MECHANISMS OF DRUG RESISTANCE IN SOFT TISSUE SARCOMA

  • Bertino, Joseph (PI)
  • Ladanyi, Marc (PI)
  • Schwartz, Gary (PI)
  • Sander, Chris (PI)
  • Antonescu, Cristina (PI)
  • Singer, Samuel (PI)
  • Cordon-Cardo, Carlos (PI)
  • Brennan, Murray (PI)
  • Brennan, Murray (PI)
  • Brennan, Murray (PI)
  • Casper, Ephraim (PI)
  • Cordon-Cardo, Carlos (PI)
  • Brennan, Murray (PI)
  • Woodruff, James (PI)
  • Leung, Denis (PI)
  • BERTINO, JOSEPH ROCCO (PI)
  • Casper, Ephraim (PI)
  • Woodruff, James (PI)
  • Leung, Denis (PI)
  • HOUGHTON, ALAN (PI)
  • Singer, Samuel (PI)
  • Ladanyi, Marc (PI)
  • Cordon-Cardo, Carlos (PI)
  • Schwartz, Gary (PI)
  • Antonescu, Cristina (PI)
  • Sander, Chris (PI)

Project Details

Description

The major goal of this project is to explore further the relationship
between tumor suppressor gene abnormalities (retinoblastoma, p53) and drug
resistance of sarcomas. The investigators will use a modified tetracycline
inducible vector system to express Rb, E2F and mutant p53 in sarcoma cell
lines to study this relationship. In collaboration with Dr. Carlos Cordon-
Cardo (Project II) the investigators will also measure the expression of
certain cell cycle control genes (Rb, MDM-2, p 53, E2F and cyclin D) in
sarcoma tumor samples and correlate this data with results of antifolate
sensitivity (DHFR and TS inhibitors) as measured by the whole cell in situ
thymidylate synthase assay.

A major cause of inherent resistance to MTX in soft tissue sarcoma
elucidated by previous studies supported by this grant is decreased
retention, due to either defects in MTX uptake, or lack of retention due to
low levels of polyglutamate formation. The investigators plan to build on
this information and to test the concept that trimetrexate administered
together with leucovorin will be non-toxic to the host, but will be
cytotoxic to sarcoma cells with these attributes. The investigators will
test tumors propagated in SCID mice, using clinically relevant schedules
for these purpose. A third cause of decreased MTX retention will also be
studied, the lysosomal enzyme gama-glutamyl hydrolase, that converts MTX
polyglutamates to MTX. Further purification and cloning of this enzyme is
planned, and the potentiating effects of inhibitors of this enzyme to
potentiate MTX cytotoxicity determined.
StatusFinished
Effective start/end date1/1/016/30/12

ASJC

  • Medicine(all)
  • Drug Discovery
  • Genetics
  • Molecular Biology
  • Biochemistry
  • Oncology
  • Cancer Research
  • Computer Science Applications
  • Statistics and Probability
  • Pathology and Forensic Medicine
  • Statistics, Probability and Uncertainty
  • Immunology