Salivary cancers are a devastating group of malignancies treated almost exclusively by surgical excision with or without radiation. The low incidences, multiple histologies, lack of molecular details and inadequate infrastructure for collecting these tumors have each contributed to the relative paucity of treatment options. We suggest that the largest impediment blocking understanding of salivary cancers and advancement of therapy has been the lack or scarcity of validated xenograft models or cell lines for study. Without freely available xenografts or cell lines mechanistic or pre-clinical studies ar not possible. Here, we propose to create mouse xenograft models of human salivary cancers of multiple histologies. We have xenografted multiple salivary types including: adenoid cystic, adenocarcinoma not otherwise specified, polymorphous low grade adenocarcinoma, carcinoma ex-pleomorphic adenoma, and salivary ductal carcinoma. We also propose to create cell lines from multiple histological types of salivary cancer using primary tumors or murine xenografted tumors as starting material. For development of cell lines, we continue to optimize our culture environment with adjustment of tumor dissociation protocols, media, plate coatings, and culture hypoxia. By making these adjustments, we have increased our success of early cell culture derived from multiple salivary cancer types, and we currently have active early passages of cells derived from adenocarcinoma not otherwise specified, polymorphous low grade adenocarcinoma, and carcinoma ex-pleomorphic adenoma. Once xenografts and cell lines are created, they will be validated by comparison of morphology (xenografts) and gene expression (xenografts and cell cultures). We have the infrastructure for collection of salivary cancers from surgical resections and have developed expertise in processing of the tumors for short-term culture and murine xenograft modeling. We will leverage these resources to create and validate murine xenograft models and cell lines for salivary cancers. These validated cell lines and xenografted tumors will be critical to advance molecular understanding of salivary cancers and will be needed for advancement of therapy.
Advancement of therapy for salivary cancers has been hampered by the lack of validated cell lines or xenograft models. We have expertise in short-term culturing, xenograft modeling of head &neck cancers from primary tumors and more recently have successfully focused on salivary cancers of various histologies (e.g. adenoid cystic carcinoma - xenografts;adenocarcinoma not otherwise specified - xenograft/ culture passage;polymorphous low grade adenocarcinoma - xenografts/early culture;carcinoma ex-pleomorphic adenoma - xenografts/early culture;mucoepidermoid carcinoma - xenograft;salivary ductal carcinoma xenograft). To advance therapy for salivary cancer, we will leverage the knowledge we have gained to increase the number of validated xenografted salivary cancers available for study, as well as use primary and xenografted tumors for initiation of cell lines for these difficult to culture tumors.
|Panaccione, Alex; Chang, Michael T; Carbone, Beatrice E et al. (2016) NOTCH1 and SOX10 are Essential for Proliferation and Radiation Resistance of Cancer Stem-Like Cells in Adenoid Cystic Carcinoma. Clin Cancer Res 22:2083-95|