Purpose
The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS).

Patients and Methods
In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for EGFR mutations. Mutation-positive patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before two-to-one random assignment to 40 mg afatinib per day or up to six cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 21 days. The primary end point was PFS by independent review. Secondary end points included tumor response, overall survival, adverse events, and patient-reported outcomes (PROs).

Results
A total of 1,269 patients were screened, and 345 were randomly assigned to treatment. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR], 0.58; 95% CI, 0.43 to 0.78; P = .001). Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). The most common treatmentrelated adverse events were diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for chemotherapy. PROs favored afatinib, with better control of cough, dyspnea, and pain.

Conclusion
Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.

Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations

KRAS Mutations and Primary Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib

The effects of titania nanotubes with embedded silver oxide nanoparticles on bacteria and osteoblasts

Tissue engineering is promising to meet the increasing need for bone regeneration. Nanostructured calcium phosphate (CaP) biomaterials/scaffolds are of special interest as they share chemical/crystallographic similarities to inorganic components of bone. Three applications of nano-CaP are discussed in this review: nanostructured calcium phosphate cement (CPC); nano-CaP composites; and nano-CaP coatings. The interactions between stem cells and nano-CaP are highlighted, including cell attachment, orientation/morphology, differentiation and in vivo bone regeneration. Several trends can be seen: (i) nano-CaP biomaterials support stem cell attachment/proliferation and induce osteogenic differentiation, in some cases even without osteogenic supplements; (ii) the influence of nano-CaP surface patterns on cell alignment is not prominent due to non-uniform distribution of nano-crystals; (iii) nano-CaP can achieve better bone regeneration than conventional CaP biomaterials; (iv) combining stem cells with nano-CaP accelerates bone regeneration, the effect of which can be further enhanced by growth factors; and (v) cell microencapsulation in nano-CaP scaffolds is promising for bone tissue engineering. These understandings would help researchers to further uncover the underlying mechanisms and interactions in nano-CaP stem cell constructs in vitro and in vivo, tailor nano-CaP composite construct design and stem cell type selection to enhance cell function and bone regeneration, and translate laboratory findings to clinical treatments.

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Bone tissue engineering via nanostructured calcium phosphate biomaterials and stem cells.

Nano-scale modification of titanium implant surfaces to enhance osseointegration

Effects of micropitted/nanotubular titania topographies on bone mesenchymal stem cell osteogenic differentiation.

siRNA delivered by EGFR-specific scFv sensitizes EGFR-TKI-resistant human lung cancer cells

Overexpression of human epidermal growth factor receptor type2 (HER2) is closely associated with aggressive progression and poor prognosis in non-small cell lung cancer (NSCLC). Here, we generated an EGFR-scFv-arginine nonamer peptide fusion protein (scFv-9R) as a cargo to deliver HER2 specific siRNA into HER2-positive NSCLC cells both in vitro and in vivo. HER2-siRNAs delivered by scFv-9R effeciently silenced HER2 expression in EGFR-positive NSCLC cells, and consequently resulted in G1 arrest and cell growth inhibition. Importantly, intravenous injection of scFv-9R/HER2-siRNA complex markedly suppressed growth of EGFR-positive NSCLC xenograft in nude mice, resulting from downregulated HER2 expression, reduced cell proliferation and enhanced cell apoptosis. Collectively, our study provides a novel therapeutic strategy for the treatment of EGFR-positive, HER2-overexpressed NSCLC.

/pdf/her2-sirna-delivered-by-egfr-specific-single-chain-antibody-3r9x34kzry.pdf

HER2-siRNA delivered by EGFR-specific single chain antibody inhibits NSCLC cell proliferation and tumor growth.

The invention discloses a fusion protein based on anti-EGFR single-chain antibody and arginine nonamer, and applications of the fusion protein. The fusion protein comprises a heavy chain variable region and a light chain variable region which are connected via connection peptides; the terminal of the light chain variable region is connected with the arginine nonamer; and amino acid sequence of the arginine nonamer is represented by SEQ ID No.3. According to the fusion protein, the heavy chain variable region and the light chain variable region of the anti-EGFR single-chain antibody are connected via the selected connection peptides, so that specificity and affinity of combination of the antibody with EGFR are maintained, and targeting performance of the constructed fusion protein on EGFR is ensured; the size of the fusion protein is reduced, so that on the one hand construction, expression and purification of the fusion protein are convenient, and cost is reduced, and on the other hand, combination of the fusion protein on EGFR is ensured, demands on molecular size and antibody activity during cellular internalization are ensured, and feasibility and accuracy of the combination of the fusion protein on EGFR and targeting tumor cellular internalization are ensured.

Li Liu

Papers

Effects of micropitted/nanotubular titania topographies on bone mesenchymal stem cell osteogenic differentiation.

siRNA delivered by EGFR-specific scFv sensitizes EGFR-TKI-resistant human lung cancer cells

HER2-siRNA delivered by EGFR-specific single chain antibody inhibits NSCLC cell proliferation and tumor growth.

Fusion protein based on anti-EGFR single-chain antibody and arginine nonamer, and applications of fusion protein