Our Science – Widemann Website
Brigitte C. Widemann, M.D.
Anticancer drug discovery and development are moving towards a more rational and targeted approach. The application of new molecularly targeted agents to the treatment of childhood cancers and neurofibromatosis type 1 (NF1) is a research objective of the Pharmacology and Experimental Therapeutics Section (PETS). In addition to studying the pharmacology, pharmacokinetics, pharmacodynamics, and toxicities of these novel agents, it is also a goal of the PETS to evaluate novel clinical trial designs and trial endpoints, which may be more applicable for molecularly targeted agents. The clinical development of farnesyltransferase inhibitors (FTI), which inhibit the posttranslational farnesylation required for the activity of wild-type and mutant ras proteins for patients with NF1 and refractory leukemias serves as an example for this approach. Pharmacodynamic endpoints that assess the effect of FTI on the target enzyme and farnesylation of cellular proteins are important endpoints of these trials. The clinical development of antimetabolites, such as raltitrexed, and agents that modulate the effects of antimetabolites, such as the recombinant bacterial enzyme, carboxypeptidase-G2 (CPDG2), is another research focus. CPDG2 hydrolyzes methotrexate (MTX) to inactive metabolites. CPDG2 provides an alternative route of elimination for MTX for patients with high-dose MTX- induced renal dysfunction, and plasma MTX concentrations declined by >95 percent within minutes in all patients. The intrathecal administration of CPDG2 has also been successfully used as a rescue agent in patients who received accidental overdoses of intrathecal MTX. A new drug application for the use of CPDG2 in HDMTX-induced renal dysfunction will be filed based on our data.
We have collaborated with Robert Arceci, Johns Hopkins Oncology Center, Baltimore, MD; Frank Balis, T. Fojo, Elizabeth Fox, and Kathy Warren, NIH; Jean Belasco, Children's Hospital of Philadelphia; Susan Blaney, Baylor University; Stewart Goldman, Children's Memorial Hospital, Chicago, IL; David Gutmann, Washington University School of Medicine, St. Louis, MO; Douglas Hyder, Children's Hospital of Los Angeles; Regina Jakacki, Children's Hospital of Pittsburgh, PA; Mark Kieran, Dana-Farber Cancer Institute; Bruce Korf, Partners Center for Human Genetics, Boston, MA; Roger Packer, Children's Hospital National Medical Center; and Gregory Reaman, Children's Oncology Group.
This page was last updated on 2/26/2013.