Small molecular inhibitors of p-STAT3: novel agents for treatment of primary and metastatic CNS cancers

Abstract

High-grade primary and metastatic central nervous system (CNS) tumors are common, deadly, and refractory to conventional therapy and have a median survival duration of less than one year. A key transcriptional factor, signal transducer and activator of transcription (STAT) 3, drives the fundamental components of tumor malignancy and metastases in the CNS. STAT3 promotes this tumorigenesis by enhancing proliferation, angiogenesis, invasion, metastasis, and immunosuppression. The clinical implementation of drugs that specifically target malignancy within the CNS is clearly a major unmet need. A group of potent, small molecule inhibitors of STAT3 display marked efficacy with minimal toxicity against malignancy in murine models, including established intracerebral tumors. The mechanism of this in vivo efficacy of the STAT3 blockade agents is a combination of direct tumor cytotoxicity and immune cytotoxic clearance. Given their ability to achieve good CNS penetration, these drugs will be taken forward into clinical trials for patients with CNS malignancies and as immunotherapeutic enhancers.