ZIA BC 010620 (ZIA) | |||
---|---|---|---|
Title | Clinical Studies to Circumvent Drug Resistance | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Bates, Susan | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $93,272 | Project Dates | 10/01/2003 - 00/00/0000 |
Fiscal Year | 2014 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Taxol (10.0%) |
Breast (25.0%) Kidney Cancer (25.0%) Kidney Disease (25.0%) Lung (25.0%) Non Hodgkins Lymphoma (25.0%) Urinary System (25.0%) |
||
Research Type | |||
Systemic Therapies - Discovery and Development Systemic Therapies - Clinical Applications |
|||
Abstract | |||
Project Summary I. Drug Resistance Due to Limited Drug Distribution Although our laboratory has shifted from studies of Pgp and ABCG2 in recent years to a focus on epigenetic therapies, we remain convinced that limited drug distribution likely contributes to drug resistance, and that there are likely diverse etiologies of limited drug distribution, one of which may be drug efflux pumps. This straightforward question cannot be answered: does restricted drug distribution play a role in cancer chemotherapy drug resistance? Numerous small trials measuring drug concentrations in tumor tissue, or pharmacodynamic imaging studies of labeled drug, suggest a wide range of drug distribution in cancer. We too observed variable uptake of a drug surrogate, sestamibi, in lung cancer. Nowhere is the issue of drug distribution more relevant than in the brain, where drug uptake is limited by the need to cross the blood brain barrier (BBB). Crossing the BBB requires an active process and evasion of the multidrug transporters ABCG2 and ABCB1, among other regulators of brain capillary endothelium. GRN1005 in CNS Metastases from Breast Cancer We have participated in a clinical trial of GRN1005, a novel drug conjugate that consists of three molecules of paclitaxel linked to a peptide that binds the LRP receptor. The conjugate was developed to cross the Blood Brain Barrier via transcytosis after binding the LRP receptor. Active drug is thought to be released in tumor cells when intracellular esterases cleave GRN1005 and release the free paclitaxel (107). Additionally, this conjugate is thought to evade the multidrug efflux transporters. GRN1005 (now ANG1005) was licensed by Geron Pharmaceuticals to conduct registration studies in glioblastoma and breast cancer after a positive signal in Phase I testing. We originally planned to participate in both a multi-institutional trial in breast cancer and to conduct a pilot trial that would include surgical resection of breast or lung cancer that had metastasized to the brain, to study the access of GNR1005 to metastatic lesions. Soon after the study opened, Geron announced that GRN1005 had failed to meet its first interim efficacy analysis - 0 responses among the first 30 patients accrued at 550 mg/m2 (whereas 4 of 13 patients (31%) had objective responses at 650 mg/m2). The trial was abruptly closed without further accrual; the multi-site PIs learned of this decision after the fact. However, review of data after the closure decision revealed that data were missing in 10 patients, and that the excessive toxicity that had led to the dose reduction to 550 mg/m2 included neutropenia in the absence of GCSF support. Geron returned the license for the drug to its original developer, Angiochem. Given our interest in this field, and our observation of activity of the agent in several NCI patients, we argued for and were allowed to keep open the NCI sub-study including FLT-PET imaging. We currently have one patient on study for over 8 months with a confirmed major response to GRN1005. II. A Novel Agent for Drug Resistant Cancers While there are multiple FDA-approved agents for renal cell cancer (RCC), all have a limited efficacy duration. To develop novel agents that would overcome or circumvent drug resistance without directly targeting drug efflux mechanisms, we collaborated with the NCI drug screen to identify com-pounds with particular activity in RCC in vitro and in xenografts (108,109). Although DNA appears to be the target for these compounds, they are unique as assessed by informatics evaluation. A lead compound, DMS612, was selected for Phase I, first in human studies carried out at the NCI (we serve as coordinating center), University of Pittsburgh, and Hershey Medical Center. We have tested 2 schedules - a day 1, 8, and 15 schedule that had cumulative thrombocytopenia as dose limiting toxicity, but minimal other toxicity. Two responses were observed; we are now studying a second schedule - day 1, 2 administ" |