Ipatasertib, an oral AKT inhibitor, in combination with Bevacizumab exhibits anti-tumorigenic effects in pre-clinical studies for endometrioid endometrial cancer: Endometrial Cancer Molecularly Targeted Therapy Consortium (045)

Abstract

Objectives: Ipatasertib (IPAT) is an orally administered selective protein kinase B (AKT) inhibitor that has demonstrated clinical activity in triple-negative breast and metastatic prostate cancer. The PI3K/AKT pathway is altered in the vast majority of endometrioid endometrial cancers (ECs). Prior preclinical research has shown that IPAT alone can significantly inhibit cell proliferation, induce apop-tosis and cellular stress in human endometrioid EC cell lines, and reduce tumor growth in a transgenic mouse model of endometrioid EC. Bevacizumab, a VEGF-A inhibitor, has shown clinical activity as a single agent in treating recurrent or progressive endometrial cancer; however, it showed no added benefit in combination with traditional chemotherapy. We aimed to evaluate the antitumorigenic effects of IPAT in combination with Bevacizumab in the LKB1fl/flp53fl/fl genetically engineered mouse model of endometrioid EC. Methods: LKB1fl/flp53fl/fl mouse model of EC was used to evaluate the effect of IPAT with Bevacizumab on endometrial tumor growth. The mice were fed a normal diet. At eight weeks of age, AdCre was injected into one side of the uterus to induce an endometrial tumor. The mice were divided into four groups (15 mice/group): Control, IPAT, B20 (Bevacizumab), and IPAT+B20 groups. The mice were treated with placebo, IPAT (50mg/kg daily intraperitoneally [IP]), B20 (5 mg/kg, IP, twice a week), or combination for four weeks starting eight weeks after AdCre injection. Immunohistochemistry was used to determine the expression of Ki67 in EC tumors. Results: Treatment with IPAT, B20, and the combination each significantly inhibited tumor growth compared to the control group in LKB1fl/flp53fl/fl mice, with a reduction in tumor weight of 79.1%, 83.8%, and 89.2%, respectively (p<0.05). The combination treatment significantly reduced tumor weight compared to IPAT or B20 groups (p<0.01). During treatment, the mice showed normal activity, tolerating the treatment well. Immunohistochemistry results demonstrated that the expression of Ki67 was significantly decreased in endometrial tumors in IPAT, B20 and the combination treatment groups compared to the control group (p<0.05). Conclusions: The combination of IPAT and Bevacizumab reduced tumor growth in a transgenic mouse model of endometrioid EC. These results suggest that the combination of IPAT with Bevacizumab is worthy of further exploration in clinical trials for EC. Objectives: Ipatasertib (IPAT) is an orally administered selective protein kinase B (AKT) inhibitor that has demonstrated clinical activity in triple-negative breast and metastatic prostate cancer. The PI3K/AKT pathway is altered in the vast majority of endometrioid endometrial cancers (ECs). Prior preclinical research has shown that IPAT alone can significantly inhibit cell proliferation, induce apop-tosis and cellular stress in human endometrioid EC cell lines, and reduce tumor growth in a transgenic mouse model of endometrioid EC. Bevacizumab, a VEGF-A inhibitor, has shown clinical activity as a single agent in treating recurrent or progressive endometrial cancer; however, it showed no added benefit in combination with traditional chemotherapy. We aimed to evaluate the antitumorigenic effects of IPAT in combination with Bevacizumab in the LKB1fl/flp53fl/fl genetically engineered mouse model of endometrioid EC. Methods: LKB1fl/flp53fl/fl mouse model of EC was used to evaluate the effect of IPAT with Bevacizumab on endometrial tumor growth. The mice were fed a normal diet. At eight weeks of age, AdCre was injected into one side of the uterus to induce an endometrial tumor. The mice were divided into four groups (15 mice/group): Control, IPAT, B20 (Bevacizumab), and IPAT+B20 groups. The mice were treated with placebo, IPAT (50mg/kg daily intraperitoneally [IP]), B20 (5 mg/kg, IP, twice a week), or combination for four weeks starting eight weeks after AdCre injection. Immunohistochemistry was used to determine the expression of Ki67 in EC tumors. Results: Treatment with IPAT, B20, and the combination each significantly inhibited tumor growth compared to the control group in LKB1fl/flp53fl/fl mice, with a reduction in tumor weight of 79.1%, 83.8%, and 89.2%, respectively (p<0.05). The combination treatment significantly reduced tumor weight compared to IPAT or B20 groups (p<0.01). During treatment, the mice showed normal activity, tolerating the treatment well. Immunohistochemistry results demonstrated that the expression of Ki67 was significantly decreased in endometrial tumors in IPAT, B20 and the combination treatment groups compared to the control group (p<0.05). Conclusions: The combination of IPAT and Bevacizumab reduced tumor growth in a transgenic mouse model of endometrioid EC. These results suggest that the combination of IPAT with Bevacizumab is worthy of further exploration in clinical trials for EC.