Xianghua Wu

miR-196a2 C allele is a low-penetrant risk factor for cancer development

Published data on the association between miR-196a2 T/C polymorphism and cancer susceptibility are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. A total of 21 studies including 10,441 cases and 12,353 controls were involved in this meta-analysis. Overall, significantly elevated cancer risk was associated with miR-196a2 C allele when all studies were pooled into the meta-analysis (TC vs. TT: OR=1.23, 95% CI=1.11-1.36; CC vs. TT: OR=1.30, 95% CI=1.14-1.48; dominant model: OR=1.25, 95% CI=1.13-1.38). In the subgroup analysis by ethnicity, significantly increased risks were found in Asains (TC vs. TT: OR=1.24, 95% CI=1.10-1.40; CC vs. TT: OR=1.31, 95% CI=1.13-1.52; dominant model: OR=1.26, 95% CI=1.12-1.41) but with bordline statistical significance in Caucasians (TC vs. TT: OR=1.15, 95% CI=1.00-1.31). In the subgroup analysis by cancer type, statistically significantly increased risks were found for breast cancer (TC vs. TT: OR=1.15, 95% CI=1.01-1.31; CC vs. TT: OR=1.30, 95% CI=1.01-1.68; dominant model: OR=1.22, 95% CI=1.00-1.50; and recessive model: OR=1.11, 95% CI=1.01-1.23) and lung cancer (CC vs. TT: OR=1.30, 95% CI=1.10-1.54; and recessive model: OR=1.18, 95% CI=1.02-1.36). When stratified by study design, statistically significantly elevated risk was found in hospital-based studies (TC vs. TT: OR=1.30, 95% CI=1.13-1.49; CC vs. TT: OR=1.37, 95% CI=1.14-1.66; dominant model: OR=1.32, 95% CI=1.15-1.53) and population-based studies (CC vs. TT: OR=1.19, 95% CI=1.06-1.35; dominant model: OR=1.13, 95% CI=1.01-1.25). Despite some limitations, this meta-analysis suggests that the miR-196a2 C allele is a low-penetrant risk factor for cancer development.

A phase II randomized trial evaluating gefitinib intercalated with pemetrexed/platinum chemotherapy or pemetrexed/platinum chemotherapy alone in unselected patients with advanced non-squamous non-small cell lung cancer

Current pemetrexed/platinum chemotherapy does not produce a satisfactory therapeutic response in advanced lung cancer patients. The aim of this study was to determine whether the administration of gefitinib, a tyrosine kinase inhibitor (TKI), intercalated with pemetrexed/platinum could improve the efficacy in chemotherapy-naïve patients with advanced non-squamous NSCLC without subsequent gefitinib maintenance therapy. Treatment-naïve patients with stage IIIB or IV NSCLC were randomly assigned to receive pemetrexed (500 mg/m2 d1) and either cisplatin (75 mg/m2 d1) or carboplatin (AUC = 5 d1) plus gefitinib (250 mg/d on days 3 to 16 of a 3-week cycle) (PC-G) or pemetrexed–platinum (PC) alone. Randomization was stratified according to the tobacco smoking status and EGFR mutational status of the patients. The primary endpoint was the non-progression rate (NPR) at 12 weeks. Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), overall survival (OS), and biosafety. The NPR at 12 weeks was 84.5% for the PC-G treatment arm and 83.1% for the PC treatment arm (P = 0.87). Median PFS was 7.9 months for the PC-G arm and 7.0 months for the PC arm (P = 0.57). The ORR was 50.0% for the PC-G arm and 47.4% for the PC arm (P = 0.78). Median survival was 25.4 mo for the PC-G arm and 20.8 mo for the PC arm (P = 0.54). The incidence of adverse events was similar between the two treatment arms, except for a higher incidence of skin rash with PC-G. Predefined subgroup analyses demonstrated that PC-G significantly increased the PFS compared with the PC regimen in patients with EGFR mutations (P = 0.017). Although gefitinib intercalated with pemetrexed/platinum chemotherapy did not improve the NPR at 12 weeks compared with chemotherapy, an improvement in the PFS for the intercalated treatment arm was seen in the subgroup of patients with EGFR mutations.

Decreased expression of RPS15A suppresses proliferation of lung cancer cells

Lung cancer is the leading cause of cancer-related death in the world. Previous report has identified ribosomal protein s15a (RPS15A) as a TGF-β-responsible gene in the lung adenocarcinoma cell line A549. In this study, we used specific si-RNA to downregulate RPS15A expression in A549 cells and found that decreased RPS15A expression significantly inhibited cell proliferation and survival, as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony formation assays. Moreover, A549 cells were obviously accumulated in the G0/G1 phase in response to RPS15A knockdown, suggesting that RPS15A inhibition could induce a diminution of proliferation through cell cycle arrest. In addition, immunohistochemistry analysis further revealed that RPS15A was overexpressed in surgically resected lung cancer tissues. In conclusion, we identify RPS15A as a novel potential oncogenic gene involved in lung carcinogenesis. This study may provide a preliminary experimental basis for a gene therapy approach for treating lung cancer.

PA-MSHA in combination with EGFR tyrosine kinase inhibitor: A new strategy to overcome the drug resistance of non-small cell lung cancer cells

The inhibition of epidermal growth factor receptor (EGFR) signaling by Gefitinib provides a promising treatment strategy for non-small cell lung cancer (NSCLC); however, drug resistance to Gefitinib and other tyrosine kinase inhibitors presents a major issue. Using NSCLC cell lines with differential EGFR status, we examined the potency of PA-MSHA (Pseudomonas aeruginosa-mannose-sensitive hemagglutinin) in combination with Gefitinib on proliferation, apoptosis, cell cycle arrest, EGFR signaling and tumor growth. PC-9, A549, and NCI-H1975 cells were treated with PA-MSHA, Gefetinib, or PA-MSHA plus Gefetinib at different concentrations and times. The effects of the drugs on proliferation, cell cycle distribution and apoptosis were evaluated. The activation of EGFR and apoptotic signaling-related molecules was evaluated by Western blotting in the presence or absence of EGFR siRNA. Tumor growth and pathway signaling activation was assessed by xenografts in nude mice. A time-dependent and concentration-dependent cytotoxic effect of PA-MSHA was observed in all NSCLC cells tested. The combination of PA-MSHA plus Gefitinib enhanced the growth inhibition, sub-G1 content and apoptosis over that observed with either agent alone. Furthermore, the combination of PA-MSHA plus Gefitinib resulted in caspase-3/caspase-9 cleavage and increased inhibition of EGFR-dependent activation of AKT and ERK phosphorylation. Combination treatment was more effective in reducing tumor size and EGFR activation than either agent alone. These data suggest that PA-MSHA and Gefitinib function additively to suppress the proliferative effects of NSCLC cells of differential EGFR status. The combination of PA-MSHA and Gefitinib provides a potential new strategy to conquer drug resistance for anti-EGFR-targeted therapy of NSCLC.

A novel point mutation in exon 20 of EGFR showed sensitivity to erlotinib

Abstract Mutations of epidermal growth factor receptor (EGFR) gene are good predictors of response to treatment with EGFR tyrosine kinase inhibitors (TKIs) for non-small cell lung cancer (NSCLC). It is well established that classic mutations, such as in-frame deletions in exon 19 and the point mutation L858R in exon 21, are associated with high sensitivity to EGFR TKIs. Though mutations in exon 20 are almost correlated with EGFR–TKIs resistance, the awareness that they might confer sensitivity to TKI treatment should be emphasized. Herein, we describe a novel mutation in exon 20 of EGFR in a Chinese male non-smoker, who was diagnosed with stage IV lung adenocarcinoma and characterized by the codon 769 point mutation GTG>GCG, which translates into alanine instead of valine (p.V769A). In this case, the patient showed a good clinical response to erlotinib after paclitaxel/cisplatin first-line and docetaxel second-line chemotherapies. Therefore, we suggest that this rare mutation (p.V769A) may be a sensitive EGFR mutation in NSCLC. The identification of novel EGFR mutations provides new predictive biomarkers for TKI treatment and is essential to the successful use of targeted therapies.

Typing of killer-cell immunoglobulin-like receptors and their cognate human leukocyte antigen class I ligands predicts survival of Chinese Han patients with metastatic non-small-cell lung cancer

Non-small-cell lung cancer (NSCLC) may establish an immunosuppressive tumor microenvironment that is conducive to tumor growth. Natural killer (NK) cells play a pivotal role in immunological surveillance. Activation of NK cells partially depends on the interactions between killer-cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I ligands. We herein investigated the association of KIRs and HLA ligands with survival in metastatic NSCLC (mNSCLC) patients treated with chemotherapy in a Chinese Han population. Polymerase chain reaction with sequence-specific primers was used to type 15 KIRs at the DNA and mRNA level and 6 HLA ligands in 70 mNSCLC patients. Survival curves were estimated using the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazard regression model was applied for multivariate survival analysis, with the stepwise selection, to determine independent predictors of survival. It was observed that patients with KIR2DS4del gene expression at the mRNA level or HLA-Bw4T80 exhibited poor overall survival (OS). The multivariate analysis revealed that HLA-Bw4T80 and KIR2DS4del expression were independent predictors of OS. This observation indicated that the KIR/HLA ligand is a promising predictor of survival in mNSCLC and may also provide a strategy for treatment stratification and patient management.

Thalidomide enhanced the efficacy of CHOP chemotherapy in the treatment of diffuse large B cell lymphoma: A phase II study

Cyclophosphamide, doxorubicin, vincristine, and prednisolone plus rituximab (R-CHOP) is the standard treatment for patients with diffuse large B cell lymphoma (DLBCL). However, rituximab cannot be popularly applied in a considerable number of patients with DLBCL because of economic reasons. To develop a new regimen to improve the outcome of these patients is extremely important. In our study, sixty five patients with DLBCL were randomly assigned to thalidomide plus CHOP group (n=32) or to CHOP alone group (n=33). Objective response rates (ORR) and complete remission rates (CRR) were 96.7% and 80.6% in T-CHOP group versus 78.9 % and 57.8 % in CHOP group, respectively (P <0.05). At a median follow-up of 96 months, median PFS for T-CHOP group was still not reached yet, and in CHOP group it was 22.9 months (95% CI [0-50.4]). (P=0.163). Median overall survival (OS) for T-CHOP group was also not reached, and the estimated median OS for CHOP group was 83.5 months, the difference of OS between the two groups is not significant (p=0.263). But, in patients with Bcl-2 positive and Bcl-6 negative, the median PFS in T-CHOP group was longer than that in CHOP group (111.0 vs 8.5 months (P=0.017). In addition, thalidomide did not significantly increase the grade 3/4 toxicity of CHOP. We concluded that the addition of thalidomide to the CHOP regimen significantly improved the CRR and showed a trend of improving clinical outcome in patients with DLBCL, especially for patients with Bcl-2 positive and Bcl-6 negative B-cell phenotype, without increased toxicity.

A phase II study of gemcitabine, vincristine, and cisplatin as second-line treatment for patients with advanced soft tissue sarcoma

AbstractPatients with advanced soft tissue sarcoma (aSTS) typically have a poor prognosis. Patients progressing to doxorubicin-based regimen have limited therapeutic options. Monotherapy with cytotoxic drugs appears to have only modest activity in the second-line setting. The purpose of this phase II study was to prospectively evaluate the safety and efficacy of combination regimen with gemcitabine, vincristine, and cisplatin (GVP) as a salvage treatment for patients with aSTS.Eligible patients were female with 18∼75 years old, and had aSTS that had progressed after 1 prior anthracyclines-based chemotherapy regimen. Patients were treated with 1,000 mg/m2 gemcitabine intravenously (IV) on days 1 and 8, 1.4 mg/m2 (max 2 mg) vincristine IV on day 1 and 25 mg/m2 cisplatin IV on days 1 through 3 every 21 days until disease progression, unacceptable toxicity or up to 6 cycles. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), over response rate (ORR) and safety. This trial was registered with www.clinicaltrials.gov (no. NCT01192633).A total of 26 patients with a median age 47 years (21–72) were recruited. ORR was 23.1% [1 complete response and 5 partial responses]. The median PFS and OS were 4.8 (95% CI, 0.1–9.5) months and 15.0 (95% CI, 6.1–23.9) months, respectively. Grade 3/4 hematologic toxicities included neutropenia (34.6%), leukopenia (23.1%), thrombocytopenia (11.5%) and anemia (3.8%). No febrile neutropenia and grade 3/4 non-hematologic toxicities occurred. The most frequent non-hematologic toxicities were nausea/vomiting (50.0%), fatigue (30.8%), and fever (11.5%).We conclude that GVP regimen is effective with a favorable safety profile as the second-line chemotherapy in aSTS patients, which warrants further investigation in a phase III study.

Protective immunity elicited by measles vaccine exerts anti-tumor effects on measles virus hemagglutinin gene-modified cancer cells in a mouse model

PurposeMeasles vaccine is widely used in China to prevent the measles virus (MV) infection. People immunized with measles vaccine can obtain long-term protective immunity. Measles virus surface glycoprotein hemagglutinin (H) can also induce MV-specific immune responses. However, little is known about whether the existence of the protective immune system against MV in the host can exert anti-tumor effects and whether the MV-H gene can serve as a therapeutic gene.MethodsWe first vaccinated mice with measles vaccine, then inoculated them with MV-H protein-expressing tumor cells and observed the rate of tumor formation. We also treated mice with H protein-expressing tumor cells with measles vaccine and assessed tumor size and overall survival.ResultsActive vaccination using measles vaccine not only protected mice from developing tumors, but also eradicated established tumors. Measles vaccine elicited H-specific IFN-γ, TNF-α and granzyme B-producing CD8+ T cells and increased cytotoxic T lymphocyte (CTL) activity specific for H antigen, which provided a strong therapeutic benefit against H protein-expressing tumors. In addition, measles vaccine decreased the population of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs).ConclusionsOur study demonstrated that tumor cells expressing H protein could activate the immune memory response against MV, which exerted specific anti-tumor effects, and indicated that the MV-H gene can be used as a potential therapeutic gene for cancer gene therapy.

Efficacy and safety of first-line pemetrexed plus carboplatin followed by single-agent pemetrexed maintenance in elderly Chinese patients with non-squamous non-small-cell lung cancer

Chemotherapy with pemetrexed plus carboplatin followed by pemetrexed maintenance therapy is a first-line regimen for patients with advanced non-squamous non-small-cell lung cancer. This phase II clinical study investigated the efficacy and safety of this regimen in older patients (aged ≥65 years) with advanced non-squamous non-small-cell lung cancer. All patients received 4 courses of induction therapy with pemetrexed (500 mg/m2) combined with carboplatin once every 3 weeks. If patients had stable disease or achieved a complete or partial tumor response after 4 courses of pemetrexed + carboplatin therapy, maintenance treatment with pemetrexed monotherapy was administered until either disease progression or intolerable toxicity occurred. The primary endpoint was progression-free survival, while secondary endpoints were the objective response rate, overall survival, and tolerability. A total of 105 elderly patients (median age, 71 years) with advanced lung adenocarcinoma were enrolled in the trial. The ORR with induction therapy was 36.2% and the disease control rate was 70.5%. Sixty-two patients (59.0%) subsequently received pemetrexed maintenance therapy. The median progression-free survival for all patients was 8.23 months (95% CI 5.85-10.62 months) and the median overall survival was 22.6 months (95% CI 20.09-25.11 months). Grade 3 or greater toxicities included neutropenia (15.3%), thrombocytopenia (9.5%), anemia (8.6%), leukopenia (4.8%), nausea (1.0%), vomiting (1.0%), and fatigue (1.0%). No treatment-related deaths occurred. These results indicate that pemetrexed combined with carboplatin therapy maintained by single-agent pemetrexed treatment of elderly patients with advanced non-squamous non-small-cell lung cancer was effective and tolerable. ClinicalTrials.gov identifier: NCT01860508.