Clinical Studies to Circumvent Drug Resistance

项目概述本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。我们的临床试验设计得到了实验室的支持，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抑制对传统药物的耐药性的研究，如P-糖蛋白介导的药物，以及旨在直接改善癌症治疗的新型药物的研究，如DMS612和GRN1005。早期的临床试验评估了P-糖蛋白的抑制作用，P-糖蛋白是一种ABC转运蛋白，通过向外转运抗癌药来调节耐药性。在这里和其他地方进行的试验中，添加一种抑制剂来逆转耐药性没有明显的好处。然而，在药物摄取的研究中继续努力是有必要的--很少有国家或国际层面的研究真正质疑癌症的药物摄取。该项目可以被认为是高风险的，对于多种肿瘤类型具有潜在的高收益，因此非常适合于NCI的壁内计划。早期的研究集中在99mTC-Sestamibi显像作为改变药物在正常组织和肿瘤组织中蓄积的替代。虽然99mTC-Sestamibi的研究提供了概念验证，表明放射性核素在正常组织中积累增加，特别是在肝脏中，但肿瘤摄取很差，而且通常不会随着Pgp抑制剂的添加而改变，这表明至少用这种方法评估药物渗透存在问题。临床中心PET部门开发了一种用于正电子发射成像的94mTC标记Sestamibi的方法，有望开发出一种更定量的显像剂。我们的临床试验测试这种显像剂是开放的，但由于缺乏药物，一年中的大部分时间都被搁置。我们希望，定量PET成像将使我们能够更好地回答塔奎达对患者肿瘤的影响有多大的问题。为什么Sestamibi在许多肿瘤患者中摄取失败，无论是否存在Tariquidar，这是一个重要的问题，并表明药物摄取独立于Pgp外排机制，可能是一个重要的新研究领域。除了PET-Sestamibi试验外，我们还开始与Robert Inennis博士、Pete Choyke博士和Karen Kurdziel博士合作，旨在评估使用PET制剂11C-N-去甲基-洛佩胺和18F-紫杉醇(FPAC)的药物累积。这些PET研究提供了在该领域取得重大进展的机会；我们将在本月招收我们的第一位患者参加FPAC研究。这些研究提供了提出更一般问题的机会--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，患者在肿瘤中对抗癌药物的摄取是一致的。这个问题从来没有被系统地研究过。我们希望放射性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。这项工作与我们与ABC转运蛋白的工作直接相关，因为这些转运蛋白构成了药物积累的一些血脑屏障障碍。在这方面，我们将加入已经在进行的合作，其中包括Pat Steig博士和JoAnne Zujeski博士。对中枢神经系统转移的研究非常困难。我们已经启动了一项关于GRN1005的研究，GRN1005是一种共轭紫杉烷，由于与LRP受体结合的多肽结合，有望通过血脑屏障摄取中枢神经系统。该化合物由Geron制药公司开发。我们已经启动了一项试点手术试验，这将使我们能够测量在使用GRN1005后，在医学上指示的外科手术中移除的中枢神经系统转移瘤中微管蛋白的稳定性。我们还参与了该公司的第二阶段疗效研究。这是当今一个关键的研究领域，患者对全身疾病的控制日益增强，中枢神经系统复发正在成为一个主要的医学问题。接受常规中枢神经系统放射治疗的患者通常并没有完全根除中枢神经系统疾病，而且还面临长期认知问题的风险，特别是随着对中枢神经系统疾病的控制日益加强。这也是内部计划可以做出重大贡献的一个领域--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中的耐药性保持着兴趣。几年前，我们与NCI的开发治疗计划合作，根据60细胞系小组的细胞毒性数据进行比较分析，确定了一些对肾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，并证实了其对肾脏的选择性。一种新的化合物类别，二甲基磺酸盐，一直在DTP的临床前开发中，其中一种，NSC-281612，被批准进行第一阶段测试。一期试验现已在美国国立卫生研究院临床中心、匹兹堡大学和好时医疗中心开放。我们已经确定骨髓毒性是主要的累积毒性，并改变了计划以减轻这种毒性。在I期有一些活动信号，宫颈癌患者有一个反应，肾癌患者有一个反应。观察到的主要毒性是血小板减少。第一阶段试验的目标之一是开发生物标记物，以评估DMS化合物治疗后肿瘤细胞或代理组织中DNA损伤的存在。到目前为止，这在伊夫·波米尔博士的实验室里是成功的，克里斯托夫·雷登博士已经记录了血液和毛囊样本中DNA损伤的证据。我们已经提交了意向书，将DMS612带到第二阶段测试。

PROJECT SUMMARY The focus of our section's research program is to develop therapeutic strategies aimed at overcoming drug resistance in cancer. 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. Earlier clinical trials evaluated inhibition of P-glycoprotein, an ABC transporter mediating resistance through outward transport of anticancer agents. In trials carried out here and in other sites, there was no clear 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. 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. Earlier studies focused on 99mTc-sestamibi imaging 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 poor and often did not change with the addition of the Pgp inhibitor, suggesting a problem with drug penetration at least assessed by this method. 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 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, the University of Pittsburgh and at Hershey Medical Center. We have identified bone marrow toxicity as the chief cumulative toxicity, and have changed the schedule to mitigate this. There were some activity signals in Phase I, one response in a patient with cervical cancer and one in a patient with renal cancer. 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. We have submitted an LOI to take DMS612 to Phase II testing.