Clinical Studies to Circumvent Drug Resistance

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，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，在治疗策略上有很多令人失望的地方。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。该项目对于多种肿瘤类型具有高风险和潜在的高收益，因此非常适合NCI内部项目。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试验的目的是在多国毒性试验结束后，收集更多关于tariquidar安全性的数据。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。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。该试验刚刚完成了最大累积，患者的治疗没有出现重大毒性。我们对非小细胞肺癌患者的疾病反应感到鼓舞。我们完成了宫颈癌和卵巢癌的累积，没有证据表明主要活性或毒性。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博士的带领下，临床中心PET部门开发了一种用94mTc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。该药物的临床试验是开放的，并增加了患者。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。除了PET-sestamibi试验外，我们还与Robert Innis博士和Karen Kurdziel博士讨论了合作，旨在使用PET制剂11c - n -去甲基-洛哌丁胺和18f -紫杉醇评估药物积累。这些PET研究为该领域的重大发展提供了机会。除了tariquidar的研究，CBA Pharma是一家开发Pgp抑制剂CBT-1的小公司。这是一种经过临床试验的口服药物。然而，该药物对Pgp的抑制作用此前并未在患者中得到证实。我们已经完成了一项临床试验，检查了Pgp抑制的替代标志物，包括在接受紫杉醇和CBT-1治疗的患者中循环CD56+单核细胞中sestamibi摄取的改变和罗丹明摄取的增加。这项小型试验在大约1年内完成。我们的实验室也对研究其他模型系统的耐药性保持兴趣。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。一种新的化合物，二甲烷磺酸盐，一直在DTP的临床前开发中，其中一种化合物，NSC-281612，已被批准进行I期试验。第一阶段的试验现在在美国国立卫生研究院临床中心开放。该研究是一项多机构一期试验，其中一个地点在匹兹堡大学，另一个地点在好时医学中心。I期试验的目标之一是开发生物标志物，以评估DMS化合物治疗后肿瘤细胞或替代组织中DNA损伤的存在。考虑到开发用于逆转耐药性的耐药调节剂的困难，另一种策略是为非多药转运体底物的已知靶点选择药物。最近FDA批准的ixabepilone就是这种策略的一个例子。这种微管蛋白靶向化合物的开发部分是因为它与p -糖蛋白缺乏相互作用，希望它能在紫杉烷受药物外排机制限制的地方有效。与FDA批准的topotecan和伊立替康相比，第二代拓扑异构酶I抑制剂diflomotecan的开发也采用了类似的策略，它不是多药转运体ABCG2外排的底物。我们的目标是开发这种化合物用于耐药肿瘤，包括肺癌、胰腺癌和乳腺癌的三阴性或基底癌。

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 was not previously confirmed in patients. We have completed 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. This small trial was completed in approximately 1 year. 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. The study is a multi-institutional Phase 1 trial with one site at University of Pittsburgh and the other at Hershey Medical Center. 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. 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 characterizes the development of diflomotecan, a second generation topoisomerase I inhibitor that, in contrast to the FDA approved agents topotecan and irinotecan, is not a substrate for efflux by the multidrug transporter ABCG2. Our goal is to develop this compound for use in drug resistant tumors including lung, pancreas, and the subset of breast cancer known as triple negative or basal.