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.
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