Anthracycline based therapy is a mainstay for many patients with solid tumor cancers. However, many of these tumors have variable levels of multiple drug resistance (MDR) transporters that reduce treatment effectiveness. The P-glycoprotein (Pgp) system specifically acts as a membrane pump to exclude anthracyclines and other common chemo therapeutics from intracellular accumulation. The activity of this transporter system can be up-regulated after exposure to anthracycline treatment and this is a suspected variable in treatment resistance and failure. In this project, we will quantify Pgp activity using a known transporter substrate, r^C]-verapamil, for tumor imaging. The uptake kinetics of this imaging agent can be used to quantify tissue Pgp activity when the tumor area under the curve from 0 to 20 min (AUC0.20) is normalized to the same AUC for blood. Imaging in sarcoma patients showed a range of [""""""""C]-verapamil kinetics in tumors. Patients with several cancer histologies undergoing anthracycline-based treatment protocols will be studied before treatment and after exposure to chemotherapy to measure the extent of acquired MDR. Careful control experiments will be needed for this study. Determine pre-treatment levels of Pgp activity in tumors using [^^C]-verapamil to test the hypothesis that tumors express a wide range of intrinsic multiple drug resistance prior to therapy. Investigate FMISO as a comparison reference for the tumor input function by normalizing the AUC for verapimil to that for FMISO. Determine the changes in tumor Pgp expression after treatment with anthracyclines using f ^C]-verapamil PET to test the hypothesis that certain tumors will show an up-regulation of Pgp transporter activity after treatment with anthracyclines. The extent of acquired MDR may or may not correlate with pre-treatment levels of [''C]-verapamll uptake. Correlate changes in f ^C]-verapamil kinetics with patient survival to test the hypothesis that patients who up-regulate their tumor Pgp activity will have shorter survival. When development of f ^C]-A(jriamycin by Proj 5 is ready for clinical studies (anticipated in yr 3), we will start comparison studies of it with [ C]- verapamil in our cancer patient groups.

Public Health Relevance

Many tumors have variable levels of multiple drug resistance (MDR) transporters: that reduce treatment effectiveness for some chemotherapy protocols. The P-glycoprotein (Pgp) system specifically acts as a membrane pump to exclude drugs from intracellular accumulation. In this project, we will quantify Pgp activity using a known transporter substrate, [[11]C]-verapamil, for tumor imaging. The uptake kinetics of this imaging agent can be used to quantify tissue Pgp activity as an important resistance factor. Imaging before treatment and after exposure to chemotherapy will measure the extent of acquired MDR and should be useful to modify chemotherapy

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA042045-24
Application #
8566989
Study Section
Special Emphasis Panel (ZCA1-RPRB-K)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
24
Fiscal Year
2013
Total Cost
$110,203
Indirect Cost
$32,957
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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