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。我们的临床试验包括对常规药物（如p -糖蛋白介导的药物）的耐药性抑制研究，以及旨在直接改善癌症治疗的新型药物（如DMS612）的研究。许多临床试验已经评估了p -糖蛋白的抑制作用，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。在这里和全球各地进行的试验中，这种逆转耐药性的治疗策略（即添加抑制剂来逆转耐药性）令人失望。尽管如此，在药物摄取研究方面的持续努力是有必要的——很少有国家或国际层面的研究真正质疑癌症中的药物摄取。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。我们研究了第三代抑制剂tariquar （XR9576）和CBT-1。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。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。该试验已完成，患者治疗无重大毒性。我们对非小细胞肺癌患者的疾病反应感到鼓舞。一个与CBT-1类似的研究现在也完成了。药代动力学研究已在William Figg博士的小组中完成。这些研究表明，大多数患者的药代动力学相互作用很小。然而，有一些异常值的患者比其他患者对钾代钾的影响更大。有趣的是，基因型分析的早期结果表明，异常患者表现出变异的单核苷酸多态性。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。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，我们还启动了与Robert Innis博士、Pete Choyke博士和Karen Kurdziel博士的合作，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。Jim Doroshow博士也在准备放射性标记的拉帕替尼，这是一种可以检测中枢神经系统中酪氨酸激酶抑制剂摄取的药物。这些PET研究为该领域的重大发展提供了机会。这些研究也为提出更普遍的问题提供了机会，即评估肿瘤组织中药物摄取的患者间差异。治疗医生的假设是患者在肿瘤中有统一的抗癌药物摄取。这个问题从未被系统地研究过。我们希望放射标记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对抗癌药物的摄取问题。这是我们小组的一个新领域，但与我们对ABC转运蛋白的研究直接相关，因为这些转运蛋白构成了一些阻碍药物积累的血脑屏障。在这项工作中，我们将加入一个正在进行的合作，其中包括博士。Pat Steeg和JoAnne Zujewski。中枢神经系统转移的研究很难进行。我们已经起草了一份LOI来研究一种共轭紫杉烷，该紫杉烷有望由于共轭物而具有优先的中枢神经系统摄取。这份意向书将很快提交；然而，找到一个适合“机会之窗”研究的患者群体，在确定治疗前测量CNS转移对化疗的反应将是具有挑战性的。然而，这是一个关键的研究领域——接受常规中枢神经系统放射治疗的患者有长期认知问题的风险，特别是随着中枢神经系统疾病的控制增加。因此，这又是一个校内项目可以做出重大贡献的领域——具有重要长期影响的高风险研究。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，并积累患者。到目前为止没有毒性。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。迄今为止，伊夫·波米耶博士的实验室已经取得了成功，克里斯托弗·雷登博士已经在血液和毛囊样本中记录了DNA损伤的证据。明年将开展的临床试验包括与罗米地辛的联合研究，以及脑转移药物渗透研究。

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, intended to directly improve treatment of cancer. A number of clinical trials have evaluated 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 here and across the globe, there has been much disappointment in this therapeutic strategy of drug resistance reversal, ie adding an inhibitor to reverse drug resistance. Nonetheless, continued effort in the study of drug uptake is warranted -- few if any studies on national or international level actually query drug uptake in cancer. 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 have studied the third generation inhibitors tariquidar (XR9576) and CBT-1. 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 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 completed, and patients were treated without major toxicity. We were encouraged by the disease responses in patients with nonsmall cell lung cancer. A similar study with CBT-1 is also now complete. Pharmacokinetic studies have been completed in Dr. William Figg's group. These studies show that pharmacokinetic interactions are minimal in the majority of patients. However, there are outliers who have a greater impact of tariquidar on PK than the remaining patients. Interestingly, early results from genotype analysis suggest that the patients who are outliers exhibit variant single nucleotide polymorphisms. 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. 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 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 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. Dr. Jim Doroshow is also preparing radiolabeled lapatinib, an agent that may make it possible to examine tyrosine kinase inhibitor uptake in CNS. These PET studies offer the opportunity to move the field forward in a significant way. These studies also offer the opportunity to ask the more general question - namely 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 is a new area for our group, but directly relevant to our work with ABC transporters, since these comprise some of the blood-brain barrier obstacle to drug accumulation. In this work 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 drafted an LOI to study a conjugated taxane that promises to have preferential CNS uptake due to the conjugate. This LOI will be submitted soon; however finding a patient population amenable to a "window of opportunity" study in which CNS metastasis response to chemotherapy measured before definitive therapy will be challenging. However, this is a critical research area -- patients who have conventional CNS radiation are at risk for long-term cognitive problems, particularly with increasing control of CNS disease.Thus, again this 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. No toxicity to date. 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 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. Clinical trials to be developed in the coming year include combination studies with romidepsin, and brain metastasis drug penetration studies.