In 2012 the estimated incidence of salivary gland cancers (SGC) in the USA was 5-6% of the expected40,250 head and neck cancers, representing an incidence of 0.9 per 100,000. Although rare overall, in thepatient population affected, SGC is a devastating disease as most primary tumors return within 10 years andare uniformly fatal, and conventional chemotherapy provides transient, if any, benefit. In particular, the lack ofmodels for preclinical drug testing and for exploration of the molecular events leading to SGC has crippledprogress on this deadly disease. The primary goals of this study are to develop a preclinical platform of SGC,and to elucidate the molecular pathogenesis of SGC, with the overarching goal of providing a rationale forfocused development of targeted treatments. To achieve the first goal, we will develop a human-in-mouseSGC xenograft platform. Implanting tumors in mice allows the generation of substantial amounts of tumortissue that facilitates complex testing not possible in the small, original human sample. The tumors aremaintained alive on mice to generate tissue for the characterization of molecular lesions in SGC, and tovalidate the xenografts as models that faithfully maintain the features in the originator tumor. We hope todevelop an in vivo platform as close to the clinic as possible that will enable future drug development andbiomarker discovery. To achieve the second goal we propose a detailed molecular characterization of primarytumors and xenografts, aided by Systems Biology integrative analyses. Our approach will combine staticanalysis of genetic events, and transcriptome and phosphoproteome analysis, with functional genetic screensusing lentiviral based short-hairpin RNA (shRNA) libraries, to identify of genes and pathways essential fortumor survival. Together, this multi-level characterization will identify functional pathways for future therapeutictargeting, generate new hypotheses regarding the pathogenesis of salivary glands cancer, and promote thefuture development of in vivo models in which to test these hypotheses.)
Salivary gland cancer is a rare and understudied disease. The biology of salivary gland cancer is largely unknown, and no major breakthroughs have occurred in the treatment of advanced salivary gland cancer patients. Furthermore, there are virtually no reliable molecular markers to aid in the diagnosis or prognosis of salivary gland tumors. Likewise, there remains a wide gap in our understanding of molecular alterations that contribute to salivary gland cancer. Understanding such events that would allow us to propose or devise additional treatment strategies that can control the unfortunate prognostic outcomes of some of these tumors.
| Keysar, Stephen B; Eagles, Justin R; Miller, Bettina et al. (2018) Salivary Gland Cancer Patient-Derived Xenografts Enable Characterization of Cancer Stem Cells and New Gene Events Associated with Tumor Progression. Clin Cancer Res 24:2935-2943 |
