Novel STAT 3 inhibitors for treating gastric cancer

ABSTRACT

Introduction: Advanced gastric cancer has a poor prognosis, with a median survival of approximately 12 months. There is a continued need to explore the use of novel treatments for this disease. STAT3 inhibitors are under evaluation in a number of early phase trials, some showing promise in gastric cancer.

Areas covered: This article explores the role of STAT 3 in gastric cancer and highlights some early phase clinical trials on STAT3 inhibition. The STAT3 protein and signalling pathway are discussed. STAT3 in the pathogenesis of gastric cancer is reviewed; pre-clinical data on the role of STAT3 in the development of cancer is presented together with early and emerging data on STAT3 inhibitors under investigation in the clinical setting. In this review, the authors searched PubMed, clinicaltrials.gov and ASCO abstracts on STAT3 inhibitors, focusing on trials recruiting gastric cancer patients.

Expert opinion: Activated STAT3 in gastric cancer is correlated with poor survival. It plays a critical role in regulating tumour growth and metastases. STAT3 inhibitors are emerging as an interesting drug in gastric cancer. However, trials utilising these agents remain in their early phase with one agent currently under evaluation in the phase III setting.

KEYWORDS:

• Gastric cancer
• STAT3
• STAT3 inhibitor

Article highlights

• STAT3 is a cytoplasmic transcription factor

• STAT3 controls transcription of key genes involved in cell proliferation, apoptosis, inflammatory response and angiogenesis.

• Activated STAT3 protein expression has been noted in 30-70% of gastric cancers.

• Phosphorylated STAT3 in gastric cancer is correlated to differentiation, stage of disease, lymph node metastases and poor survival.

• There are a number of STAT 3 inhibitors in early phase (I-II) development in gastric cancer, with some early promising data in other gastrointestinal malignancies.

• Napabucasin is the only STAT 3 inhibitor in advanced gastric cancer under evaluation in the phase III setting, used in combination with paclitaxel.

This box summarizes key points contained in the article.

Declaration of interest

I Chau is on the advisory board off Sanofi Oncology, Eli Lilly and Company, Bristol-Myers Squibb, Merck Serono, Gilead Sciences, Merck Sharp and Dohme and Janssen-Cilag. He has also received research funding from Sanofi Oncology, Roche, Merck Serono and Novartis as well as honorarium from Taiho Pharmaceutical Co. Ltd, Pfizer Inc, Amgen Inc and Bayer Healthcare. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.