Napabucasin: An Update on the First-in-Class Cancer Stemness Inhibitor

Napabucasin (BBI608) is an orally administered small molecule that blocks stem cell activity in cancer cells by targeting the signal transducer and activator of transcription 3 pathway. The signal transducer and activator of transcription 3 pathway is over-activated in many types of cancer and has been shown to be an important pathway in cancer stem cell-mediated propagation of cancer. Cancer stem cells are a subpopulation of cancer cells considered to be the primary source of tumor growth, metastasis, and resistance to conventional therapies, and thus, responsible for cancer relapse. This review describes the clinical development program of this first-in-class cancer stemness inhibitor, including preclinical discovery, early clinical trials, current phase III clinical trial evaluation, and future therapeutic combinations. The therapeutic potential of napabucasin was first reported in a preclinical study that demonstrated the potent anti-tumor and anti-metastatic activity of napabucasin in several different cancer types, both in vitro and in vivo. In mouse models, napabucasin was effective both as a monotherapy and in combination with other agents; in particular, synergy was observed with paclitaxel in vivo. Napabucasin clinical trials have demonstrated encouraging anti-tumor activity as monotherapy and in combination with conventional therapeutics, with no significant pharmacokinetic interactions when used in combination therapies. Adverse events attributed to napabucasin have been predominantly mild, although some patients have experienced grade 3 gastrointestinal adverse events. More severe adverse events required reduced or discontinued dosing of napabucasin or medication to reverse or manage symptoms. In conclusion, napabucasin may prove useful in targeting cancer stem cells, with the potential to suppress metastasis and prevent relapse in patients with varying cancer types.