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 is completed, 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. Pharmacokinetic studies have just 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 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 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. 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. Unfortunately, we lost Dr. Merrill Egorin to this collaboration during the last month. His thoughts and expertise will be greatly missed. 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. 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 studies including ixabepilone and a combination study with XRT.
Showing the most recent 10 out of 30 publications
