Date of Graduation
8-2015
Document Type
Thesis (MS)
Program Affiliation
Biomedical Sciences
Degree Name
Masters of Science (MS)
Advisor/Committee Chair
Anil K. Sood
Committee Member
Gary E. Gallick
Committee Member
Prahlad Ram
Committee Member
Wei Hu
Committee Member
Pratip Bhattacharya
Abstract
Purpose: The PI3K/AKT/P70S6K pathway is an attractive therapeutic target in ovarian and uterine malignancies due to its high rate of dysregulation and key roles in tumor growth. Here, we examined the biological effects of MSC2363318A, which is a novel inhibitor of AKT1, AKT3, and P70S6K.
Experimental Design: Orthotopic murine models of ovarian and uterine cancer were utilized to study the effect of MSC2363318A on survival and regression. Moreover, in vitro experiments (MTT, Western blot analysis, plasmid transfection, and reverse phase protein array [RPPA]) were carried out to characterize underlying mechanisms and potential biomarkers of response.
Results: MSC2363318A decreased tumor growth and metastases in multiple murine orthotopic models of ovarian (SKOV3ip1, HeyA8, and Igrov1) and uterine (Hec1a) cancer and reduced proliferation (Ki67) and angiogenesis (CD31) indices and increased cell death (cleaved caspase-3) markers. Synergy between MSC2363318A and paclitaxel was observed in vitro in protected (IC50 ≥ 5 µM) cell lines. RPPA identified YAP1 as a candidate marker to predict cell lines that were most sensitive to MSC2363318A (R=0.675, p=0.0015). After establishment of a bevacizumab resistant endothelial cell line, RF-24, we demonstrate that resensitization to bevacizumab occurs with the addition of MSC2363318A.
Conclusions: MSC2363318A has therapeutic efficacy in multiple pre-clinical models of ovarian and uterine cancer. These findings support clinical development of dual AKT/P70S6K inhibition.
Keywords
ovarian cancer, uterine cancer, AKT inhibitors, YAP1, P70S6K, angiogenesis, bevacizumab, adaptive resistance