PR-104 + sorafenib

PR-104 + sorafenib is a combination of two investigational anti-cancer agents evaluated primarily for advanced hepatocellular carcinoma (HCC). PR-104 is a phosphate ester dinitrobenzamide mustard pre-prodrug that is rapidly hydrolyzed in the body to PR-104A, which is then activated under hypoxic conditions or by aldo-keto reductase 1C3 (AKR1C3) to form cytotoxic nitrogen mustards. These metabolites crosslink DNA, leading to cell death, particularly in hypoxic tumor cells[6][8]. Sorafenib is an oral multikinase inhibitor that blocks several kinases involved in tumor cell proliferation and angiogenesis, including RAF kinases and vascular endothelial growth factor receptors (VEGFR)[1][5]. The rationale for combining these drugs was based on the observation that sorafenib can increase intratumoral hypoxia, potentially enhancing the activity of hypoxia-targeted agents like PR-104[4]. However, clinical studies found this combination poorly tolerated due to significant toxicities such as thrombocytopenia and neutropenia; development for HCC was discontinued[3][7].

Brand names

Nexavar

Other names

PR104PR-104PR 104