The therapeutic potential of inhibitors of the signal transducer and activator of transcription 3 for central nervous system malignancies

Abstract

Background: High-grade primary and metastatic central nervous system (CNS) tumors are common, deadly, and refractory to conventional therapy and continue to be therapeutically challenging. A key nodal transcriptional factor, the signal transducer and activator of transcription 3 (STAT3), drives the fundamental components of tumor malignancy and metastases in the CNS by enhancing proliferation, angiogenesis, invasion, metastasis, and immunosuppression. The introduction of STAT3 inhibitors in clinical trials for this patient population is imminent.

Methods: STAT3 inhibitors have been extensively tested in a variety of preclinical murine models.

Results: The STAT3 inhibitor, WP1066, has displayed 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.

Conclusions: Given their direct antitumor cytotoxic effects, STAT3 inhibitors may exert therapeutic activity in the monotherapy setting but may also have compelling use as immunotherapeutic modulators or as a salvage therapy.

Keywords: Central nervous system; cytotoxic agent; glioma; immunotherapy; metastasis; signal transducer and activator of transcription 3.