Selected Projects
Preclinical Studies of Antineoplastic Drug Metabolism and Disposition
The Facility has been critical to the successful competition for and completion of a variety of UPCI research programs. Among the most prominent of these is Contract NO1-CM-07106, "Preclinical Pharmacology Studies of Antineoplastic and Antiretroviral Agents", which is one of six such contracts funded by the NCI to develop information in support of molecules proposed for subsequent clinical trials. Since 1999, the Facility has developed and validated assays for 17-DMAG, halofuginone, B17, wortmannin, OMDPI, and benzaldehyde dimethane sulfonate. These assays have involved HPLC, as well as HPLC/MS or HPLC/MS/MS instrumentation. These assays have been applied to murine and, in some cases, rat and dog PK studies performed at the UPCI, as well as to NCI-funded toxicology programs working with the same agents as sent to the UPCI for animal pharmacokinetic studies. Four of the agents for which CPAF performed preclinical studies under this contract are currently in NCI-sponsored phase I trials.
CPFAF has also provided important support to Program Project 5P30CA047904-160002, "Molecular Therapeutics and Drug Discovery Program". Within the past year, the Facility has developed assays for JR-oxime and DA-3003-1 and then applied those assays to murine PK studies. In addition to quantitation of parent compound in plasma and other biological matrices in preclinical models, the Facility has identified numerous metabolites of many of the agents listed above.
Clinical Studies of Antineoplastic Drug Metabolism and Disposition
The Facility provides essential and critical support for the clinical trials program at the UPCI. The availability of sophisticated analytical instrumentation and PK modeling capabilities was crucial to the UPCI's successful competition for UO1-CA-099168-01, "Phase I Clinical Trials of Novel Anticancer Agents". The Facility has been highly successful in leveraging analytical chemical assays developed from preclinical models into application in clinical trials. Examples include assays for 17-AAG, 17-DMAG, paclitaxel, and halofuginone. Additional methods development in support of clinical trials involved novel LC/MS assays for paclitaxel, docetaxel, a new assay for halofuginone, and imatinib. The application of these assays in a broadbased drug development program is apparent from the accompanying list of protocols currently supported by the Facility.
Of note is the fact that the Facility also has been active in utilizing assays developed in support of clinical trials for subsequent studies in preclinical models, with the important outcome of acquisition by UPCI investigators of peer-reviewed research funding based, to some extent, on preliminary data developed with those assays. Examples of such activities include development by the Facility of HPLC and HPLC/MS/MS assays for quantitation of 9-nitrocamptothecin and its metabolite 9-aminocamptothecin in samples from a variety of clinical trials and the subsequent application of those assays in animal pharmacology studies. Preliminary data generated in animal models led to successful application by Dr. Robert Parker to the Whittaker Foundation of a grant, titled "Model-based Optimal Scheduling for Cancer Chemotherapy".
CPAF also has attempted to extend its capabilities into instrumentation not necessarily associated with destructive analytical chemical assays and instrumentation. An extensive program in non-invasive assessment of drug concentration in animal and patient tissues originated within the Facility. The Facility's development of suitable assays for quantitation of gadolinium texaphyrin and lutetium texaphyrin has been extended into comparative studies, wherein HPLC measurements of these materials are compared with other assessments made non-invasively using elastic-scattering spectrometry. These studies, performed in collaboration with Drs. Ramesh Ramanathan and John Comerci, both members of the Molecular Therapeutics and Drug Discovery Program, served as important preliminary data in support of the recently successful response of Boston University (PI: Irving Bigio) to RFA CA-003-02 application, titled "Optical Spectroscopy for Management of Cancer Treatment", in which Dr. Julie Eiseman of the Molecular Therapeutics and Drug Discovery Program is serving as P.I. on Project 3 and Dr. Egorin is serving as a Co-Investigator on the same project. Furthermore, Dr. Robert Parker is serving as Co-Director of the Technical Support Core in this grant, thereby further enhancing the analytical instrumentation available within the Facility. These assays also have provided important support to the R21, titled "Photodynamic Therapy with Lutrin™ in Cervical Dysplasia", for which Dr. Comerci is the P.I.
CPAF supports clinical research performed by several programs, including studies within the Lung SPORE and Lung and Thoracic Malignancies Program, the Brain Tumor Program, and the Prostate and Urologic Cancers Program. Specifically, the Facility is serving as a Central Reference Laboratory for Brain Tumor Consortium Protocol, NABTC 01-08, "Phase II Trial of STI571 (NSC 71605) in Patients with Recurrent Meningioma", on which Dr. Frank Lieberman of the Brain Tumor Program is a Co-Investigator. The Facility is quantitating gemcitabine concentrations in plasma and cerebrospinal fluid of patients entered onto UPCI Protocol 02-036, "Intrathecal Gemcitabine Therapy for Neoplastic Meningitis: A Phase I and Pharmacokinetic Study", which is being performed under the auspices of the Brain Tumor Program. The Facility is performing assays to quantify toremifene in plasma samples from patients entered onto UPCI Protocol 00-105, "A Phase II Randomized, Controlled Clinical Trial of the Antiestrogen GTx-006 in Subjects with Prostate Cancer",for which Dr. Joel Nelson of the Prostate and Urologic Cancers Program is the P.I. In a similar fashion, the Facility provided analytical chemical quantitation of concentrations of gemcitabine and its metabolite dFdU in plasma and urine of patients entered onto UPCI protocol 99-039, "Intravesical Gemcitabine Therapy for BCGRefractory Superficial Carcinoma of the Bladder: A Phase I and Pharmacokinetic Study", which has been published in the Journal of Clinical Oncology and is serving as the basis for a phase III study designed to register gemcitabine as intravesical therapy for superficial carcinoma of the bladder. Additional gemcitabine assays are being performed in support of UPCI Protocol 01-132, "A Phase I Study of Intrapleural Gemcitabine for Malignant Pleural Effusions", which is being performed under the auspices of the Lung and Thoracic Malignancies Program. The Facility also is functioning as a reference laboratory for NCI-sponsored studies of Gleevec and other agents. Also, the Facility is one of three reference laboratories for Cancer and Leukemia B Cooperative Group B trials.
Beyond its activities for the UPCI and the NCI, the Facility serves numerous other medical institutions and pharmaceutical companies. Academic partners include Memorial Sloan-Kettering Cancer Institute, University of Texas at San Antonio, Oregon University of Health Sciences, Medical College of Virginia, Case Western Reserve University, New York University, University of Wisconsin, Wayne State University, City of Hope, Washington University, Ohio State University, Texas Children's Hospital, University of Rochester, and the AIDS Malignancy Consortium. Industrial partners include Novartis, Eli Lilly, Bristol Myers-Squibb, and Aventis, among others. Of note, the Facility's quality and capacity has been recognized as it has been designated the central reference analytical and pharmacokinetic modeling resource for phase IV clinical studies of Gleevec.