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: 10226363
• 负责人: Samuel Adam Tyler Sprowls
• 金额: --
• 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 2021-08-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226363
• 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.

项目摘要 转移性病变约占所有CNS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，往往只能提供姑息性支持，但 包括手术、化疗和放射治疗。观察到电离辐射破坏BTB， 然而，辐射暴露后分子事件的机制和时间过程仍然很差 明白差距：目前对放射治疗后的事件顺序没有共识， 脑转移瘤患者，以及化疗是否可以有效地与窗口的时间 BTB的最大破坏。在F99阶段，我的目标是阐明时间线， 临床相关剂量，辐射诱导的BTB开口，并确定是否有两种批准的治疗，当 在最大破坏的窗口给予，在适当的时间而不是在 随机本申请中提出的训练计划采用了各种各样的实验技术 包括转移性脑癌的动物模型、多种成像方式、小剂量放射治疗的使用、以及放射治疗的应用。 动物，设计临床可翻译的实验，并以严谨和完整的方式进行科学研究， 竞争领域。该项目使用了一种创新的方法，结合我们的新的脑嗜性乳腺癌细胞 线与小动物辐射技术。在此，我们将使用我们独特的多模态荧光和 磷光成像技术来监测BTB渗透性的变化。我会完成这项研究 在保罗·R博士的指导下洛克曼的实验室拥有良好的出版记录， 乳腺癌脑转移领域的资金。该奖项的F99阶段与剩余的 2年我有我的时间在制药和药理学研究生课程在西方 弗吉尼亚大学。我们的机构环境有足够的条件进行研究 和培训，这不仅证明了质量和实力提供的建议， 我们大学的教师在这个奖项的K 00阶段，我将确定一个机构的博士后导师 有一个强大的癌症中心，使我能够进一步研究BBB/BTB的细胞和分子基础， 从一个不同的，但互补的途径调节脑转移。两者结合在一起， 这个奖项的各个阶段将为我提供建立自己作为一个成功的癌症研究人员的手段 并使我能够为我自己的独立癌症研究实验室奠定基础， 研究BTB在CNS转移性病变中的分子相互作用和新的治疗策略。

项目成果

GAP43-dependent mitochondria transfer from astrocytes enhances glioblastoma tumorigenicity.

• DOI: 10.1038/s43018-023-00556-5
• 发表时间: 2023-05
• 期刊: NATURE CANCER
• 影响因子: 22.7
• 作者: Watson, Dionysios C. C.;Bayik, Defne;Storevik, Simon;Moreino, Shannon Sherwin;Sprowls, Samuel A. A.;Han, Jianhua;Augustsson, Mina Thue;Lauko, Adam;Sravya, Palavalasa;Rosland, Gro Vatne;Troike, Katie;Tronstad, Karl Johan;Wang, Sabrina;Sarnow, Katharina;Kay, Kristen;Lunavat, Taral R.;Silver, Daniel J.;Dayal, Sahil;Joseph, Justin Vareecal;Mulkearns-Hubert, Erin;Ystaas, Lars Andreas Romo;Deshpande, Gauravi;Guyon, Joris;Zhou, Yadi;Magaut, Capucine R.;Seder, Juliana;Neises, Laura;Williford, Sarah E.;Meiser, Johannes;Scott, Andrew J. J.;Sajjakulnukit, Peter;Mears, Jason A. A.;Bjerkvig, Rolf;Chakraborty, Abhishek;Daubon, Thomas;Cheng, Feixiong;Lyssiotis, Costas A. A.;Wahl, Daniel R. R.;Hjelmeland, Anita B. B.;Hossain, Jubayer A. A.;Miletic, Hrvoje;Lathia, Justin D. D.
• 通讯作者: Lathia, Justin D. D.

Circadian Influences on Chemotherapy Efficacy in a Mouse Model of Brain Metastases of Breast Cancer.

• DOI: 10.3389/fonc.2021.752331
• 发表时间: 2021
• 期刊: Frontiers in oncology
• 影响因子: 4.7
• 作者: Walker WH 2nd;Sprowls SA;Bumgarner JR;Liu JA;Meléndez-Fernández OH;Walton JC;Lockman PR;DeVries AC;Nelson RJ
• 通讯作者: Nelson RJ

Ultrasound-mediated disruption of the blood tumor barrier for improved therapeutic delivery.

• DOI: 10.1016/j.neo.2021.04.005
• 发表时间: 2021-07
• 期刊: Neoplasia (New York, N.Y.)
• 作者: Arsiwala TA;Sprowls SA;Blethen KE;Adkins CE;Saralkar PA;Fladeland RA;Pentz W;Gabriele A;Kielkowski B;Mehta RI;Wang P;Carpenter JS;Ranjan M;Najib U;Rezai AR;Lockman PR
• 通讯作者: Lockman PR

Blood-tumor barrier opening by MRI-guided transcranial focused ultrasound in a preclinical breast cancer brain metastasis model improves efficacy of combinatorial chemotherapy.

• DOI: 10.3389/fonc.2023.1104594
• 发表时间: 2023
• 期刊: Frontiers in oncology
• 影响因子: 4.7

Modulation of the blood-tumor barrier to enhance drug delivery and efficacy for brain metastases.

• DOI: 10.1093/noajnl/vdab123
• 发表时间: 2021-11
• 期刊: Neuro-oncology advances
• 作者: Blethen KE;Arsiwala TA;Fladeland RA;Sprowls SA;Panchal DM;Adkins CE;Kielkowski BN;Earp LE;Glass MJ;Pritt TA;Cabuyao YM;Aulakh S;Lockman PR
• 通讯作者: Lockman PR