GIP Receptor

Park JS, Hong MH, Chun YJ, Kim HR, Cho BC

Park JS, Hong MH, Chun YJ, Kim HR, Cho BC. effects in preclinical studies; however, clinical studies specifically assessing their activity against the JAK/STAT pathway in solid tumors have not yet been conducted. In summary, JAK inhibition is a viable option for targeting the JAK/STAT pathway in solid tumors and merits further testing in clinical trials. xenograft models of neuroblastoma[78,79], HCC (in which there UNC 669 was a JAK1 S703I mutation)[40], and KRAS-mutated lung adenocarcinoma[80], among others, ruxolitinib treatment significantly inhibited tumor growth. Ruxolitinib treatment was associated with an increase in CD8+ T cells in pancreatic malignancy xenograft models and a decrease in myeloid-derived suppressor cells in KRAS-mutated lung adenocarcinoma models, indicating an impact on immune activity[52,80]. Ruxolitinib has also been shown to overcome drug resistance and increase sensitivity to several chemotherapeutic or targeted brokers. In preclinical and models of cisplatin-resistant NSCLC, with increased JAK2 and STAT3 activation levels, the addition of ruxolitinib to cisplatin decreased STAT3 activation and cell growth, enhanced apoptosis, and inhibited tumor growth[81]. In myxoid liposarcoma malignancy stem cells, which can be resistant to chemotherapy due to upregulated JAK/STAT signaling, ruxolitinib treatment inhibited phosphorylation of STAT3 and cell viability, overcoming chemotherapy resistance[82]. Ruxolitinib in combination with antibodies against cytokines such as IL-6 (tocilizumab) improved survival in mice bearing ovarian malignancy tumors. Ruxolitinib in combination with paclitaxel reduced cell proliferation and colony formation in ovarian malignancy cell lines and inhibited tumor growth in models[83,84]. Ruxolitinib has been UNC 669 shown to improve sensitivity to oncolytic viral therapy in HNC[85], pancreatic malignancy[86], glioblastoma multiforme (GBM)[87], and NSCLC[88]. Collectively, the security profile of ruxolitinib in conjunction with encouraging preclinical findings in a UNC 669 variety of tumor models make ruxolitinib a stylish therapeutic agent against solid tumors. Several clinical trials have studied the impact of ruxolitinib FOXO3 in patients with solid tumors. In a Phase II study of ruxolitinib and capecitabine in patients with pancreatic malignancy who failed to respond to gemcitabine, known as the RECAP trial, there was improved survival among a subgroup of patients with inflammation, defined by a C-reactive protein (CRP) greater than the population median of 13 mg/L (“type”:”clinical-trial”,”attrs”:”text”:”NCT01423604″,”term_id”:”NCT01423604″NCT01423604)[89]. Given these initial encouraging results, ruxolitinib was administered to patients with pancreatic malignancy and an elevated CRP in two Phase III trials, JANUS 1 (“type”:”clinical-trial”,”attrs”:”text”:”NCT02117479″,”term_id”:”NCT02117479″NCT02117479) and JANUS 2 (“type”:”clinical-trial”,”attrs”:”text”:”NCT02119663″,”term_id”:”NCT02119663″NCT02119663). In both trials, patients were randomized to be treated with either ruxolitinib and capecitabine or placebo and capecitabine. However, these studies were terminated as there was no increase in overall or progression-free survival observed in the group receiving ruxolitinib compared with placebo[90]. The combination of ruxolitinib and capecitabine in breast cancer patients with elevated CRP was also investigated in a Phase II clinical trial (“type”:”clinical-trial”,”attrs”:”text”:”NCT02120417″,”term_id”:”NCT02120417″NCT02120417). While patients receiving ruxolitinib and capecitabine experienced a more favorable health-related quality of life end result, this study was terminated because there was no improvement in overall survival compared to the group receiving placebo and capecitabine[91]. A Phase II trial of ruxolitinib in triple-negative breast cancer confirmed inhibition of STAT3 activation in patient tumor samples; however, no clinical response was observed, as evaluated by the RECIST criteria, and the study was terminated (“type”:”clinical-trial”,”attrs”:”text”:”NCT01562873″,”term_id”:”NCT01562873″NCT01562873)[92,93]. The most recently completed clinical trial (results not reported or published) included a Phase II study screening ruxolitinib in combination with exemestane in patients with UNC 669 estrogen receptor-positive breast cancer (“type”:”clinical-trial”,”attrs”:”text”:”NCT01594216″,”term_id”:”NCT01594216″NCT01594216). The addition of ruxolitinib to regorafenib in a Phase II trial in patients with colorectal malignancy did not show a difference in overall survival or progression-free.