Clinical Studies of Multidrug Resistance Reversal

多药耐药性逆转的临床研究

基本信息

批准号：
7733111
负责人：
susan bates
金额：
$ 15.19万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7733111
关键词：
ABCG2 gene ATP-Binding Cassette Transporters Alkanesulfonates Antineoplastic Agents Bioinformatics Biological Assay Biological Markers Biological Models CBT-1 Camptothecin Analogue Cell Adhesion Cell Line Cells Cervical Class Clinic Clinical Clinical Research Clinical Trials Closure Collaborations Computer Simulation Cultured Cells DNA Damage Data Databases Denmark Development Developmental Therapeutics Program Disease Disease Resistance Dose Drug Efflux Drug Kinetics Drug resistance End Point Enrollment Evaluation Extramural Activities Gene Expression Generations Goals Hour Image In Vitro Intramural Research Program Intravenous Ixabepilone Kidney Label Laboratories Literature Loperamide Lung Malignant Neoplasms Malignant neoplasm of ovary Mediating Methods Modeling Molecular Profiling Mononuclear Multi-Drug Resistance NCAM1 gene New Agents Non-Small-Cell Lung Carcinoma Numbers Oral P-Glycoprotein P-Glycoproteins Paclitaxel Patients Peripheral Pharmaceutical Preparations Pharmacodynamics Phase Phase I Clinical Trials Phase II Clinical Trials Plastics Positron Positron-Emission Tomography Preclinical Drug Evaluation Preparation Protein Overexpression Protocols documentation Radioisotopes Randomized Controlled Clinical Trials Renal Cell Carcinoma Reporting Research Research Ethics Committees Resistance Rhodamine Rhodamines Risk Safety Sampling Schedule Surrogate Markers Tariquidar Taxane Compound Technetium Tc 99m Sestamibi Testing Therapeutic Tissues Topotecan Toxic effect Translations Tubulin Tumor Tissue United States Food and Drug Administration Universities Valspodar Vinorelbine Week Work XR 9576 base concept cytotoxicity design docetaxel drug efficacy in vitro Model in vivo inhibitor/antagonist interest irinotecan kidney cell multi drug transporter neoplastic cell novel pre-clinical programs research study resistance mechanism response taxane tumor uptake

项目摘要

The focus of our section's research program is to develop therapeutic strategies aimed at overcoming drug resistance in cancer. Our research has been dedicated to the translation of drug resistance reversal strategies to the clinic. The design of our clinical trials has been enhanced by laboratory support that has allowed us to analyze clinical samples and interpret the clinical trial findings. A significant clinical trial effort has related to the inhibition of P-glycoprotein, an ABC transporter mediating resistance through outward transport of anticancer agents. These studies, which have been carried out collaboratively with Dr. Tito Fojo, evaluate the hypothesis that Pgp modulation may increase anticancer drug efficacy. In trials carried out across the globe, beginning with the failed first-generation trials that employed agents without sufficient potency, and continuing with the failed second-generation trials centered on valspodar with its accompanying need for anticancer agent dose reduction, there has been much disappointment in therapeutic strategy. Even a multinational randomized trial combining the new agent tariquidar with paclitaxel or vinorelbine closed early for toxicity. It must be stated that there is no convincing proof to date that this strategy will eventually be shown to provide clinical benefit and the resistance reversal paradigm remains a hypothesis. However, the failed earlier strategies do not negate strong evidence supporting continued development of Pgp antagonists. The project can be viewed as high risk with potentially high gain for multiple tumor types and thus very appropriate for the NCI intramural program. Current studies are evaluating the third generation inhibitor tariquidar (XR9576). In our completed Phase I interaction study with vinorelbine and tariquidar, total inhibition of Pgp-mediated drug efflux was observed in CD56+ cells, with persistence of inhibition for 48 hours after a single intravenous dose of tariquidar. 99mTc-sestamibi imaging was employed as a surrogate for altered drug accumulation in normal and tumor tissues. More than half of the patients had detectable increases in tumor uptake of 99mTc-sestamibi. Our goal in launching a new tariquidar trial was to gather more data regarding the safety of tariquidar following closure of a multinational trial for toxicity. Docetaxel was chosen as an excellent Pgp substrate with known efficacy that could be benefited by increasing drug accumulation in lung, cervical, or ovarian cancer. In planning an interaction trial of docetaxel with tariquidar, we selected an effective but conservative dose of docetaxel - 75 mg/m2 on a q-3-week schedule. The trial was designed with both pharmacokinetic and pharmacodynamic assays. To examine whether tariquidar interferes with docetaxel clearance, careful pharmacokinetics will be performed on a dose of docetaxel administered with and without tariquidar. In addition to pharmacokinetic analysis, 99mTc-sestamibi studies are performed in each enrolled patient with and without tariquidar, and our laboratory carries out CD56+ rhodamine assays in peripheral mononuclear cells. The trial has just completed maximum accrual, and patients were treated without major toxicity. We have been encouraged by the disease responses in patients with nonsmall cell lung cancer. We completed accrual in cervical and ovarian cancer without evidence of major activity or toxicity. Although the 99mTc-sestamibi studies provide good proof-of-concept showing increased radionuclide accumulation following tariquidar, the studies are poorly quantitative because they are planar images and background often overwhelms differences. Led by Dr. Peter Herscovitch, the Clinical Center PET department developed a method to label sestamibi with 94mTc for positron emission imaging, promising a more quantitative imaging agent. A clinical trial testing this agent has is open and accruing patients. It is our hope that the quantitative PET imaging will allow us to better answer the question of how much impact tariquidar can have on patient tumors. In addition to the PET-sestamibi trial, we have discussed collaborations with Dr. Robert Innis and Dr. Karen Kurdziel aimed at evaluating drug accumulation using PET agents 11C-N-desmethyl-loperamide and 18F-paclitaxel. These PET studies offer the opportunity to move the field forward in a significant way. In addition to the tariquidar studies, our group was approached by CBA Pharma, a small company developing a Pgp inhibitor CBT-1. This is an oral agent that has been in clinical trials. However, inhibition of Pgp by this agent has not been confirmed in patients. We have confirmed activity of the agent in an ex vivo assay. A clinical trial examining surrogate markers of Pgp inhibition including altered sestamibi uptake and increased rhodamine uptake in circulating CD56+ mononuclear cells in patients treated with paclitaxel and CBT-1 has been submitted for final review by the IRB. Our laboratory also maintains an interest in studying drug resistance in other model systems. Several years ago, in collaboration with the NCI's Developmental Therapeutics Program, we identified a number of compounds with selectivity against renal cell caner, based on COMPARE analysis using cytotoxicity data in the 60 cell line panel. These compounds were evaluated in our laboratory and the renal selectivity confirmed. One class of these compounds, the dimethane sulfonates, has been continuously in preclinical development at DTP and one, NSC-281612, has been approved for Phase I testing. A protocol is in preparation, and an IND will be submitted. One of the goals in the Phase I trial will be the development of biomarkers to evaluate the presence of DNA damage in tumor cells or surrogate tissues following treatment with the DMS compound. A second aspect of this latter project is the evaluation of other mechanisms of drug resistance using Bioinformatics strategies. This project is carried out in collaboration with Dr. Wilfred Stein, Hebrew University, Jerusalem, and Dr. Thomas Litman, University of Copenhagen, Denmark. Two separate bioinformatics strategies identified cell adhesion as a mechanism of resistance, using gene expression data in clinical samples reported in publicly available databases. These experiments resonated with a literature already available suggesting that cell adhesion was an important mechanism of resistance. Interestingly, evaluation of in vitro models of cell adhesion -- such as spheroid formation-- have suggested that cells cultured in this manner have similar gene expression profiles to confluent cells cultured on plastic. This would suggest that spheroid cultures per se cannot serve as models of intrinsic drug resistance and that other in vitro models should be developed. Given the difficulties in developing drug resistance modulators for resistance reversal, an alternate strategy is to select drugs for know targets that are not substrates for multidrug transporters. The recent FDA approval of ixabepilone is one example of such a strategy. This tubulin-targeted compound was developed in part because of its lack of interaction with P-glycoprotein in the hopes that it would be effective where taxanes were limited by drug efflux mechanisms. A similar strategy charact [summary truncated at 7800 characters]

我们部分研究计划的重点是制定旨在克服癌症耐药性的治疗策略。我们的研究致力于将耐药性逆转策略转化为诊所。实验室支持增强了我们的临床试验的设计，这使我们能够分析临床样本并解释临床试验结果。一项重大的临床试验工作与抑制P-糖蛋白的抑制作用，P-糖蛋白是ABC转运蛋白通过抗癌剂向外运输介导抗性的ABC转运蛋白。这些研究已经与Tito Fojo博士合作进行，评估了PGP调节可能会提高抗癌药物功效的假设。在全球进行的试验中，从失败的第一代试验开始，该试验雇用了没有足够效力的代理商，并继续进行以valspodar为中心的失败的第二代试验，其伴随抗癌药剂量减少的需求是减少治疗策略的失望。即使是一项跨国随机试验，将新的药物塔基动物与紫杉醇或乙烯苯甲苯甲苯甲苯甲甲或乙烯苯甲胺结合起来，以提早因毒性而结束。必须指出的是，迄今为止尚无令人信服的证据表明，最终将证明该策略可以提供临床益处，而阻力逆转范式仍然是一个假设。但是，失败的早期策略并没有否定支持PGP拮抗剂持续发展的有力证据。该项目可以看作是高风险，对于多种肿瘤类型而言可能具有很高的增益，因此非常适合NCI壁内计划。当前的研究正在评估第三代抑制剂塔基动物（XR9576）。在我们完成的I期与Vinorelbine和Tariquidar的相互作用研究中，在CD56+细胞中观察到了PGP介导的药物外排的总抑制作用，单次静脉内剂量的塔氨基氨基化剂后持续抑制48小时。 99MTC-SESTAMIBI成像被用作正常和肿瘤组织中药物积累的替代物。超过一半的患者的肿瘤摄取量可检测到99mTC-STAMIBI。我们发起新的塔里奎尔试验的目标是收集有关毒性毒性封闭后塔基动物安全性的更多数据。多西他赛被选为具有已知功效的出色PGP底物，可以通过增加肺，宫颈癌或卵巢癌的药物积累而受益。在计划与Tariquidar的多西他赛的互动试验时，我们在Q-3周时间表中选择了有效但保守的多西他赛-75 mg/m2。该试验是通过药代动力学和药效学测定设计的。为了检查塔基动物是否会干扰多西他的清除率，将对有或没有塔氨基烷的一定剂量进行仔细的药代动力学。除了药代动力学分析外，在有或没有塔氨基酯的每个入学的患者中还进行了99mTC-Sestamibi研究，我们的实验室在外周核细胞中进行CD56+若丹明分析。该试验刚刚完成最大应计，患者接受治疗而没有重大毒性。非小细胞肺癌患者的疾病反应使我们感到鼓舞。我们在宫颈癌和卵巢癌中完成了应计，而没有重大活性或毒性的证据。尽管99MTC-SESTAMIBI研究提供了良好的概念验证，显示塔基达岛后放射性核素的积累增加，但这些研究的数量很差，因为它们是平面图像和背景通常压倒性的差异。在彼得·赫斯科维奇（Peter Herscovitch）博士的带领下，临床中心宠物部门开发了一种用94mtc标记塞斯塔米比（Sestamibi）进行正电子发射成像的方法，并有望成为更定量的成像剂。该药物的临床试验测试是开放和应计的。我们希望定量的宠物成像能够使我们能够更好地回答塔基动物对患者肿瘤产生多少影响的问题。除了进行宠物史密比试验外，我们还讨论了与Robert Innis博士和Karen Kurdziel博士的合作，旨在使用PET Agents 11C-N-二甲基 - 氯甲酰胺和18F-甲状腺素进行评估药物积累。这些宠物研究提供了以一种重要的方式推动该领域前进的机会。除了塔基动物研究外，我们的小组还与开发PGP抑制剂CBT-1的小型公司CBA Pharma接触。这是一种正在临床试验的口服药物。但是，该药物对PGP的抑制尚未在患者中得到证实。我们已经在离体测定中证实了该代理的活性。一项检查PGP抑制作用的替代标志物的临床试验，包括改变肉芽素摄取的改变和若丹明摄取量增加的CD56+单核细胞中紫杉醇和CBT-1治疗的患者的循环中，IRB提交了最终审查。我们的实验室还保持了研究其他模型系统中耐药性的兴趣。几年前，基于使用60个单元线板中的细胞毒性数据进行比较，我们与NCI的发育治疗计划合作，确定了许多具有选择性的化合物对肾细胞罐头的选择性。这些化合物在我们的实验室中进行了评估，并确认了肾脏选择性。这些化合物中的一类是二甲烷磺酸盐，在DTP的临床前发育中一直是I期测试的临床前开发。正在准备协议，并将提交IND。 I阶段试验的目标之一是开发生物标志物，以评估用DMS化合物处理后肿瘤细胞中DNA损伤或替代组织的存在。后一个项目的第二个方面是使用生物信息学策略评估其他耐药性机制。该项目与耶路撒冷希伯来大学的Wilfred Stein博士和丹麦哥本哈根大学的Thomas Litman博士合作进行。两种单独的生物信息学策略使用在公开数据库中报道的临床样本中使用基因表达数据鉴定出细胞粘附是一种抗性机制。这些实验与已经可用的文献产生了共鸣，这表明细胞粘附是抗药性的重要机制。有趣的是，对细胞粘附的体外模型（例如球体形成）的评估表明，以这种方式培养的细胞具有与在塑料上培养的融合细胞相似的基因表达谱。这表明球体培养本身不能用作内在耐药性的模型，并且应该开发其他体外模型。鉴于难以开发耐药性调节剂以抗抗性逆转，另一种策略是为不是多药转运蛋白底物的知识靶标的药物。 ixabepilone的FDA最近批准是这种策略的一个例子。这种靶向微管蛋白的化合物的开发部分是因为它与P-糖蛋白缺乏相互作用，希望在紫杉烷受到药物排出机制限制的情况下它将有效。类似的策略Charact [摘要以7800个字符截断]