The investigator's recent studies have implicated the selective interaction of geldanamycin (GA) with certain cellular heat shock proteins in mediating anti-tumor activity, but the specific molecular consequences of this interaction in clinically relevant tumor models remain unclear. In this application, studies are proposed which will examine GA effects on the assembly and function of two heat shock protein-containing multimolecular complexes known to be important in the biology of many breast cancers; namely, the estrogen receptor (ER) and mutant p53. Reconstitution experiments using reticulocyte lysate will be used to identify the specific components of the ER and p53 complexes and assess drug effects on the dynamics of complex assembly. At the whole-cell level, GA effects on steady state-expression, subcellular localization and transcriptional transactivating activity of the two targets will be examined. Lastly, p53 and ER expression will be examined in breast tumor xenografts growing in SCID mice treated with GA. These experiments should define useful biologic endpoints for drug action in vivo and will allow assessment of the significance of the molecular effects observed in tissue culture for tumorigenicity in animals.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA069537-03
Application #
2700656
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Johnson, George S
Project Start
1996-05-01
Project End
2001-04-30
Budget Start
1998-05-01
Budget End
1999-04-30
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Arizona
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85721