bortezomib + sorafenib

Bortezomib + sorafenib is an investigational combination therapy consisting of two small molecule drugs with distinct but potentially synergistic antineoplastic mechanisms. Bortezomib is a reversible inhibitor of the 26S proteasome, disrupting protein degradation and leading to cell cycle arrest and apoptosis, primarily through inhibition of NF-κB signaling and related pathways. Sorafenib is a multi-targeted kinase inhibitor that blocks tumor proliferation by inhibiting RAF kinases (including Raf-1 and B-Raf) as well as several receptor tyrosine kinases involved in angiogenesis (such as VEGFRs, PDGFR-β, FLT3, KIT, RET). Preclinical studies have shown that the combination can synergistically induce mitochondrial injury and apoptosis in various solid tumor and leukemia cell lines by modulating multiple signaling pathways including Akt inhibition. Clinically, this combination has been evaluated in phase 1/2 trials for advanced solid tumors, renal cell carcinoma (RCC), acute myeloid leukemia (AML), multiple myeloma (MM), and other malignancies[1][2][4][8]. The recommended phase 2 dose established was sorafenib 200 mg twice daily continuously with bortezomib 1 mg/m² intravenously on days 1, 4, 8, and 11 every 21 days[1][2]. While some preliminary efficacy was observed—such as partial responses or stable disease—the overall clinical benefit has been limited; further development for certain indications like RCC has not been recommended due to lack of sufficient efficacy[8].