PP2A as a potential therapeutic target for breast cancer: Current insights and future perspectives.

Breast cancer has become the most prevalent malignancy worldwide; however, therapeutic efficacy is far from satisfactory. To alleviate the burden of this disease, it is imperative to discover novel mechanisms and treatment strategies. Protein phosphatase 2 A (PP2A) comprises a family of mammalian serine/threonine phosphatases that regulate many cellular processes. PP2A is dysregulated in several human diseases, including oncological pathologies, and plays a pivotal role in the initiation and progression of tumours. The role of PP2A as a tumour suppressor has been extensively studied, and its regulation can serve as a target for anticancer therapy. Recent studies have shown that PP2A is a tumour promotor. PP2A-mediated anticancer therapy may involve two opposing mechanisms: activation and inhibition. In general, the contradictory roles of PP2A should not be overlooked, and more work is needed to determine the molecular mechanism by which PP2A affects in tumours. In this review, the literature on the role of PP2A in tumours, especially in breast cancer, was analysed. This review describes relevant targets of breast cancer, such as cell cycle control, DNA damage responses, epidermal growth factor receptor, immune modulation and cell death resistance, which may lead to effective therapeutic strategies or influence drug development in breast cancer.

Microarray profile analysis identifies ETS1 as potential biomarker regulated by miR-23b and modulates TCF4 in gastric cancer.

BACKGROUND: Gastric cancer (GC), a common malignancy of the human digestive system, represents the second leading cause of cancer-related deaths worldwide. Early detection of GC has a significant impact on clinical outcomes. The aim of this study was to identify potential GC biomarkers. METHODS: In this study, we conducted a multi-step analysis of expression profiles in GC clinical samples downloaded from TCGA database to identify differentially expressed miRNAs (DEMs) and differentially expressed mRNAs (DEGs). Potential prognostic biomarkers from the available DEMs were then established using the Cox regression method. Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to investigate the biological role of the predicted target genes of the miRNA biomarkers. Then, the prognostic DEM-mediated regulatory network was constructed based on transcription factor (TF)-miRNA-target interaction. Subsequently, the consensus genes were further determined based on the overlap between DEGs and these target genes of DEMs. Besides, expression profile, co-expression analysis, immunity, and prognostic values of these prognostic genes were also investigated to further explore the roles in the mechanism of GC tumorigenesis. RESULTS: We got five miRNAs, including miR-23b, miR-100, miR-143, miR-145, and miR-409, which are associated with the overall survival of GC patients. Subsequently, enrichment analysis of the target genes of the miRNA biomarkers shown that the GO biological process terms were mainly enriched in mRNA catabolic process, nuclear chromatin, and RNA binding. In addition, the KEGG pathways were significantly enriched in fatty acid metabolism, extracellular matrix (ECM) receptor interaction, and proteoglycans in cancer pathways. The transcriptional regulatory network consisting of 68 TFs, 4 DEMs, and 58 targets was constructed based on the interaction of TFs, miRNAs, and targets. The downstream gene ETS1 of miR-23b and TCF4 regulated by ETS1 were obtained by the regulatory network construction and co-expression analysis. High expression of ETS1 and TCF4 indicated poor prognosis in GC patients, particularly in the advanced stages. The expression of ETS1 and TCF4 was correlated with CD4+ T cells, CD8+ T cells, and B cells. CONCLUSIONS: miR-23b, ETS1, and TCF4 were identified as the prognostic biomarkers. ETS1 and TCF4 had potential immune function in GC, which provided a theoretical basis for molecular-targeted combined immunotherapy in the future.

Elevated Neutrophil-to-Lymphocyte Ratio Is Associated With Poor Outcomes for Melanoma Patients Treated With PD-1 Inhibitor or Chemotherapy in a Chinese Population.

Background: Previous studies have suggested that an elevated pre-treatment neutrophil-to-lymphocyte ratio (NLR) is associated with worse outcomes in patients with a variety of cancers. The purpose of this retrospective analysis is to investigate the prognostic value of the NLR in a Chinese melanoma population. Methods: Melanoma patients were divided into two groups based on pre-treatment NLR values (≥3 vs. <3). Cox proportional hazard regression analysis and the Kaplan-Meier method were employed to study the prognostic role of the NLR for overall survival (OS) and progression-free survival (PFS). Results: A total of 159 melanoma patients were included in this study, including 40 patients treated with PD-1 inhibitor and 119 patients treated with chemotherapy. In the PD-1 inhibitor group, the median OS was 18.0 months in the low NLR subgroup and 5.6 months in the high NLR subgroup; the median PFS was 7.0 and 2.2 months, respectively. In chemotherapy group, the median OS was 23.0 months in the low NLR group and 8.0 months in the high NLR group, and the median PFS was 9.0 and 4.0 months, respectively. Multivariate analysis showed that the NLR was significantly associated with OS and PFS in melanoma patients treated with either PD-1 inhibitor immunotherapy or chemotherapy. Conclusion: In the Chinese population, an elevated NLR was closely related to worse survival in patients with melanoma treated with either PD-1 inhibitor monotherapy or chemotherapy.

Elevated platelet-to-lymphocyte corresponds with poor outcome in patients with advanced cancer receiving anti-PD-1 therapy.

OBJECTIVES: The purpose of this retrospective analysis was to investigate the prognostic value of PLR for PD-1 inhibitors. METHODS: Patients were divided into different subgroups according to PLR. Univariate survival analysis and a multivariate Cox proportional hazards regression model were used to assess the association between PLR and overall survival (OS) or progression-free survival (PFS). RESULTS: The optimal cut-off value of baseline PLR was 164. Among the total 85 patients, 34 patients presented with PLR ≥ 164, and 51 presented with PLR < 164, respectively. The median OS for the high PLR group was 7.0 months (95% CI: 4.1-9.9 months), and it was not reached for the low PLR group (P < 0.001). The median PFS was 3.0 months (95% CI: 1.9-4.1 months) vs. 9.8 months (95% CI: 6.1-13.5 months) for the high and low PLR groups, respectively (P < 0.001). In multivariate analysis, a PLR > 164 and body mass index (BMI) > 24.0 were independently associated with OS (hazard ratio [HR]: 3.549, 95% confidence interval [CI]: 1.901-6.625, P < 0.001 and HR: 0.496, 95% CI: 0.260-0.945, P = 0.033), meanwhile PLR was also significantly associated with inferior PFS (HR: 2.567, 95% CI: 1.551-4.249, P < 0.001). Disease control rate for high and low PLR group was 38.2% and 74.5%, respectively, and it was also correlated with elevated PLR (P = 0.001). CONCLUSION: This retrospective analysis indicates that PLR could be used as a biomarker to stratify patients who will have a better response to anti-PD-1 agents.

A study of the clinical characteristics and prognosis of advanced mucosal and cutaneous melanoma in a Chinese population.

AIM: To investigate the characteristics and prognosis of melanoma in a Chinese population. MATERIALS & METHODS: Total of 162 advanced melanoma patients were analyzed retrospectively. Kaplan-Meier method and Log rank test were used for survival analysis. RESULTS: The median progression-free survival of mucosal and cutaneous melanoma patients was 13 versus 8 months (p = 0.005), 14 versus 10 months in immunotherapy group (p = 0.022), 6 versus 4 months in chemotherapy group (p = 0.040). Age was an independent risk factor for mucosal melanoma patients. Staging and treatment regimen were independent risk factors for cutaneous melanoma patients. The lungs, liver and brain were most common metastasis locations. CONCLUSION: The prognosis of patients with advanced mucosal melanoma is better than cutaneous melanoma in China. There are significant differences between the two subtypes of melanoma.

Efficacy and safety of trastuzumab as maintenance or palliative therapy in advanced HER2-positive gastric cancer.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC) is a unique subtype of this disease. Few studies focus on the feasibility of trastuzumab as maintenance or palliative therapy for patients with HER2-positive advanced GC. PATIENTS AND METHODS: We retrospectively analyzed the data of 11 patients, evaluated the efficacy and safety of trastuzumab, and attempted to investigate the prognostic factors for trastuzumab treatment. Among the 11 patients, one achieved partial response (PR), six achieved stable disease (SD), and four were evaluated as progressive disease (PD). RESULTS: The overall response rate (ORR) was 9.10%, and the disease control rate (DCR) was 63.64%. The median overall survival (OS) was 6.10 months, and the median progression-free survival (PFS) was 6.10 months. A significant association was found between trastuzumab treatment cycles and efficacy (P=0.027), cycles and PFS (P=0.001), and cycles and OS (P=0.005). Among the five patients who accepted more than five cycles of trastuzumab, the median OS and median PFS achieved 23.83 months and 14.67 months, respectively. Moreover, we have found the correlation between tumor marker changes and efficacy (P=0.002) and HER2 status and PFS (P=0.027). No association was found between HER2 status and OS (P=0.597). CONCLUSION: The most common adverse events were left ventricular ejection fraction (LVEF) reduction, fatigue, and anorexia. LVEF reduction was found in seven of 11 patients, but the absolute decline in the LVEF was within 10% from the baseline. The results of this study suggest that trastuzumab is a feasible option as maintenance or palliative therapy for patients with HER2-positive metastatic GC.

Platelet-to-lymphocyte ratio in peripheral blood: A novel independent prognostic factor in patients with melanoma.

OBJECTIVES: This retrospective study aimed to investigate the prognostic value of pre-treatment platelet-to-lymphocyte ratio (PLR), which is an inflammatory indicator, in patients with melanoma. METHODS: Patients in this retrospective analysis were admitted between January 1, 2010 and December 31, 2015 in Henan Cancer Hospital. Receiver operating characteristic (ROC) curve was performed the optimal cut-off value for PLR. The 140 patients were divided into two groups: high PLR group and low PLR group. The relationship between PLR and overall survival (OS) was analyzed. The Kaplan-Meier and Log rank tests were used for univariate survival analysis and Cox proportional hazards regression model for multivariate analysis. RESULTS: The optimal cut-off value of PLR determined by ROC curve was 120.15. Univariate and Cox multivariate survival analysis all showed that PLR and clinical stage were factors affecting OS in melanoma patients (P < 0.05). The overall median OS was 21.0 months (95% confidence interval (CI): 18.1-23.9), for 17.0 months in the high PLR group, and 34.0 months in the low PLR group (hazard ratio: 0.436, 95% CI: 0.291-0.652, P < 0.001), respectively. Clinical subgroup analysis showed that PLR was a risk factor in patients with stage II, III, and IV disease (P < 0.05). CONCLUSION: The elevated PLR was an independent prognostic predictor for OS in patients with melanoma.

Clinical effects of autologous cytokine-induced killer cell-based immunotherapy in the treatment of endometrial cancer: a case report and literature review.

Endometrial cancer is the most prevalent gynecological malignancy in the USA, and its treatment involves surgery, chemotherapy, and radiotherapy. Cytokine-induced killer (CIK) cell-based treatments have shown antitumor activity against several solid tumors. However, to the best of our knowledge, there are no reports yet of CIK immunotherapy in the treatment of endometrial cancer, and consequently, little is known about its efficacy and safety. Here, we report a case of an endometrial cancer patient receiving a combination treatment with CIK cells immunotherapy and chemotherapy. Assessment for clinical features was carried out after every two cycles of CIK immunotherapy and chemotherapy. No severe toxicity was observed after infusion of CIK cells. After 4 cycles of treatment, the patient achieved complete response and showed elevated Karnofsky Performance Status scores with an overall survival time of 13.6 months. The combination therapy improved the quality of life and prolonged patient survival time, which suggested that CIK cell therapy might be a potentially beneficial option for endometrial cancer.

Autologous cytokine-induced killer cell immunotherapy may improve overall survival in advanced malignant melanoma patients.

AIMS: Our study was conducted to explore the efficacy of autologous cytokine-induced killer (CIK) cells in patients with advanced malignant melanoma. Materials & Methods: Here we reviewed 113 stage IV malignant melanoma patients among which 68 patients received CIK cell immunotherapy alone, while 45 patients accepted CIK cell therapy combined with chemotherapy. Results: We found that the median survival time in CIK cell group was longer than the combined therapy group (21 vs 15 months, p = 0.07). In addition, serum hemoglobin level as well as monocyte proportion and lymphocyte count were associated with patients' survival time. CONCLUSIONS: These indicated that CIK cell immunotherapy might extend survival time in advanced malignant melanoma patients. Furthermore, serum hemoglobin level, monocyte proportion and lymphocyte count could be prognostic indicators for melanoma.