Methylation of NRN1 is a novel synthetic lethal marker of PI3K-Akt-mTOR and ATR inhibitors in esophageal cancer.

Wnt, PI3K-Akt-mTOR, and NF-κB pathways were reported to be involved in DNA damage repair (DDR). DDR-deficient cancers become critically dependent on backup DNA repair pathways. Neuritin 1 (NRN1) is reported to be involved in PI3K-Akt-mTOR, and its role in DDR remains unclear. Methylation-specific PCR, siRNA, flow cytometry, esophageal cancer cell lines, and xenograft mouse models were used to examine the role of NRN1 in esophageal cancer. The expression of NRN1 is frequently repressed by promoter region methylation in human esophageal cancer cells. NRN1 was methylated in 50.4% (510/1012) of primary esophageal cancer samples. NRN1 methylation is associated significantly with age (P < .001), tumor size (P < .01), TNM stage (P < .001), differentiation (P < .001) and alcohol consumption (P < .05). We found that NRN1 methylation is an independent prognostic factor for poor 5-y overall survival (P < .001). NRN1 inhibits colony formation, cell proliferation, migration, and invasion, and induces apoptosis and G1/S arrest in esophageal cancer cells. NRN1 suppresses KYSE150 and KYSE30 cells xenografts growth in nude mice. PI3K signaling is reported to activate ATR signaling by targeting CHK1, the downstream component of ATR. By analyzing the synthetic efficiency of NVP-BEZ235 (PI3K inhibitor) and VE-822 (an ATR inhibitor), we found that the combination of NVP-BEZ235 and VE-822 increased cytotoxicity in NRN1 methylated esophageal cancer cells, as well as KYSE150 cell xenografts. In conclusion, NRN1 suppresses esophageal cancer growth both in vitro and in vivo by inhibiting PI3K-Akt-mTOR signaling. Methylation of NRN1 is a novel synthetic lethal marker for PI3K-Akt-mTOR and ATR inhibitors in human esophageal cancer.

Immune checkpoint inhibitors combined with chemotherapy for the treatment of advanced pancreatic cancer patients.

Immune checkpoint inhibitors (ICIs) represent a major breakthrough for cancer treatment. However, evidence regarding the use of ICIs in pancreatic cancer (PC) remained scarce. To assess the efficacy and safety of ICIs plus chemotherapy, patients with advanced PC were retrospectively recruited and were treated with either chemotherapy alone or chemotherapy plus ICIs. Patients previously treated with any agents targeting T-cell co-stimulation or checkpoint pathways were excluded. The primary outcome was overall survival (OS). The secondary outcomes were progression-free survival (PFS), overall response rate (ORR) and safety. In total, 58 patients were included (combination, n = 22; chemotherapy, n = 36). The combination group showed a significantly longer OS than the chemotherapy group [median, 18.1 vs 6.1 months, hazard ratio (HR) 0.46 (0.23-0.90), P = 0.021]. The median PFSs were 3.2 months in the combination group and 2.0 months in the chemotherapy group [HR 0.57 (0.32-0.99), P = 0.041]. The combination group and the chemotherapy group had similar ORRs (18.2% vs 19.4%, P = 0.906). All patients who achieved a partial response received a doublet chemotherapy regimen regardless of co-treatment with ICIs. Grade 3 or higher adverse events occurred in 31.8% of the patients in the combination group and in 16.9% of those receiving chemotherapy. Although the incidence of serious treatment-related adverse events was higher in the combination group than in the chemotherapy group, the difference was not significant (P = 0.183). Our findings suggest that the combination of ICIs with chemotherapy is both effective and tolerable for advanced PC. ICIs combined with a doublet chemotherapy regimen might be a preferable choice.

Anti-PD-1 therapy combined with chemotherapy in patients with advanced biliary tract cancer.

BACKGROUND: Evidence for the efficacy of immunotherapy in biliary tract cancer (BTC) is limited and unsatisfactory. METHODS: Chinese BTC patients receiving a PD-1 inhibitor with chemotherapy, PD-1 inhibitor monotherapy or chemotherapy alone were retrospectively analyzed. The primary outcome was overall survival (OS). The key secondary outcomes were progression-free survival (PFS) and safety. Patients previously treated with any agent targeting T cell costimulation or immune checkpoints were excluded. RESULTS: The study included 77 patients (a PD-1 inhibitor plus chemotherapy, n = 38; PD-1 inhibitor monotherapy, n = 20; chemotherapy alone, n = 19). The median OS was 14.9 months with a PD-1 inhibitor plus chemotherapy, significantly longer than the 4.1 months with PD-1 inhibitor monotherapy (HR 0.37, 95% CI 0.17-0.80, P = 0.001) and the 6.0 months with chemotherapy alone (HR 0.63, 95% CI 0.42-0.94, P = 0.011). The median PFS was 5.1 months with a PD-1 inhibitor plus chemotherapy, significantly longer than the 2.2 months with PD-1 inhibitor monotherapy (HR 0.59, 95% CI 0.31-1.10, P = 0.014) and the 2.4 months with chemotherapy alone (HR 0.61, 95% CI 0.45-0.83, P = 0.003). Grade 3 or 4 treatment-related adverse events were similar between the anti-PD-1 combination group and the chemotherapy alone group (34.2% and 36.8%, respectively). CONCLUSIONS: Anti-PD-1 therapy plus chemotherapy is an effective and tolerable approach for advanced BTC.

Clinical observation of immune checkpoint inhibitors in the treatment of advanced pancreatic cancer: a real-world study in Chinese cohort.

BACKGROUND: In recent years, immune checkpoint inhibitors have been used with great success in the treatment of various cancers. However, when used in monotherapy, immune checkpoint inhibitors have a poor effect on pancreatic cancer. This study assessed the efficacy and safety of the use of immune checkpoint inhibitors for the treatment of advanced pancreatic cancer. PATIENTS AND METHODS: We evaluated patients with advanced pancreatic cancer who were treated with PD-1/PD-L1 inhibitors from 2015-2017. All the patients received PD-1/PD-L1 inhibitors as a monotherapy or in combination with other treatments, such as chemotherapy, targeted therapy, and CTLA-4 inhibitors at the recommended dosages. RESULTS: For the 43 patients enrolled, the objective response rate was 10.5%, the disease control rate was 50%, the median progression-free survival was 2.3 months, and the median overall survival (mOS) was 5.1 months. The mOS was longer for patients receiving combined therapy than for those receiving PD-1/PD-L1 inhibitor monotherapy (5.4 vs 2.0 months, P = 0.020). Patients receiving immune therapy as a first-line treatment had prolonged survival compared with those receiving it as a second-line or multiple-line treatment, but the difference was not statistically significant (mOS: 7.0 vs 5.1 vs 2.8 months, P = 0.161). There was a reduction in the serum level of CA19-9 associated with the response to treatment. Adverse events were tolerable and were mainly grade 1 and 2. The immune-related adverse events that occurred were hypothyroidism, diarrhea, and rash. CONCLUSION: Immune checkpoint inhibitors showed a certain efficacy in the treatment of advanced pancreatic cancer and could confer long-term survival benefits. Combined therapy was more effective and may serve as an alternative option. Further studies should be performed.

Dynamic testing of stimulative and suppressive biomarkers on peripheral blood cells at early stages of immunotherapy predicts response in advanced cancer patients.

PURPOSE: Immunotherapy against malignant tumors has shown considerable clinical efficacy, especially agents targeting the programmed death 1 (PD-1) pathway. In this study, we set out to dynamically determine the relationships between clinical benefit and changes in immune biomarkers on peripheral blood monocular cells (PBMCs) and try to establish a model to predict the response at an early stage of treatment. EXPERIMENTAL DESIGN: All patients recruited from December 2016 to July 2017 were treated in the Cancer Center of the Chinese People's Liberation Army General Hospital with nivolumab or pembrolizumab, and with or without chemotherapy. We investigated nine checkpoint molecules PD-1, CTLA-4, TIM-3, LAG-3, BTLA, CD160, Ki-67, OX40, and GITR on CD4+, CD8+, and NK cells by flow cytometry in patients before and after receiving each treatment of anti-PD-1 agents. RESULTS: We found that the responder group showed higher expressions of PD-1 on CD4+ and NK cells than the non-responder group after the first cycle of immunotherapy, and lower expression of CTLA-4, GITR, and OX40 after the second cycle of immunotherapy. A simple model of the combination of biomarkers was generated to predict the immunotherapeutic effect, revealing that elevation of key biomarkers after the first cycle of immunotherapy, followed by a decrease in their expression after the second cycle, was associated with a better outcome from immunotherapy at an early stage of treatment of cancer. CONCLUSION: Our work indicates that by testing biomarkers on patients' PBMCs at an early stage of treatment, the immunotherapeutic effect can be predicted, thus improving patient outcomes and cost efficiency.