SAN DIEGO – A novel dual AKT and P70S6K inhibitor decreased tumor growth metastases in multiple animal models of ovarian and uterine cancer, results from a novel study demonstrated. It also prolonged survival and led to regression and stabilization of tumor growth in uterine cancer mouse models.
MSC2363318A, an investigational agent being developed by EMD Serono, is a novel inhibitor of AKT1, AKT3, and P70S6K, Dr. Rebecca A. Previs said in an interview in advance of the annual meeting of Society of Gynecologic Oncology, where she would be presenting the study results. “Due to the high rate of dysregulation of the PI3K/AKT/P70S6K pathway in ovarian and uterine malignancies, we tested this compound in multiple animal models of ovarian and uterine cancer,” she said. “Dual AKT/P70S6K inhibition provides a novel therapeutic approach by promoting improved PI3K/AKT pathway inhibition while avoiding the negative effects of AKT activation through compensatory feedback loops, including IRS-1. Additionally, inhibition of two targets further downstream in a hyperactive pathway in solid malignancies could avoid the side effects seen with historical pan-PI3K inhibitors. The present investigation is the first report of this novel compound.”
Dr. Rebecca A. Previs
Dr. Previs, of the University of Texas MD Anderson Cancer Center, Houston, and her , used orthotopic murine models of ovarian and uterine cancer, and MTT, Western blot analysis, and plasmid transfection to determine the biological and mechanistic effects of MSC2363318A. High-throughput analyses were carried out to identify underlying mechanisms and biomarkers of response.
The researchers found that dual inhibition of AKT and P70S6K had therapeutic efficacy in multiple preclinical models by directly promoting apoptosis of tumor cells, halting proliferation, and reducing angiogenesis. They observed treatment synergy in both uterine and ovarian cancer types with the combination of MSC2363318A and paclitaxel, a commonly used chemotherapy drug (P less than .001). High-throughput analyses identified YAP1 as a candidate biomarker to predict cell lines that were most sensitive to MSC2363318A (P = .0015).
“Our investigation supports further clinical development of MSC2363318A in ovarian and uterine cancer patients,” Dr. Previs said. “This compound could be used in combination with paclitaxel in the frontline setting or to restore sensitivity to anti-angiogenic therapies like bevacizumab in the setting of recurrent disease.”
She acknowledged certain limitations of the study, including the fact that it used preclinical models of ovarian and uterine cancer. “Clinical proof of activity is pending upcoming trials,” she said.
Dr. Previs reported that EMD Serono provided the study drug and provided partial research support.