Resminostat plus sorafenib in hepatocellular carcinoma (HCC) as apotential new treatment approach in platelet-driven solid tumors.

Abstract

e14571 Background: A phase I/II clinical trial in advanced hepatocellular carcinoma (HCC) conducted by Yakult Honsha (NCT02400788) indicated the combination of the HDAC inhibitor resminostat and sorafenib was beneficial compared to sorafenib for patients with a platelet count ≥150.000/µl at baseline. In line with the role of platelets in tumor progression, in HCC, high platelet count is linked to bad prognosis, increased tumor size and metastasis, e.g. via induction of epithelial-to-mesenchymal transition (EMT), as well as to resistance against sorafenib, the current standard of care first-line treatment in HCC. Methods: To provide a preclinical rationale for the observed benefit, different HCC cell lines were used to investigate the role of platelets and interplay with the compounds. Results: While the potency of sorafenib was counteracted by platelet factors, resminostat´s anti-proliferative activity was not affected by platelets. A key feature of cancer is cellular invasiveness, a prerequisite of metastasis. Using in-vitro invasion assays, we observed that platelets increased the invasive capacity of HCC cells. The combination of resminostat and sorafenib, but not monotherapy treatments, counteracted platelet-induced cell invasion. Conclusions: Resminostat’s anti-proliferative effects, even in sorafenib insensitive cells together with block of platelet-induced invasion of HCC cells by the combination could explain the observed benefit for the combination treatment in advanced HCC patients with a platelet count ≥150.000/µl at baseline. As platelets play a critical role in tumor progression, EMT and metastasis not only in HCC but also in other solid tumor indications, our data suggest the combination of resminostat and multi-kinase inhibitor as a promising regimen for the treatment of solid tumors, especially in platelet-driven extensive disease.