Explore the vast range of titles available.

The successes achieved by chimeric antigen receptor-modified T （CAR-T） cells in hematological malignancies raised the pos- sibility of their use in non-small lung cancer （NSCLC）. In this phase I clinical study （NCT01869166）, patients with epidermal growth factor receptor （EGFR）-positive （〉50% expression）, relapsed/refractory NSCLC received escalating doses of EGFR-targeted CAR-T cell infusions. The EGFR-targeted CAR-T cells were generated from peripheral blood after a 10 to 13-day in vitro expansion. Serum cytokines in peripheral blood and copy numbers of CAR-EGFR transgene in peripheral blood and in tissue biopsy were monitored periodically. Clinical responses were evaluated with RECISTI.1 and im- mune-related response criteria, and adverse events were graded with CTCAE 4.0. The EGFR-targeted CAR-T cell infusions were well-tolerated without severe toxicity. Of 11 evaluable patients, two patients obtained partial response and five had stable disease for two to eight months. The median dose of transfused CAR＋ T cells was 0.97x 10^7 cells kg J （interquar- tile range （IQR）, 0.45 to 1.09x 10^7 cells kg 1）. Pathological eradication of EGFR positive tumor cells after EGFR-targeted CAR-T cell treatment can be observed in tumor biopsies, along with the CAR-EGFR gene detected in tumor-infiltrating T cells in all four biopsied patients. The EGFR-targeted CAR-T cell therapy is safe and feasible for EGFR-positive advanced re- lapsed/refractory NSCLC.

Sulforaphane is a common antioxidant selectively abundant in cruciferous plants, which exhibits effective anti-cancer actions in control of tumorigenesis or progression of various cancers. A recent study has shown that sulforaphane attenuates the EGFR signaling pathway in non-small cell lung cancer （NSCLC）, suggesting its potential anti-metastatic effects. In this study we assessed the involvement of sulforaphane and miR-616-5p in epithelial-mesenchymal transition （EMT） and NSCLC metastasis. Sulforaphane suppressed the cell proliferation in human NSCLC cell lines H1299, 95C and 95D with IC50 values of 9.52±1.23, 9.04±1.90 and 17.35±2.03 μmol/L, respectively. At low concentrations （1-5 μmol/L）, sulforaphane dose-dependently inhibited the migration and invasion of 95D and H1299 cells with relatively high metastatic potential. The anti-metastatic action of sulforaphane was confirmed in 95D and H1299 cell xenografts in vivo. In fresh NSCLC tissue samples from 179 patients, miR-616-5p levels were upregulated in late-stage NSCLCs, and strongly correlated with risk of NSCLC recurrence and metastasis. Consistent with the clinic observation, miR- 616-5p levels in the 3 NSCLC cell lines were correlated with their metastatic ability, and were decreased by sulforaphane treatment. Silencing miR-616-5p markedly suppressed the migration and invasion of 95D cells in vitro and NSCLC metastasis in vivo. Further studies revealed that miR-616-5p directly targeted GSK313 and decreased its expression, whereas sulforaphane decreased miR-616-5p levels by histone modification, and followed by inactivation of the GSK3β/β-catenin signaling pathway and inhibition of EMT, which was characterized by loss of epithelial markers and acquisition of a mesenchymal phenotype in NSCLC cells. Our findings suggest that sulforaphane is a potential adjuvant chemotherapeutic agent for the prevention of NSCLC recurrence and metastasis, and miR-616-5p can be clinically utilized as a biomarker or therapeutic target to inhibit metastasis.

There have been exponential gains in immuno-oncology in recent times through the development of immune checkpoint inhibitors. Already approved by the U.S. Food and Drug Administration for advanced melanoma and non-small cell lung cancer, immune checkpoint inhibitors also appears to have significant antitumor activity in multiple other tumor types. An exciting component of immunotherapy is the durability of antitumor responses observed, with some patients achieving disease control for many years. Nevertheless, not all patients benefit, and efforts should thus now focus on improving the efficacy of immunotherapy through the use of combination approaches and predictive biomarkers of response and resistance. There are multiple potential rational combinations using an immunotherapy backbone, including existing treatments such as radiotherapy, chemotherapy or molecularly targeted agents, as well as other immunotherapeutics. The aim of such antitumor strategies will be to raise the tail on the survival curve by increasing the number of long term survivors, while managing any additive or synergistic toxicities that may arise with immunotherapy combinations. Rational trial designs based on a clear understanding of tumor biology and drug pharmacology remain paramount. This article reviews the biology underpinning immuno-oncology, discusses existing and novel immunotherapeutic combinations currently in development, the challenges of predictive biomarkers of response and resistance and the impact of immuno-oncology on early phase clinical trial design.

Previous studies have shown that microRNA-1304 （miR-1304） is dysregulated in certain types of cancers, including non-small cell lung cancer （NSCLC）, and might be involved in tumor survival and/or growth. In this study we investigated the direct target of miR-1304 and its function in NSCLC in vitro. Human lung adenocarcinoma cell lines （A549 and NCI-H1975） were studied. The cell proliferation and survival were investigated via cell counting, MTT and colony-formation assays. Cell apoptosis and cell cycle were examined using annexin V-PE/7-AAD and PI staining assays, respectively. The dual-luciferase reporter assay was used to verify post-transcriptional regulation of heme oxygenase-1 （HO-1） by miR-1304. CRISPR/Cas9 was used to deplete endogenous miR-1304. Overexpression of MiR-1304 significantly decreased the number and viability of NSCLC cells and colony formation, and induced cell apoptosis and Go/ G~ phase cell cycle arrest. HO-1 was demonstrated to be a direct target of miR-1304 in NSCLC cells. Restoration of HO-1 expression by hemin （20 IJmol/L） abolished the inhibition of miR-1304 on cell growth and rescued miR-1304-induced apoptosis in A549 cells. Suppression of endogenous miR-1304 with anti-1304 significantly increased HO-1 expression and promoted cell growth and survival in A549 cells. In 17 human NSCLC tissue samples, miR-1304 expression was significantly decreased, while HO-1 expression was significantly increased as compared to normal lung tissues. MicroRNA-1304 is a tumor suppressor and HO-1 is its direct target in NSCLC. The results suggest the potential for miR-1304 as a therapeutic target for NSCLC.

In recent years, further understanding of the interaction between the immune system and tumor growth has led to the development of several immunotherapies. These immunotherapies include cancer vaccines and immune checkpoint inhibitors that have been tested in various solid tumors, including those traditionally considered non-immunogenic, such as non-small cell lung cancer （NSCLC）. In physiological state, T-cell-mediated immune response against foreign antigens is regulated by stimulatory and inhibitory signals, which are critical to prevent autoimmunity and protect normal tissues after immune system activation.

Activating RAS mutations are common in human tumors. These mutations are often markers for resistance to therapy and subsequent poor prognosis. So far, targeting the RAF-MEK-ERK and PI3K-AKT signaling pathways downstream of RAS is the only promising approach in the treatment of cancer patients harboring RAS mutations. RAL GTPase, another downstream effector of RAS, is also considered as a therapeutic option for the treatment of RAS-mutant cancers. The RAL GTPase family comprises RALA and RALB, which can have either divergent or similar functions in different tumor models. Recent studies on non-small cell lung cancer （NSCLC） have showed that different RAS mutations selectively activate specific effector pathways. This observation requires broader validation in other tumor tissue types, but if true, will provide a new approach to the treatment of RAS-mutant cancer patients by targeting specific downstream RAS effectors according to the type of RAS mutation. It also suggests that RAL GTPase inhibition will be an important treatment strategy for tumors harboring RAS glycine to cysteine （G12C） or glycien to valine （G12V） mutations, which are commonly found in NSCLC and pancreatic cancer.

Aim： Dexamethasone （DEX） is a widely used synthetic glucocorticoid, which has shown anti-cancer efficacy and anti-estrogenic activity. In this study we explored the possibility that DEX might be used as an endocrine therapeutic agent to treat human non-small cell lung cancer （NSCLC）. Methods： The viability and proliferation of human NSCLC cell lines A549 and H1299 were assessed in vitro. Anti-tumor action was also evaluated in A549 xenograft nude mice treated with DEX （2 or 4 mg.kg-l.d-1, ig） or the positive control tamoxifen （50 mg.kg-l.d-1, ig） for 32 d. The expression of estrogen sulfotransferase （EST） in tumor cells and tissues was examined. The intratumoral estrogen levels and uterine estrogen responses were measured. Results： DEX displayed mild cytotoxicity to the NSCLC cells （IC5o 〉500 pmol/L） compared to tamoxifen （IC5o 〈50 pmol/L）, but it was able to inhibit the cell proliferation at low micromolar ranges. Furthermore, DEX （0.1-10 pmol/L） dose-dependently up-regulated EST expression in the cells, and inhibited the cell migration in vitro. Triclosan, a sulfation inhibitor, was able to diminish DEX-caused inhibition on the cell viability. In A549 xenograft nude mice, DEX or tamoxifen administration remarkably suppressed the tumor growth Moreover, DEX administration dose-dependently increased EST expression in tumor tissues, and reduced intratumoral estrogen levels as well as the volumes and weights of uterine. Conclusion： DEX suppresses the growth of A549 xenograft tumors via inducing EST and decreasing estradiol levels in tumor tissues, suggesting that DEX may be used as anti-estrogenic agent for the treatment of NSCLC.

Aim： To investigate the expression profile of microRNAs in inoperable advanced non-small cell lung cancer （NSCLC） patients receiving chemotherapy and the potential relevance of microRNAs to clinicopathological characteristics and prognosis. Methods： Serum samples were taken from 260 inoperable advanced NSCLC patients and 260 healthy individuals. All the patients received cisplatin-based chemotherapy, including NP/NC regimens, GP/GC regimens, and TP/TC regimens. The serum levels of microRNAs （miR-125b, miR-lOb, miR-34a and miR-155） were determined by quantitative real-time PCR. Results： Serum levels of the 4 microRNAs examined in NSCLC patients were significantly increased as compared with healthy individuals. The levels of miR-125b and miR-155 were changed in a similar pattern： the patients with stage IV disease had the highest one, while the patients with stage III A and stage III B disease showed similar increased levels. The levels of miR-lOb and miR-34a in the patients with different stages were increased to similar extent. The level of miR-125b in pooriy differentiated cancer was significantly higher than those in well and moderately differentiated cancers, while the levels of miR-lOb, miR-34a, and miR-155 did not significantly differ with cancer differentiation. Among the 4 microRNAs examined, only miR-125b was significantly associated with therapeutic response, exhibiting higher expression levels in non-responsive patients. Furthermore, the high level of miR-125b was significantly correlated with poor patient survival. A multivariate Cox regression analysis showed that the expression level of miR-125b was an independent prognostic marker in NSCLC patients. Conclusion： Our results suggest that miR-125b is a potential diagnostic or prognostic biomarker for NSCLC. This finding has important implications for development of targeted therapeutics to overcome chemotherapeutic resistance in NSCLC.

Recurrent inactivating mutations in components of SWI/SNF chromatin-remodeling complexes have been identified across cancer types, supporting their roles as tumor suppressors in modulating oncogenic signaling pathways. We report here that SMARCE1 loss induces EGFR expression and confers resistance to MET and ALK inhibitors in non-small cell lung cancers （NSCLCs）. We found that SMARCE1 binds to regulatory regions of the EGFR locus and suppresses EGFR transcription in part through regulating expression of Polycomb Repressive Complex component CBX2. Addition of the EGFR inhibitor gefitinib restores the sensitivity of SMARCEl-knockdown cells to MET and ALK inhibitors in NSCLCs. Our findings link SMARCE1 to EGFR oncogenic signaling and suggest targeted treatment options for SMARCEl-deficient tumors.

Few effective therapeutic options are currently available for the treatment of non-small cell lung cancer （NSCLC） with brain metastases （BM）. Recent evidence shows that NSCLC patients with BMs respond well to afatinib, but little is known about the underlying mechanisms. In this study, we evaluated the efficacy of afatinib in treatment of BMs in mice and investigated whether afatinib could actively penetrate the brain-blood barrier and bind to its target. NSCLC BM model was established in nude mice by intracerebral injection of PC-9.luc cells. The tumors were measured weekly using in vivo quantitative biotuminescence. The mice are administrated afatinib （15, 30 mg.kg-1.d-1, ig） for 14 d. The antitumor efficacy of afatinib was determined by tumor growth inhibition （TGI）, which was calculated as [1-（change of tumor volume in treatment group/control group）×100]. Pharmacokinetic characteristics were measure in mice receiving a single dose of afatinib （30 mg/kg, ig）. Pharmacodynamics of afatinib was also assessed by detecting the expression of pEGFR （Tyr1068） in brain tumor loci using immunohistochemistry. Administration of afatinib （15, 30 mg.kg-1.d-1） dose-dependently inhibited PC-9 tumor growth in the brain with a TGI of 90.2% and 105%, respectively, on d 14. After administration of afatinib （30 mg/kg）, the plasma concentration of afatinib was 91.4±31.2 nmol/L at 0.5 h, reached a peak （417.1±119.9 nmol/L） at 1 h, and was still detected after 24 h. The cerebrospinal fluid （CSF） concentrations followed a similar pattern. The T1/2 values of afatinib in plasma and CSF were 5.0 and 3.7 h, respectively. The AUC（0-24h） values for plasma and CSF were 2375.5 and 29.1 nmol/h, respectively. The plasma and CSF concentrations were correlated （r=0.844, P〈0.01）. Pharmacodynamics study showed that the expression levels of pEGFR were reduced by 90% 1 h after afatinib administration. The Emax was 86.5%, and the EC50 was 0.26 nmol/L. A positive correlation between CSF concentrations and pEGFR modulation was revealed. Afatinib penetrates the BBB in NSCLC BM mice and contributes to the brain tumor response. The CSF exposure level is correlated with the plasma level, which in turn is correlated with the modulation of pEGFR in the tumor tissues. The results support for the potential application of afatinib in NSCLC patients with BMs.