Improving Delivery of Molecularly-Targeted Therapy to Invasive Glioma Cells

改善侵袭性胶质瘤细胞的分子靶向治疗

基本信息

批准号：
8608423
负责人：
William Elmquist
金额：
$ 29.79万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8608423
关键词：
Address Animal Model Animals Biological Markers Bioluminescence Blood - brain barrier anatomy Brain Brain Neoplasms Cells Central Nervous System Neoplasms Clinical Clinical Trials Dasatinib Data Disease Drug Delivery Systems Drug Efflux Epidermal Growth Factor Receptor Erlotinib Excision Exhibits Failure Gene Transfer Genetic Genotype Glioblastoma Glioma Human Image Imatinib In Vitro Investigation Knock-out Knockout Mice Lead MAPK3 gene Malignant neoplasm of brain Measurement Measures Medical Microscopic Modeling Molecular Target Mouse Strains Mus Nude Rats Operative Surgical Procedures Outcome P-Glycoprotein PDGFRB gene Patients Pharmaceutical Preparations Phosphorylation Plasma Prodrugs Progression-Free Survivals Proto-Oncogene Proteins c-akt Receptor Tyrosine Kinase Gene Recurrence Relapse Relative (related person)Signal Transduction Structure Study models Surgical margins System Testing Therapeutic Transfection Tyrosine Kinase Inhibitor Wild Type Mouse Xenograft Model Xenograft procedure antitumor agent base chemotherapeutic agent clinically relevant cytotoxicity drug efficacy effective therapy glioma cell line human ABCG2 protein improved in vivo inhibitor/antagonist mouse model neoplastic cell nerve stem cell novel overexpression plasmid DNA public health relevance research study response small molecule targeted delivery tumor tumor growth tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is a disease of the entire brain. Even complete surgical resection of the tumor-bearing hemisphere inevitably leads to recurrence and has been abandoned. Nonetheless, the majority of clinical trials employing small molecule drugs have focused their measurements of efficacy (both clinical outcome and biomarkers) on the bulk tumor mass that can be surgically removed. This is done in spite of mounting evidence that suggests the inevitable relapse and lethality of GBM is due to a failure to effectively target invasive glioma cells. Brain tumor cells overexpress protective active efflux transport systems, including p-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). The blood-brain barrier (BBB) in the tumor core is "leaky", allowing systemic drug delivery, but glioma cells infiltrate normal brain structures centimeters away from the margin of surgical resection where the BBB is intact and has functional efflux transport systems. Molecularly- targeted anti-tumor agents such as tyrosine kinase inhibitors (TKIs, e.g., imatinib, erlotinib, dasatinib) have their efficacy limited by sequential barriers to delivery to the actual target, including barriers to macroscopic distribution (active efflux at the BBB) and barriers to microscopic delivery (active efflux from invasive glioma cell). Therefore, drug delivery strategies that (1) improve the delivery of selected "molecularly-targeted" chemotherapeutic agents through the BBB, and (2) improve the intracellular drug accumulation in invasive glioma cells, will significantly enhance the efficacy of molecularly-targeted therapy. Our central hypothesis is that invasive glioma cells can be targeted through specific inhibition of active efflux at the level of both the BBB and the invasive tumor cell leading to improved efficacy of molecularly-targeted tyrosine kinase inhibitors. We propose three specific aims to test this hypothesis. Aim 1 will characterize strategies to improve TKI delivery and efficacy in both human and mouse primary glioma cell lines. Aim 2 will determine the influence of active efflux, and optimize strategies to overcome efflux, on TKI efficacy in a novel spontaneous mouse model of glioma that grows invasively. Aim 3 will determine the influence of inhibiting active efflux transport using a novel prodrug targeting Pgp and BCRP on the efficacy of TKIs in a primary human glioma xenograft model that grows invasively relative to traditional xenografts. Completion of these aims will indicate if active efflux transport at the BBB, the invasive glioma cell barrier, or both is an important mechanism that can influence the efficacy of molecularly-targeted therapy by limiting drug delivery to the invasive glioma cell. If successful, this information should be readily translatable to clinical trials and lead to eventual improvement in the treatment of gliomas, and other tumors of the central nervous system.

描述（由申请人提供）：多形性胶质母细胞瘤（GBM）是一种全脑疾病。即使完全手术切除荷瘤半球也不可避免地会导致复发，因此已被放弃。尽管如此，大多数使用小分子药物的临床试验都将疗效测量（临床结果和生物标志物）集中在可以通过手术切除的大块肿瘤上。尽管越来越多的证据表明 GBM 不可避免的复发和致命是由于未能有效地靶向侵袭性神经胶质瘤细胞，但仍然这样做。脑肿瘤细胞过度表达保护性主动外排转运系统，包括 p-糖蛋白 (Pgp) 和乳腺癌抗性蛋白 (BCRP)。肿瘤核心的血脑屏障（BBB）是“渗漏的”，允许全身药物输送，但神经胶质瘤细胞会浸润距离手术切除边缘几厘米的正常大脑结构，其中血脑屏障完好无损，并具有功能性的外排运输系统。分子靶向抗肿瘤药物，例如酪氨酸激酶抑制剂（TKI，例如伊马替尼、厄洛替尼、达沙替尼），其功效受到递送至实际靶点的连续障碍的限制，包括宏观分布的障碍（血脑屏障的主动流出）和微观递送的障碍（侵袭性神经胶质瘤细胞的主动流出）。因此，药物递送策略（1）改善选定的“分子靶向”化疗药物通过血脑屏障的递送，以及（2）改善侵袭性神经胶质瘤细胞的细胞内药物积累，将显着增强分子靶向治疗的疗效。我们的中心假设是，可以通过在 BBB 和侵袭性肿瘤细胞水平上特异性抑制活性外流来靶向侵袭性神经胶质瘤细胞，从而提高分子靶向酪氨酸激酶抑制剂的功效。我们提出了三个具体目标来检验这一假设。目标 1 将描述改善人类和小鼠原代神经胶质瘤细胞系中 TKI 递送和功效的策略。目标 2 将确定主动外排的影响，并优化克服外排的策略对新型侵袭性生长的自发性胶质瘤小鼠模型中 TKI 疗效的影响。目标 3 将确定使用靶向 Pgp 和 BCRP 的新型前药抑制主动外排转运对原代人神经胶质瘤异种移植模型中 TKI 功效的影响，该模型相对于传统异种移植物呈侵入性生长。这些目标的完成将表明血脑屏障、侵袭性神经胶质瘤细胞屏障或两者的主动外排转运是否是一种重要机制，可以通过限制药物递送至侵袭性神经胶质瘤细胞来影响分子靶向治疗的疗效。如果成功，这些信息应该很容易转化为临床试验，并最终改善神经胶质瘤和其他中枢神经系统肿瘤的治疗。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Insight into the cooperation of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) at the blood-brain barrier: a case study examining sorafenib efflux clearance.

DOI：
10.1021/mp200465c
发表时间：
2012-03-05
期刊：
Molecular pharmaceutics
影响因子：
4.9
作者：
Agarwal S;Elmquist WF
通讯作者：
Elmquist WF

Breast cancer resistance protein and P-glycoprotein in brain cancer: two gatekeepers team up.

DOI：
10.2174/138161211797440186
发表时间：
2011
期刊：
Current pharmaceutical design
影响因子：
3.1
作者：
Agarwal S;Hartz AM;Elmquist WF;Bauer B
通讯作者：
Bauer B

Delivery of molecularly targeted therapy to malignant glioma, a disease of the whole brain.

DOI：
10.1017/s1462399411001888
发表时间：
2011-05-13
期刊：
Expert reviews in molecular medicine
影响因子：
6.2
作者：
Agarwal S;Sane R;Oberoi R;Ohlfest JR;Elmquist WF
通讯作者：
Elmquist WF

ABCG2 and ABCB1 Limit the Efficacy of Dasatinib in a PDGF-B-Driven Brainstem Glioma Model.

DOI：
10.1158/1535-7163.mct-15-0093
发表时间：
2016-05
期刊：
Molecular cancer therapeutics
影响因子：
5.7
作者：
Mittapalli RK;Chung AH;Parrish KE;Crabtree D;Halvorson KG;Hu G;Elmquist WF;Becher OJ
通讯作者：
Becher OJ

Brain metastases from renal cell carcinoma in the era of tyrosine kinase inhibitors.

酪氨酸激酶抑制剂时代肾细胞癌脑转移。

DOI：
10.1016/j.clgc.2012.11.001
发表时间：
2013
期刊：
Clinical genitourinary cancer
影响因子：
3.2
作者：
Dudek,ArkadiuszZ;Raza,Ahmad;Chi,Ming;Singhal,Meghali;Oberoi,Rajneet;Mittapalli,RajendarK;Agarwal,Sagar;Elmquist,WilliamF
通讯作者：
Elmquist,WilliamF