Delivery of gefitinib with an immunostimulatory nanocarrier improves therapeutic efficacy in lung cancer.

Background: Combining different cancer treatments represents a promising strategy to improve the therapeutic outcome for lung cancer patients with or without druggable gene alterations. Methods: We previously developed a polyethylene glycol-based (PEG-based) immunostimulatory nanocarrier (PEG2k-Fmoc-NLG919) which can efficiently co-deliver an indoleamine 2,3-dioxygenase-1 (IDO1) inhibitor and the chemotherapeutic agent, paclitaxel. This method was found to improve cancer therapy by simultaneously performing immuno- and chemo-therapy. However, whether this nanocarrier could deliver targeted drugs to implement targeted therapy together with immunotherapy remains unclear. Results: Here, we report that the delivery of the classical tyrosine kinase inhibitor (TKI), gefitinib, with the optimized PEG5k-Fmoc-NLG919 nanocarrier, increased the sensitivity of lung cancer cells to gefitinib in vitro. Gefitinib was gradually but sufficiently released from the nanocarrier with comparable capacity to inhibit epidermal growth factor receptor (EGFR) activity as using free gefitinib directly. More importantly, treatment with gefitinib-loaded PEG5k-Fmoc-NLG919 could suppress lung tumor development more efficiently than gefitinib alone in vivo by inducing an immune active microenvironment with more functional CD8+ T cells and less regulatory T cell infiltration. Conclusions: Our study therefore demonstrates that delivery of small molecular targeted drugs with the immunostimulatory nanocarrier is a straightforward strategy for improving antitumor response for lung cancer therapy

Kaplan-Meier curves for disease-free survival by treatment arm.

<p>Kaplan-Meier curves for disease-free survival by treatment arm.</p

Randomized Adjuvant Chemotherapy of <i>EGFR</i>-Mutated Non-Small Cell Lung Cancer Patients with or without Icotinib Consolidation Therapy

<div><p>Background</p><p>Epidermal growth factor receptor (<i>EGFR</i>) mutations occur in up to 50% of Asian patients with non-small cell lung cancer (NSCLC). Treatment of advanced NSCLC patients with <i>EGFR</i>-tyrosine kinase inhibitor (<i>EGFR</i>-TKI) confers a significant survival benefit. This study assessed the efficacy and safety of chemotherapy with or without icotinib in patients undergoing resection of stage IB to ⅢA <i>EGFR</i>-mutated NSCLC.</p><p>Methods</p><p>Patients with surgically resected stage IB (with high risk factors) to ⅢA <i>EGFR</i>-mutated NSCLC were randomly assigned (1:1) to one of two treatment plans. One group received four cycles of platinum-based doublet chemotherapy every three weeks, and the other group received platinum-based chemotherapy supplemented with consolidation therapy of orally administered icotinib (125 mg thrice daily) two weeks after chemotherapy. The icotinib treatment continued for four to eight months, or until the occurrence of disease relapse, metastasis or unacceptable icotinib or chemotherapy toxicity. The primary endpoint was disease-free survival (DFS).</p><p>Results</p><p>41 patients were enrolled between Feb 9, 2011 and Dec 17, 2012. 21 patients were assigned to the combined chemotherapy plus icotinib treatment group, while 20 patients received chemotherapy only. DFS at 12 months was 100% for icotinib-treated patients and 88.9% for chemotherapy-only patients (p = 0. 122). At 18 months DFS for icotinib-treated vs. chemotherapy-only patients was 95.2% vs. 83.3% (p = 0. 225), respectively, and at 24 months DFS was 90.5% vs. 66.7% (p = 0. 066). The adverse chemotherapy effects predominantly presented as gastrointestinal reactions and marrow suppression, and there was no significant difference between the two treatment groups. Patients in the chemotherapy plus icotinib treatment group showed favorable tolerance to oral icotinib.</p><p>Conclusions</p><p>The results suggest that chemotherapy plus orally icotinib displayed better DFS compared with chemotherapy only, yet the difference in DFS was not significant. We would think the preliminary result here was promising, and further trials with larger sample sizes might confirm the efficiency of adjuvant TKI in selected patients.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT02430974" target="_blank">NCT02430974</a></p></div

Trial profile.

<p>Trial profile.</p

TUSC3 accelerates cancer growth and induces epithelial-mesenchymal transition by upregulating claudin-1 in non-small-cell lung cancer cells

Lung cancer is the most frequent cause of cancer-related deaths worldwide, but its molecular pathogenesis is poorly understood. The tumor suppressor candidate 3 (TUSC3) gene is located on chromosome 8p22 and is universally acknowledged as a cancer suppressor. However, our research has demonstrated that TUSC3 expression is significantly upregulated in non-small-cell lung cancer compared to benign controls. In this study, we analyzed the consequences of TUSC3 knockdown or overexpression on the biological functions of non-small-cell lung cancer cell lines. To identify the molecules and signaling pathways with which TUSC3 might interact, we completed immunoblotting, quantitative polymerase chain reaction, microarray, co-immunoprecipitation, and immunofluorescence assays. We demonstrated that TUSC3 knockdown leads to decreased proliferation, migration, and invasion, and reduced xenograft tumor growth of non-small-cell lung cancer cell lines, whereas opposite results were observed with overexpression of TUSC3. In addition, TUSC3 knockdown suppressed epithelial-mesenchymal transition by downregulating the expression of claudin-1, which plays an indispensable role in EMT progress. On the contrary, overexpression of TUSC3 significantly enhanced EMT progress by upregulating claudin-1 expression. Overall, our observations suggest that TUSC3 accelerates cancer growth and induces the epithelial-mesenchymal transition in non-small-cell lung cancer cells; we also identified claudin-1 as a target of TUSC3