Clinical Studies to Circumvent Drug Resistance

规避耐药性的临床研究

• 批准号: 8552750
• 负责人: susan bates
• 金额: $ 12.88万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 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/8552750
• 关键词: ATP-Binding Cassette Transporters; Alkanesulfonates; Antineoplastic Agents; Area; Binding; Biological Markers; Biological Models; Blood; Blood - brain barrier anatomy; Bone Marrow; CBT-1; Cell Line; Cells; Central Nervous System Diseases; Clinic; Clinical; Clinical Research; Clinical Trials; Cognitive; Collaborations; Computer Simulation; DNA Damage; Data; Development; Developmental Therapeutics Program; Drug Efflux; Drug resistance; Generations; Goals; Hair follicle structure; Histone Deacetylase Inhibitor; Image; In Vitro; International; Intramural Research Program; Kidney; Label; Laboratories; Liver neoplasms; Loperamide; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Medical; Medical center; Metastatic Neoplasm to the Central Nervous System; Metastatic malignant neoplasm to brain; Methods; NCAM1 gene; Normal tissue morphology; Operative Surgical Procedures; P-Glycoprotein; Paclitaxel; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Phase I Clinical Trials; Physicians; Positron; Positron-Emission Tomography; Preclinical Drug Evaluation; Publishing; Radiation; Radioisotopes; Radiolabeled; Relapse; Renal Cell Carcinoma; Research; Resistance; Rhodamine; Risk; Sampling; Schedule; Site; Solid Neoplasm; Systemic disease; Tariquidar; Taxane Compound; Technetium Tc 99m Sestamibi; Testing; Therapeutic; Therapy Clinical Trials; Thrombocytopenia; Tissues; Toxic effect; Translations; Treatment Efficacy; Tubulin; Tumor Tissue; United States National Institutes of Health; Universities; Variant; Work; base; cancer therapy; cytotoxicity; design; docetaxel; high risk; improved; in vivo; inhibitor/antagonist; interest; kidney cell; lapatinib; malignant breast neoplasm; neoplastic cell; novel; pre-clinical; programs; radiotracer; receptor; taxane; therapy development; tumor; uptake

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. Our clinical trials involve studies of inhibition of resistance to conventional agents such as that mediated by P-glycoprotein, and studies of novel agents such as DMS612 and GRN1005, intended to directly improve treatment of cancer. A number of clinical trials evaluated inhibition of P-glycoprotein, an ABC transporter mediating resistance through outward transport of anticancer agents. In trials carried out here and across the globe, there was disappointment in this therapeutic strategy of drug resistance reversal, ie no benefit from adding an inhibitor to reverse drug resistance. Nonetheless, continued effort in the study of drug uptake is warranted -- few if any studies on a national or international level actually query drug uptake in cancer. To that end we are collaborating with Peter Choyke and Karen Kurdziel to evaluate F18-labeled paclitaxel (FPAC), which is then evaluated by PET imaging. This, in addition to the sestamibi study described below constitute two studies aimed at evaluating drug accumulation in tumors, actually an understudied mechanism of drug resistance. 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. We completed and published two studies with third generation inhibitors tariquidar (XR9576) and CBT-1. In both studies we examined Pgp-mediated drug efflux was observed in circulating CD56+ cells, inhibition of rhodamine efflux observed for both agents. 99mTc-sestamibi imaging was employed as a surrogate for altered drug accumulation in normal and tumor tissues. Although the 99mTc-sestamibi studies provided proof-of-concept showing increased radionuclide accumulation in normal tissue, particularly in the liver, tumor uptake was much less prevalent and often did not change with the addition of the Pgp inhibitor. The 99mTc studies are poorly quantitative because they are planar images and background often overwhelms differences. The Clinical Center PET department developed a method to label sestamibi with 94mTc for positron emission imaging, promising a more quantitative imaging agent. Our clinical trial testing this imaging agent is open but was on hold much of the year due to lack of drug. It is now reopened. 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. The question of why sestamibi uptake fails in many patient tumors whether or not tariquidar is present is an important one and suggests that drug uptake, independent of a Pgp efflux mechanism, may be an important new area for study. In addition to the PET-sestamibi trial, we have initiated collaborations with Dr. Robert Innis, Dr. Pete Choyke, and Dr. Karen Kurdziel aimed at evaluating drug accumulation using PET agents 11C-N-desmethyl-loperamide and 18F-paclitaxel (FPAC). These PET studies offer the opportunity to move the field forward in a significant way; we will accrue our first patient to the FPAC study this month.These studies offer the opportunity to ask the more general question - to assess interpatient variation in drug uptake in tumor tissue. The assumption among treating physicians is that patients have uniform anticancer drug uptake in tumors. This question has never been systematically studied. It is our hope that radiolabeled imaging studies will begin to assess this question. Also important is the question of CNS uptake of anticancer agents. This work is directly relevant to our work with ABC transporters, since these comprise some of the blood-brain barrier obstacle to drug accumulation. In this we will join a collaboration already ongoing that includes Drs. Pat Steeg and JoAnne Zujewski. Studies of CNS metastases are very difficult to carry out. We have initiated a study with GRN1005, a conjugated taxane that promises to have CNS uptake due to conjugate with a peptide that binds the LRP receptor for transit across the blood brain barrier. The compound is being developed by Geron Pharmaceuticals. We have initiated a pilot surgery trial that will allow us to measure tubulin stabilization in CNS metastases removed at medically indicated surgical procedures after GRN1005 administration. We are also participating in the company?s Phase II efficacy study. This is a critical research area ? today, patients have increasing control of systemic disease and CNS relapse is emerging as a major medical problem. Patients who have conventional CNS radiation often do not have CNS disease completely eradicated and are also at risk for long-term cognitive problems, particularly with increasing control of CNS disease. This again is an area where the intramural program can contribute significantly - high-risk research with important long-term impact. 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 new compound class, the dimethane sulfonates, has been continuously in preclinical development at DTP and one, NSC-281612, was approved for Phase I testing. The Phase I trial is now open at the NIH clinical center and accruing patients. The study is a multi-institutional Phase 1 trial with one site at University of Pittsburgh and the other at Hershey Medical Center. We have identified bone marrow toxicity as the chief cumulative toxicity, and have changed the schedule to mitigate this. Thrombocytopenia is the primary toxicity observed. One of the goals in the Phase I trial has been the development of biomarkers to evaluate the presence of DNA damage in tumor cells or surrogate tissues following treatment with the DMS compound. This has been successful to date in the laboratory of Dr. Yves Pommier, with Dr. Christophe Redon already documenting evidence of DNA damage in blood and hair follicle samples.

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。我们的临床试验涉及对抑制对常规剂的抑制作用，例如P-糖蛋白介导的抗药性，以及对DMS612和GRN1005等新型药物的研究，旨在直接改善癌症的治疗方法。 许多临床试验评估了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。在这里和全球进行的试验中，这种耐药性逆转的治疗策略令人失望，即添加抑制剂以逆转耐药性无益。尽管如此，保证在药物摄取研究方面的持续努力是有必要的 - 几乎没有关于国家或国际水平的研究实际上是在癌症中查询药物的吸收。为此，我们正在与Peter Choyke和Karen Kurdziel合作评估F18标记的紫杉醇（FPAC），然后通过PET成像对其进行评估。 除了下面描述的Sestamibi研究外，这还构成了两项旨在评估肿瘤中药物积累的研究，实际上是一种研究的耐药性机制。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。 我们完成并发表了两项研究，并与第三代抑制剂塔基动物（XR9576）和CBT-1一起完成了研究。 在这两项研究中，我们在循环CD56+细胞中观察到了PGP介导的药物外排，两种药物观察到的若丹明外排抑制。 99MTC-SESTAMIBI成像被用作正常和肿瘤组织中药物积累的替代物。尽管99MTC-SESTAMIBI研究提供了概念验证的证明，显示正常组织中放射性核素的积累增加，尤其是在肝脏中，但肿瘤摄取的摄入量不那么普遍，并且随着PGP抑制剂的添加通常不会改变。 99MTC研究的定量很差，因为它们是平面图像，背景通常压倒了差异。临床中心宠物部开发了一种用94MTC标记正电子发射成像的方法，有望成为更定量的成像剂。 我们对该成像剂进行的临床试验测试开放，但由于缺乏药物，一年中的大部分时间都持有。现在已重新开放。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。为什么肉毒杆菌是否存在的许多患者肿瘤失败的问题是一个重要的问题，这是一个重要的问题，这表明与PGP外排机制无关的药物吸收可能是研究的重要新领域。 除了PET-SESTAMIBI试验外，我们还与Robert Innis博士，Pete Choyke博士和Karen Kurdziel博士进行了合作，旨在使用PET Agents 11C-N-甲基甲基甲基酰胺和18F-甲酰胺（FPAC）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。我们将在本月进行FPAC研究。这些研究提供了提出更一般性问题的机会 - 评估肿瘤组织中药物摄取的插室变化。治疗医师的假设是患者在肿瘤中具有均匀的抗癌药物摄取。这个问题从未系统地研究。我们希望放射标记的成像研究将开始评估这个问题。同样重要的是中枢神经系统吸收抗癌药的问题。这项工作与我们与ABC转运蛋白的工作直接相关，因为这些工作构成了药物积累的一些血脑屏障障碍。在这方面，我们将加入一项已经进行的合作，其中包括DRS。 Pat Steeg和Joanne Zujewski。 中枢神经系统转移的研究很难进行。我们已经对GRN1005进行了一项研究，该研究是一种共轭紫杉烷，有望通过与肽结合结合LRP受体在血液脑屏障中转运的肽引起的CNS摄取。该化合物是由Geron Pharmaceuticals开发的。我们已经开始了一项初步手术试验，该试验将使我们能够测量在GRN1005给药后通过医学指示的手术程序去除的中枢神经系统转移中的微管蛋白稳定。我们还参加了公司的第二阶段效力研究。 这是一个关键的研究领域？如今，患者对全身性疾病的控制越来越大，并且中枢神经系统复发正在成为主要的医疗问题。 常规中枢神经系统辐射的患者通常没有完全消除中枢神经系统疾病，并且也有长期认知问题的风险，尤其是随着CNS疾病的控制增加。这再次是壁内计划可以显着贡献的领域 - 高风险研究具有重要的长期影响。 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。 在DTP的临床前开发中，一种新的化合物类别是二甲烷磺酸盐，NSC-281612在临床前开发中被批准用于I期测试。 I期试验现已在NIH临床中心开放，并为患者累积。这项研究是一项多机构的1阶段试验，在匹兹堡大学，另一个地点在Hershey Medical Center。 我们已经将骨髓毒性确定为主要累积毒性，并改变了缓解这种情况的时间表。血小板减少症是观察到的主要毒性。 I期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损伤的存在或替代组织。迄今为止，在伊夫·帕米尔（Yves Pommier）博士的实验室中，这已经成功了，克里斯托夫·雷登（Christophe Redon）博士已经记录了血液和毛囊样品中DNA损伤的证据。