Therapeutic targeting of STAT3 pathways in pancreatic adenocarcinoma: A systematic review of clinical and preclinical literature

Abstract

Background/Objectives Pancreatic ductal adenocarcinoma is a highly lethal disease with increasing incidence. Due to high resistance, chemo/radiotherapy has limited success in pancreatic cancer and only marginally prolongs patient survival. Therefore, novel biomarkers and therapeutic targets are needed. In the present review, we performed a comprehensive summary of therapeutic approaches targeting the GP130/JAK/STAT3 pathway. Methods We systematically reviewed the PubMed and Embase databases for preclinical and clinical studies, from inception to October 4, 2020, on drugs targeting the GP130/JAK/STAT3 pathway. Bias assessments and qualitative analyses were performed. Results Twenty-five preclinical and nine clinical trials were included in the review. All preclinical studies reported a favorable outcome in terms of pancreatic ductal adenocarcinoma progression. Futhermore, drugs targeting the GP130/JAK/STAT3 pathway were shown to be efficient chemosensitizers. However, high publication bias was assumed. In the clinical setting, bazedoxifene and itacitinib improved patient outcomes. Conclusion Preclinical studies strongly suggest significant efficacy of drugs targeting GP130/JAK/STAT3 in the treatment of pancreatic ductal adenocarcinoma and that these molecules are effective chemosensitizers. Though only a few trials have shown the efficacy in a clinical setting, the STAT3 pathway remains a promising drug target for future treatment of pancreatic ductal adenocarcinoma and may help overcome chemotherapy resistance.

STAT3 in tumor fibroblasts promotes an immunosuppressive microenvironment in pancreatic cancer

“…Whereas targeting STAT3 remains a clinically promising target for solid tumors including PDAC, only a few clinical trials have shown favorable outcomes ( Peisl et al, 2021 ). However, many of these clinical studies do not examine the influence of the various STAT3 inhibitors on the stroma or immune cells ( Peisl et al, 2021 ).…”

“…Whereas targeting STAT3 remains a clinically promising target for solid tumors including PDAC, only a few clinical trials have shown favorable outcomes ( Peisl et al, 2021 ). However, many of these clinical studies do not examine the influence of the various STAT3 inhibitors on the stroma or immune cells ( Peisl et al, 2021 ). Despite many advances in the field of cancer immunotherapy, PDAC remains resistant to approved immunotherapeutic strategies, such as checkpoint inhibition therapy ( Royal et al, 2010 ; Brahmer et al, 2012 ).…”

5-epi-Sinuleptolide from Soft Corals of the Genus Sinularia Exerts Cytotoxic Effects on Pancreatic Cancer Cell Lines via the Inhibition of JAK2/STAT3, AKT, and ERK Activity

“…STAT3 is constitutively activated in pancreatic cancer via phosphorylation of Tyr705, as found in human tumor specimens as well as in various pancreatic cancer cell lines [49,50]. An increasing number of studies have shown that STAT3 activation plays a pivotal role in the progression, metastasis, and drug resistance of pancreatic cancer [51,52].…”

STAT3 Inhibitors: A Novel Insight for Anticancer Therapy of Pancreatic Cancer

“…Some STAT3 inhibitors have not shown a clear advantage in patients with pancreatic cancer [ 123 , 124 , 134 ]. Research on STAT3 inhibitors should focus on the following points: First, although STAT3 inhibitors have achieved good results in the experimental phase currently, they are limited by the limitations of monogenic drugs and further studies could be conducted to explore their use in combination with other classical chemotherapeutic drugs to improve the single- therapy of limitations and drug resistance to monotherapy.…”

“…However, adverse events with AZD1480 occurred mainly neurologically, including dizziness, anxiety, ataxia, memory loss, hallucinations, and behavioral changes, and the cause of such adverse events is not known, leading to further clinical trials of the drug. In addition, JAK inhibitors such as momelotinib and ruxolitinib have also shown some adverse effects [ 123 ]. In patients with pancreatic cancer, 88% of patients reported grade 3 or 4 adverse events after using momelotinib [ 124 ].…”