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 转移性病变包括所有中枢神经系统肿瘤的约80％。其中，乳腺癌脑转移 包括所有脑转移的三分之一。治疗选择很少，通常只提供姑息性支持，但是 包括手术，化学疗法和放射治疗。观察到电离辐射会破坏BTB， 但是，辐射暴露后分子事件的机制和时间过程仍然很差 理解。差距：当前在放射治疗后的事件序列尚未达成共识 患有脑转移的患者，以及是否可以有效地使用化学疗法 BTB的最大破坏。我在F99阶段的目标是阐明时间表 临床相关的剂量，辐射引起的BTB开口，并确定是否有两种批准的治疗剂 在最大干扰的窗户上给出，在计时时会导致细胞毒性增加而不是在 随机的。该应用程序中规定的培训计划采用了多种实验技术 包括转移性脑癌的动物建模，多种成像方式，在小型中使用辐射 动物，临床翻译实验的设计以及在严格和 竞争领域。该项目使用一种创新的方法，结合了我们的新型脑热带乳腺癌细胞 具有小动物辐射技术的线。本文中，我们将使用我们独特的多模式荧光和 磷光成像技术以监测BTB渗透性的变化。我将完成这项研究 在保罗·R·洛克曼（Paul R. Lockman）博士的指导下，他的实验室拥有出色的出版物记录 乳腺癌脑转移领域的资金。该奖项的F99阶段与其余 我在West的药物和药理学科学研究生课程中度过了2年 弗吉尼亚大学。我们的机构环境已经足够的位置来进行研究 和该提案中描述的培训，这不仅证明了 我们大学的教师。在该奖项的K00阶段，我将确定机构的博士后导师 凭借强大的癌症中心，我可以进一步追求BBB/BTB的细胞和分子基础 来自不同但互补的大道的脑转移调节。结合在一起，两个 该奖项的阶段将为我提供成为成功的癌症研究员的手段 并使我能够为自己的独立癌症研究实验室奠定基础 BTB在中枢神经系统转移性病变和新型治疗策略中的分子相互作用的研究。

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

A Review of Mathematics Determining Solute Uptake at the Blood-Brain Barrier in Normal and Pathological Conditions.

• DOI: 10.3390/pharmaceutics13050756
• 发表时间: 2021-05-19
• 期刊: Pharmaceutics
• 影响因子: 5.4
• 作者: Sprowls SA;Saralkar P;Arsiwala T;Adkins CE;Blethen KE;Pizzuti VJ;Shah N;Fladeland R;Lockman PR
• 通讯作者: Lockman PR

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