Clinical Studies of Multidrug Resistance Reversal

我们部门研究计划的重点是开发旨在克服癌症耐药性的治疗策略。我们的研究一直致力于将耐药性逆转策略转化为临床。在实验室的支持下，我们的临床试验设计得到了加强，这使我们能够分析临床样本并解释临床试验结果。一项重要的临床试验与p -糖蛋白的抑制有关，p -糖蛋白是一种ABC转运蛋白，通过抗癌药物的外转运介导耐药性。这些研究是与Tito Fojo博士合作进行的，并评估了Pgp调节可能增加抗癌药物疗效的假设。在全球范围内进行的试验中，从失败的第一代试验开始，因为使用的药物没有足够的效力，然后是失败的第二代试验，主要集中在缬草酰胺及其伴随的抗癌药物剂量减少的需要，在这一领域有很多令人失望的事情。就连一项多国随机试验也因为毒性问题而提前结束，该试验将新药物tariquar与紫杉醇或长春瑞滨联合使用。必须指出的是，到目前为止，还没有令人信服的证据表明这种策略最终会提供临床益处，而且耐药性逆转模式仍然是一种假设。然而，失败的早期策略并不能否定支持Pgp拮抗剂继续发展的有力证据。目前的研究正在评估第三代抑制剂tariquar （XR9576）。在我们完成的vinorelbine和tariquidar的I期相互作用研究中，在CD56+细胞中观察到pgp介导的药物外排的完全抑制，单次静脉注射tariquidar后抑制持续48小时。99mTc-sestamibi成像被用作正常和肿瘤组织中药物积累改变的替代方法。超过一半的患者有可检测到的99mTc-sestamibi肿瘤摄取增加。我们开展一项新的tariquidar试验的目的是收集更多关于tariquidar与一种化疗药物联合使用的安全性的数据，并确定一种可以作为单一药物使用的组合。多西他赛被选为一种极好的Pgp底物，具有已知的疗效，可以通过增加肺癌、宫颈癌或卵巢癌的药物积累而受益。在计划多西他赛与tariquar的相互作用试验时，我们选择了一个有效但保守的多西他赛剂量- 75 mg/m2，每q-3周。该试验设计了药代动力学和药效学分析。为了检查他奎达是否会干扰多西他赛的清除，将对多西他赛加用和不加用他奎达的剂量进行仔细的药代动力学研究。为了限制患者在没有调节剂的情况下治疗的时间长度，研究的药代动力学部分以两次40mg /m2的多西他赛剂量进行，间隔一周。给药顺序在第1天和第8天之间随机分配。患者开始以75 mg/m2的剂量治疗，每3周，在第二个周期中联合tariquidar。除了药代动力学分析，99mTc-sestamibi研究在每个入组患者中进行，有或没有tariquidar，我们的实验室在外周单核细胞中进行CD56+罗丹明测定。该试验是开放的，患者无重大毒性，迄今已有16名患者入组。尽管99mTc-sestamibi研究提供了很好的概念证明，表明在tariquida后放射性核素积累增加，但这些研究的定量很差，因为它们是平面图像，背景往往压倒差异。在Peter Herscovitch的带领下，临床中心PET部门开发了一种用9400 mtc标记sestamibi用于正电子发射成像的方法，有望成为一种更定量的显像剂。该药物的临床试验已经获得了IRB的批准，FDA的批准正在等待中。我们期待从Tito Fojo的肾上腺皮质癌和肾细胞癌试验中招募患者，以及上述的tariquidar试验。我们希望定量PET成像能让我们更好地回答tariquar对患者肿瘤有多大影响的问题。可以认为，他魁达是最有希望进入临床开发的Pgp抑制剂。志愿者研究表明其缺乏内在毒性，CD56+试验表明Pgp抑制的持久性，并且检测到对细胞色素P450的抑制很小或没有抑制。药代动力学相互作用研究表明，迄今为止与tariquar联合试验的三种抗癌药物（长春瑞滨、阿霉素或紫杉醇）对清除率的影响最小。然而，一个值得关注的问题是抑制Pgp本身可能会增加对表达Pgp的骨髓干细胞的毒性。这可能由于没有药代动力学相互作用的药效学作用而导致毒性。因此，Pgp抑制剂的未来发展取决于安全性和有效性的证明。除了对tariquidar的研究外，我们的实验室还对其他模型系统的耐药性保持着兴趣。几年前，我们与NCI的发育治疗项目合作，基于对60个细胞系的细胞毒性数据进行比较分析，确定了一些对肾细胞癌具有选择性的化合物。这些化合物在我们的实验室进行了评估，并证实了肾脏选择性。其中一类化合物，二甲烷磺酸盐，一直在DTP的临床前开发中，并且正在接近可以考虑进行临床试验的点。

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 have been carried out collaboratively with Dr. Tito Fojo and 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 this field. 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.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 in combination with a chemotherapeutic agent and to identify a combination that could be used as a single agent. 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 is 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. To limit the length of time that a patient is treated without the modulator, the pharmacokinetic portion of the study is carried out on two 40 mg/m2 docetaxel doses, one week apart. The order of administration of tariquidar is randomized between the day 1 and day 8 doses. Patients begin therapy with 75 mg/m2 q-3-weeks in combination with tariquidar in the second cycle. 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 is open and accruing patients without major toxicity, with 16 patients enrolled to date.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 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 received IRB approval, with FDA approval pending. We anticipate enrolling patients from Tito Fojo's adrenocortical and renal cell cancer trials, as well as the tariquidar trial described above. 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. It can be argued that tariquidar is the most promising Pgp inhibitor to enter clinical development. Volunteer studies showed its lack of intrinsic toxicity, CD56+ assays suggest durability of Pgp inhibition, and minimal or no inhibition of cytochrome P450 has been detected. Pharmacokinetic interaction studies suggested minimal impact on the clearance of the three anticancer agents tested in combination with tariquidar to date: vinorelbine, doxorubicin, or paclitaxel. However, one concern is the possibility that inhibition of Pgp per se may increase toxicity to Pgp-expressing bone marrow stem cells. This could result in toxicity due to a pharmacodynamic effect without a pharmacokinetic interaction. Thus, the future development of Pgp inhibitors depends upon demonstration of safety as well efficacy. In addition to the tariquidar studies, our laboratory has maintained an interest in 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 are nearing the point at which clinical trials can be considered.