Project description:Identify therapeutic vulnerabilities of palbociclib resistance in metastatic breast cancer patient-derived xenograft models and identify key biomarkers that correlate with development of resistance to inform new treatment directions
Project description:Non-small-cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. The high mortality is very often a consequence of its late diagnosis when the cancer is already locally advanced or has disseminated. Advances in the study of NSCLC tumors have been achieved by using in vivo models, such as patient-derived xenografts. Apart from drug screening, this approach may also be useful for study of the biology of the tumors. In the present study, surgically resected primary lung cancer samples (n = 33) were implanted in immunodeficient mice, and nine were engrafted successfully, including seven adenocarcinomas, one squamous-cell carcinoma, and one large-cell carcinoma. ADC tumors bearing the KRAS-G12C mutation were the most frequently engrafted in our PDX collection. Protein expression of vimentin, ezrin, and Ki67 were evaluated in NSCLC primary tumors and during serial transplantation by immunohistochemistry, using H-score. Our data indicated a more suitable environment for solid adenocarcinoma, compared to other lung tumor subtypes, to grow and preserve its architecture in mice, and a correlation between higher vimentin and ezrin expression in solid adenocarcinomas. A correlation between high vimentin expression and lung adenocarcinoma tumors bearing KRAS-G12C mutation was also observed. In addition, tumor evolution towards more proliferative and mesenchymal phenotypes was already observed in early PDX tumor passages. These PDX models provide a valuable platform for biomarker discovery and drug screening against tumor growth and EMT for lung cancer translational research.
Project description:To probe the tissue source (cancer cell VS stromal cell) of gene expression in the mixed tumor samples, we took advantage of a set of Urothelial Cancer patient-derived xenograft (PDX) models given that the transcriptome in these models is a mixture of human RNA (derived from cancer cells) and mouse RNA (derived from stromal cells).
Project description:Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations do not respond to anti-PD-1 (L1) as well as tumors without an EGFR mutation. We showed in a xenograft mouse model of EGFR-mutated NSCLC that, neither durvalumab nor oleclumab alone inhibited tumor growth compared to the isotype control. In contrast, the combination of both antibodies significantly inhibited tumor growth and increased gene expressions that corresponded to inflammation and T cell function in tumors treated. We used microarrays to study gene expressions that corresponded to enhanced immune response in antibody-treated mice.