Phosphoinositide 3-kinase delta (PI3Kδ) inhibitors have shown anti-tumor efficacy in leukemia in the clinic and one such compound, idelalisib, was approved by the FDA for the treatment of relapsed chronic lymphocytic leukemia (CLL) in 2014. A novel PI3Kδ inhibitor, YY-20394, was developed with specific selectivity against PI3Kδ and inhibited PI3Kδ expressing human tumor cells growth both in vitro and in vivo. YY-20394 was then tested in orthotopic murine breast carcinoma 4T1 model in BALB/c mice. Despite mild killing against 4T1 tumor cells in vitro with an IC50 of around 28 μM, YY-20394 significantly inhibited 4T1 primary tumor growth as well as lung metastasis with dose dependency. It also extended the overall survival of 4T1 tumor bearing animals both in resection and non-resection settings. The inhibition of primary tumor growth and metastasis were attenuated in BALB/c nude mice, indicating T cells played an important role in YY-20394's anti-tumor/anti-metastasis efficacy. YY-20394 displayed significant anti-tumor efficacy in other syngeneic mouse tumor models tested including mouse colorectal cancer models MC-38 model in C57BL/c mice and CT26 model in BALB/c mice. More importantly, YY-20394 synergistically enhanced the anti-tumor efficacy of anti-PD-L1 antibody in CT26 model with 100% of the animals survived during a 60 day experimental period. YY-20394 is well tolerated by the animals with no treatment-related toxicity observed in these efficacy studies. These data suggest the YY-20394, a novel PI3Kδ inhibitor, represents a promising and safe immune modulator and shows great potential in combining with immune check point inhibitors in cancer therapies.
Citation Format: ZuSheng Xu, Yangtong Lou, Jie Tan, Chong Wang, Xiaomei Ge, Ying Gu, He Zhou. A novel PI3K delta inhibitor suppresses tumor progression by immune modulation [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B048.
- ©2016 American Association for Cancer Research.