Development of Mouse Models of Ovarian Cancer for Studying Tumor Biology and Testing Novel Molecularly Targeted Therapeutic Strategies
Final rept. 1 Jul 2008-30 Jun 2011
MICHIGAN UNIV ANN ARBOR
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The objective of this project was to create genetically engineered mouse GEM models that in addition to developing ovarian carcinomas similar to human endometrioid carcinomas, also express a reporter for Caspase-3 activity, a hallmark of cells undergoing apoptosis. During the three year funding period, we generated stable lines of transgenic mice carrying a Cre-inducible luciferase reporter ROSA26LSL-Luc or apoptosis reporter ApoptosisLSL-Luc and verified function of the reporter transgenes in vivo. Using ApcfloxfloxPtenfloxfloxROSA26LSL-Luc and ApcfloxfloxPtenfloxfloxApoptosisLSL-Luc mice generated as part of this project, we demonstrated that bioluminescence imaging can be used to monitor ovarian tumor progression and drug response in vivo. In addition, we showed that ApcfloxfloxPtenfloxfloxApoptosisLSL-Luc mice can be used to image treatment-dependent induction of apoptosis. Efficacy of a targeted therapeutic agent Akt inhibitor, Perifosine, alone and in combination with a standard chemotherapeutic agent Cisplatin was evaluated. Our studies revealed that combination therapy resulted in enhanced levels of apoptosis compared to either agent alone, and suggest this may be a promising approach for treating women with advanced stage ovarian endometrioid adenocarcinomas with PI3KAktmTOR signaling pathway defects.
- Medicine and Medical Research