BACKGROUND Adding radiotherapy (RT) to systemic therapy improves progression-free survival (PFS) and overall survival (OS) in oligometastatic non-small cell lung cancer (NSCLC). Whether these findings translate to EGFR-mutated NSCLC remains unknown. The SINDAS trial (NCT02893332) evaluated first-line tyrosine kinase inhibitor (TKI) therapy for EGFR-mutated synchronous oligometastatic NSCLC, and randomized to up-front RT vs. no RT; we now report the pre-specified interim analysis at 68% accrual. METHODS Inclusion criteria were biopsy-proven EGFR-mutated adenocarcinoma (per amplification refractory mutation system or next generation sequencing), with synchronous (newly-diagnosed, treatment-naïve) oligometastatic (≤5 metastases; ≤2 lesions in any one organ) NSCLC without brain metastases. All patients received a first-generation TKI (gefitinib, erlotinib, or icotinib), and randomization was between no RT vs. RT (25–40 Gy in 5 fractions depending on tumor size/location) to all metastases and the primary tumor/involved regional lymphatics. The primary endpoint (intention-to-treat) was PFS. Secondary endpoints included OS and toxicities. All statistical tests were 2-sided. RESULTS A total of 133 patients (n = 65 TKI only, n = 68 TKI+RT) were enrolled (2016–2019). The median follow-up was 23.6 months. The respective median PFS was 12.5 months vs. 20.2 months (p < .001), and the median OS was 17.4 months vs. 25.5 months (p < .001) for TKI only vs TKI+RT. Treatment yielded no grade 5 events and a 6% rate of symptomatic grade 3–4 pneumonitis in the TKI+RT arm. Based on the efficacy results of this pre-specified interim analysis, the ethics committee recommended premature cessation of this trial. CONCLUSIONS As compared to a first-line TKI alone, addition of up-front local therapy using RT statistically significantly improved PFS and OS for EGFR-mutated NSCLC.

Abstract. Previous studies have demonstrated that nicotinamide N-methyltransferase (NNMT) is aberrantly expressed in a number of tumors. In the present study, it was demonstrated that the gene and protein levels of NNMT were significantly increased in gastric cancer cells. Furthermore, upregulation of NNMT significantly increased the expression of mesenchymal markers, including α-smooth muscle actin (SMA), vimentin and fibronectin, but decreased the levels of epithelial cadherin. Since transforming growth factor (TGF)-β1 may serve a key function in epithelial-mesenchymal transition (EMT), the effects of NNMT on the expression of TGF-β1 were investigated in BGC-823 cells. The results demonstrated that overexpression of NNMT significantly induced the expression of TGF-β1. However, knockdown of NNMT inhibited the expression of TGF-β1, mothers against decapentaplegic homolog (Smad)2 and α-SMA. Additionally, pre-incubation with TGF-β1 partially eliminated NNMT-mediated changes in EMT. Collectively, the results demonstrated that upregulation of NNMT in gastric cancer cells may increase the expression of TGF-β1, therefore activating TGF-β1/Smad signaling, which in turn promotes EMT.

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Immunogene therapy provides a new strategy for the treatment of colorectal cancer. Compared to plasmid DNA, mRNA possesses several advantages as a therapeutic nucleic acid material and shows high potential in cancer therapy. Although efforts have been made to conquer the limited efficiency of mRNA delivery, most of the current mRNA vectors possess complex structures or compositions, which introduces additional toxicity and hinders their further clinical application. Hence, it is highly necessary to develop potent mRNA delivery systems with simple structures. Here, we report efficient mRNA delivery using the biodegradable micelle delivery system of DMP (DOTAP-mPEG-PCL). Biodegradable DMP micelles were simply prepared by the self-assembly of cationic lipid DOTAP and the diblock polymer monomethoxy poly­(ethylene glycol)–poly­(ε-caprolactone). With an average size of only 30 nm, we proved that these single-structured cationic micelles are highly potent in condensing and protecting mRNA molecules, with a delivery efficiency of 60.59% on C26 mouse colon cancer cells. The micelles triggered specific internalization pathways and were fully degraded in vivo. After binding with IL-22BP (interleukin-22 binding protein)-encoding mRNA, a strongly elevated IL-22BP mRNA level was detected in C26 cells. After intraperitoneal and intratumoral injection of the DMP/mIL-22BP complex, strong inhibition effects on C26 colon cancer models were observed, with high therapeutic efficiency and safety when systemically administrated. These data suggest that the DMP micelle is an advanced single-structured mRNA delivery system with high safety.

Small interfering RNA (siRNA)-based gene therapy has provided an alternative strategy for cancer therapy. One of the key components within gene therapy process is the delivery system. As a novel non-viral gene vector, DMP, prepared by modifying mPEG-PCL micelle with cationic DOTAP lipid, has been prepared and successfully applied in plasmid DNA-based colon cancer gene therapy study. However, its potential in siRNA delivery is unknown. In this study, the preparation process of DMP was optimized and the anti-cancer efficacies of the DMP/siMcl1 and DMP/siBcl-xl complexes were studied on a mouse colon cancer model. Our results demonstrated that DMP cationic micelle-delivered siRNAs could effectively inhibit the growth of C26 colon cancer cells in vitro . Meanwhile, intratumoral administration of DMP/siMcl1 and DMP/siBcl-xl complexes obviously suppressed subcutaneous tumor model in vivo. These results suggest the DMP/siRNA complex to be a potential candidate for cancer gene therapy.

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Increase of the number of infiltrating macrophages and its contribution to the tumor inflammatory microenvironment may result in the development of the type I endometrial carcinoma.