ABSTRACT
PURPOSE: Evaluating drug responses using primary patient-derived cells ex vivo represents a potentially rapid and efficient approach to screening for new treatment approaches. Here, we sought to identify neratinib combinations in HER2 mutant non-small cell lung cancer (NSCLC) patient xenograft-derived organotypic spheroids (XDOTS) using a short-term ex vivo system. EXPERIMENTAL DESIGN: We generated two HER2-mutant NSCLC PDX models [DFCI359 (HER2 exon19 755_757LREdelinsRP) and DFCI315 (HER2 exon20 V777_G778insGSP)] and used the PDX tumors to generate XDOTS. Tumor spheroids were grown in a microfluidic device and treated ex vivo with neratinib-based drug combinations. Live/dead quantification was performed by dual-labeling deconvolution fluorescence microscopy. The most efficacious ex vivo combination was subsequently validated in vivo using the DFCI359 and DFCI315 PDXs and a HER2 YVMA genetically engineered mouse model. RESULTS: Both neratinib and afatinib, but not gefitinib, induced cell death in DFCI359 XDOTS. The combinations of neratinib/trastuzumab and neratinib/temsirolimus enhanced the therapeutic benefit of neratinib alone in DFCI315 and DFCI359. The combination of neratinib and trastuzumab in vivo was more effective compared with single-agent neratinib or trastuzumab and was associated with more robust inhibition of HER2 and downstream signaling. CONCLUSIONS: The XDOTS platform can be used to evaluate therapies and therapeutic combinations ex vivo using PDX tumors. This approach may accelerate the identification and clinical development of therapies for targets with no or few existing models and/or therapies.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Mutation , Receptor, ErbB-2/genetics , Animals , Apoptosis/drug effects , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Proliferation/drug effects , Female , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mice , Mice, Inbred NOD , Mice, SCID , Quinolines/administration & dosage , Receptor, ErbB-2/antagonists & inhibitors , Receptor, ErbB-2/metabolism , Spheroids, Cellular , Trastuzumab/administration & dosage , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Photolithographic patterning of a xanthate precursor to poly(3,4-diphenyl-2,5-thienylene vinylene) is described. Unlike xanthate precursors to poly(p-phenylene vinylene), the thienylene vinylene analogue patterns as a positive tone resist. Characterization of irradiated films reveals photooxidative cleavage of the vinylene linker decreases the molecular weight of the polymer (increasing the solubility of the UV-exposed areas). As a result of the mechanism, the developed pattern sees no UV light exposure, which is a significant advantage compared with negative-tone-conjugated polymer resists. Single micron resolution of a low-bandgap polymer is achieved in an efficient and scalable process.
