Abstract
PurposeRegorafenib, an oral multikinase inhibitor, has demonstrated survival benefit in metastatic colorectal cancer (mCRC) patients that have progressed after all standard therapies. However, novel strategies to improve tolerability and enhance anti-cancer efficacy are needed.Experimental designWe have evaluated in vitro the effects of regorafenib in combination with silybin, a biologically active component extracted from the seeds of Silybum marianum, in a panel of human colon cancer cells. Furthermore, we have prospectively treated a cohort of 22 refractory mCRC patients with regorafenib plus silybin.ResultsTreatment with regorafenib determined a dose-dependent growth inhibition whereas treatment with silybin had no anti-proliferative effects among all cancer cells tested. The combined treatment with regorafenib and silybin induced synergistic anti-proliferative and apoptotic effects by blocking PI3K/AKT/mTOR intracellular pathway. Moreover, combined treatment with regorafenib and silybin increased the production of reactive oxygen species levels within cells. In an exploratory proof of concept clinical study in a cohort of 22 mCRC patients after failure of all standard therapies, the clinical activity of regorafenib in combination with silybin was assessed. A median progression-free survival of 10.0 months and a median overall survival of 17.6 months were observed in these patients. These results suggest that the combined treatment potentially increases the clinical efficacy of regorafenib. Moreover, due to its anti-oxidative properties, silybin could protect patients from drug-induced liver damages, allowing to continue an effective anti-cancer therapy.ConclusionsThe present study suggests that silybin in combination with regorafenib is a promising strategy for treatment of metastatic colorectal patients.
Highlights
Novel advances in metastatic colorectal cancer therapies have led over the last two decades to an increase in median overall survival (OS) of patients from 12 months, during the 5-fluoruracil (5-FU)-based chemotherapy era to approximately 30 months due to development of new therapeutic agents [1,2]
Experimental design: We have evaluated in vitro the effects of regorafenib in combination with silybin, a biologically active component extracted from the seeds of Silybum marianum, in a panel of human colon cancer cells
These results suggest that the combined treatment potentially increases the clinical efficacy of regorafenib
Summary
Novel advances in metastatic colorectal cancer (mCRC) therapies have led over the last two decades to an increase in median overall survival (OS) of patients from 12 months, during the 5-fluoruracil (5-FU)-based chemotherapy era to approximately 30 months due to development of new therapeutic agents [1,2] In this scenario, regorafenib is an oral multikinase inhibitor that targets different protein kinases involved in key oncogenic pathways, such as angiogenesis by blocking vascular endothelial growth factor receptor-1 (VEGFR-1), 2 and 3 and tyrosine kinases, immunoglobulin and epidermal growth factor (EGF) homology domain 2 (TIE-2) tyrosine kinase; such as tumor progression by inhibition KIT, RET, RAF-1 and BRAF; and such as tumor microenvironment by blocking platelet derived growth factor receptor-β (PDGR-β) and fibroblast growth factor receptor (FGFR) tyrosine kinases [3,4]. The toxicity profile, including liver toxicity, fatigue and hand and foot skin reactions (HFSR), has limited drug use in clinical practice [8] These concerns have produced an urgent need for the identification of compounds that are able to limit regorafenib side effects and, for improving regorafenib tolerability and, at the same time, enhancing its clinical activity. We have explored the potential clinical role of combined treatment in a prospective cohort of 22 mCRC patients that have progressed following administration of all available standard therapies
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