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

• 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
• 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

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）：多形胶质母细胞瘤（GBM）是整个大脑的疾病。即使是对肿瘤半球的完全手术切除也不可避免地会导致复发，并被放弃。但是，使用小分子药物的大多数临床试验都集中在可以通过手术去除的大量肿瘤肿块上的疗效测量（临床结果和生物标志物）。尽管有越来越多的证据表明GBM的复发和致死性是由于未能有效靶向侵入性神经胶质瘤细胞所致。脑肿瘤细胞过表达保护性活跃的外排运输系统，包括P-糖蛋白（PGP）和乳腺癌耐药性蛋白（BCRP）。肿瘤核心中的血脑屏障（BBB）是“漏水”，可以全身性药物递送，但是胶质瘤细胞渗入正常的脑结构，远离BBB完整的手术切除缘且具有功能外排运输系统的外科手术切除边缘。分子靶向的抗肿瘤剂，例如酪氨酸激酶抑制剂（例如TKIS，例如imatinib，imatinib，erlotinib，dasatinib）具有限制的疗效，受到顺序传递到实际靶标的障碍的限制，包括对宏观分布的障碍（包括在BBB中的积极外观）和微观的单元格（活性）（活性）（活性）（活性）（活性）（活性）（活性）（活性）（活性）（活性）（活性）（活性）（活性）。因此，（1）改善通过BBB改善所选“分子靶向”化学治疗剂的药物输送策略，以及（2）改善侵入性神经胶质瘤细胞中细胞内药物的积累，将显着提高分子靶向治疗的功效。我们的中心假设是，可以通过在BBB和浸润性肿瘤细胞水平上特异性抑制活性外排来靶向侵入性神经胶质瘤细胞，从而改善了分子靶向的酪氨酸激酶抑制剂的疗效。我们提出了三个特定的目的来检验这一假设。 AIM 1将表征改善人和小鼠原发性神经胶质瘤细胞系中TKI递送和功效的策略。 AIM 2将确定主动外排的影响，并优化克服外排的策略，对新型自发性小鼠神经胶质瘤模型的TKI疗效，该模型的增强。 AIM 3将确定使用新型前药对PGP和BCRP抑制主动外排运输的影响，对TKI在原发性人神经胶质瘤模型中的功效，该模型相对于传统的异种移植物而增强。这些目的的完成将表明是否在BBB，侵入性神经胶质瘤细胞屏障或两者都是重要的机制，可以通过将药物递送到侵入性神经胶质瘤细胞来影响分子靶向治疗的功效。如果成功，则应容易将这些信息转换为临床试验，并最终改善神经胶质瘤的治疗以及中枢神经系统的其他肿瘤。

项目成果

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