined together, the two phases of this award will provide me with the means to establish myself as a successful cancer researcher and enable me to lay the foundation for my own independent cancer research laboratory predicated on the study of the molecular interworking of the BTB in CNS metastatic lesions and novel treatment strategies.

项目概要 转移性病变约占所有中枢神经系统肿瘤的 80%。其中，乳腺癌脑转移 占所有脑转移瘤的三分之一。治疗选择很少，而且通常只能提供姑息支持，但是 包括手术、化疗和放射治疗。观察到电离辐射会破坏 BTB， 然而，辐射暴露后分子事件的机制和时间进程仍然很差 明白了。差距：目前对于放射治疗后的事件顺序尚未达成共识 脑转移患者的情况，以及是否可以有效地安排化疗时间 BTB 的最大破坏。我在 F99 阶段的目标是阐明时间线，在一定范围内 临床相关剂量，辐射引起的 BTB 开口，并确定是否两种批准的治疗方法，当 在干扰最大的窗口给予，在适当的时机而不是在 随机的。本申请中提出的培训计划采用了多种实验技术 包括转移性脑癌的动物模型、多种成像方式、小规模放射治疗的使用 动物、临床可转化实验的设计以及以严格和完整的方式进行科学 竞争领域。该项目采用创新方法结合我们的新型脑向性乳腺癌细胞 行小动物放射治疗技术。在这里，我们将使用我们独特的多模态荧光和 磷光成像技术可监测 BTB 渗透性的变化。我将完成这项研究 在 Paul R. Lockman 博士的指导下，他的实验室拥有良好的发表记录和出色的 乳腺癌脑转移领域的资金。该奖项的 F99 阶段与其余阶段一致 我在 West 制药和药理学研究生项目学习了 2 年 弗吉尼亚大学。我们的机构环境足以进行研究 以及本提案中描述的培训，这不仅证明了该提案所提供的质量和实力 我们大学的教师。在这个奖项的K00阶段，我将在一个机构确定一名博士后导师 拥有强大的癌症中心，使我能够进一步追求 BBB/BTB 的细胞和分子基础 来自不同但互补的途径对脑转移的调节。两者结合在一起， 该奖项的各个阶段将为我提供使自己成为一名成功的癌症研究员的方法 并使我能够为自己的独立癌症研究实验室奠定基础 研究 CNS 转移灶中 BTB 的分子相互作用和新的治疗策略。