Two therapeutic potentials for HCC managements : novel notch1 inhibitor PF-03084014 suppressed tumor growth and metastasis in HCC orthotropic model ; and CDK1 inhibitor in combination with sorafenib inhibited HCC patient-derived xenografts (PDX) tumor

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common cancer globally and the third leading cause of cancer-related death. Less than 20% of patients diagnosed with HCC have access to resection. All kinds of factor alone or combined could participate in the process of HCC tumorigenesis, including HBV, HCV, autoimmune hepatitis, alcohol, aflatoxin, vinyl chloride, hemochromatosis, diabetes mellitus, obesity, oral contraceptives and life habits. Genetic mutations as well as epigenetic alterations can silence tumor suppressor genes and activate tumor oncogenes leading to tumor aggression. Liver CSCs are one of the cause leading to heterogeneity that contribute to treatments failure. The Notch1 and Wnt/β-Catenin signaling play essential role in CSCs stemness, such as self-renewal, proliferation, differentiation and chemotherapy resistance. In our previous study, it was shown Notch1 played a crucial role in liver cancer progression. Notch1 high expression was associated with clinicopathological parameters. Using a novel Notch1 inhibitor PF-03084014, in our study I focused on liver CSCs that have been recently postulated to contribute to tumor resistance and heterogeneity. I found PF-03084014 could suppress CSCs-derived orthotopic tumor models through the Notch1-Stat3 signaling pathway. For tumor metastasis, PF-03084014 could also inhibit lung metastasis from the liver via (epithelial-mesenchymal transition) EMT process reversal. Due to the anticancer and antimetastasis effect, it illustrated that Notch1 could be a therapeutic target to inhibit by PF-03084014 to reach accepted outcomes for HCC patients. Sorafenib is the only FDA approved drug for HCC patients, and the cell cycle has important roles in tumor biology. To overcome drug resistance and find other effective therapies, I attempted to combined treatments for HCC. Sorafenib in combination with CDK1 inhibitor suppressed tumor growth on patient-derived xenograft (PDX) models via CDK1/PDK1/β-catenin. The PDX model is the most predictable tool to mimic clinical outcomes. I showed combined treatment of CDK1 inhibitor RO3306 with sorafenib had a synergistic effect on PDX cases. Moreover, the combinatorial treatment could overcome the single drug resistance, which dramatically enhanced the antitumor effect in HCC. The adverse effects of this combinatorial treatment were acceptable, which paves the way for further clinical trials. In summary, my study showed: (1) PF-03084014 targeted CSCs to inhibit tumor growth and metastasis via Notch1-Stat3 inactivation; (2) Sorafenib in the combination with CDK1 inhibitor RO3306 had synergistic antitumor effect on PDX tumor models through targeting CDK1/PDK1/β-catenin pathway. Due to the high degree of treatment correlation between the clinical and PDX models, reasonable combined therapeutic application to CDK1 aberrant HCC patient may be suggested to significantly improve the clinical outcome.