The Problem: Approximately 3,300 new cases of salivary gland tumors are reported each year in the USA. Surgery is still the primary treatment modality because chemotherapy and radiotherapy are largely ineffective. As a consequence, the morbidity related to the standard-of-care is high and the 5-year survival for patients with advanced salivary gland cancer is low. Notably, the scarcity of animal models has been recently identified by the NIH/NIDCR as a major impediment for the development of effective therapies for salivary gland cancer. Hypothesis: Cancer stem cells are defined by their ability to self-renew and to generate a phenotypically diverse progeny that recapitulates the tumor of origin. The fact that cancer stem cells can drive tumorigenesis and are resistant to therapy suggests that they may influence the outcome of salivary gland cancer patients. However, little is known about the role of cancer stem cells in the pathobiology of these tumors. In preliminary studies, we identified a sub-population of cells that express high levels of ALDH and CD44 (putative cancer stem cell markers) in human salivary gland tumors. ALDH/CD44 sorting distinguished a sub-population of highly tumorigenic cells from a primary human mucoepidermoid carcinoma and from a neoplastic salivary gland cell line (HSG). Preliminary evidence suggest that endothelial cell-secreted factors enhance the survival and self-renewal of salivary gland cancer stem cells (SGCSC) and that blockade of IL-6 prevent endothelial cell-induced activation of STAT3 (a known regulator of stemness). Notably, the expression of IL-6 and its receptors (IL-6R, gp130) is significantly higher in human salivary gland tumors than in controls. Collectively, these data led to the hypothesis that endothelial cell-initiated signaling is critical for the survival of SGCSC and for response to chemotherapy. To address this hypothesis, we propose the following specific aims:
Specific Aim #1 : To characterize a xenograft model of salivary gland cancer that is generated by human salivary gland cancer stem cells and is vascularized with functional human blood vessels.
Specific Aim #2 : To define the effect of endothelial cell-derived IL-6 on the survival and self-renewal of salivary gland cancer stem cells.
Specific Aim #3 : To study the contribution of the crosstalk between endothelial cells and stem cells on the response of salivary gland tumors to chemotherapy. Significance and Impact: More effective therapies are urgently needed to improve the outcomes of patients with malignant salivary gland cancer. Such therapies are likely to come from studies that enhance the understanding of mechanisms underlying the pathobiology of this disease. Here, we will develop a mouse model of human salivary gland cancer with humanized vasculature and use it to study the role of salivary gland cancer stem cells on response to therapy. Our ultimate goal is to discover new, mechanism-based, therapeutic strategies that improve the survival and quality of life of patients with salivary gland cancer.
to public health of the proposed research lies in its potential to lead to improvements in the clinical outcomes of patients with advanced salivary gland tumors. This is critical since the current benefits of therapy are modest for these patients, and their 5-year survival remains very low. The proposed research outlines strategies for obtaining such improvements by 1) characterizing a model of human salivary gland cancer, and by 2) evaluating the role of tumor-associated endothelial cells and salivary gland cancer stem cells on response to chemotherapy. The information derived from these studies might lead to the identification of new strategies to improve the response of salivary gland tumors to chemotherapy.
|Pearson, Alexander T; Finkel, Kelsey A; Warner, Kristy A et al. (2016) Patient-derived xenograft (PDX) tumors increase growth rate with time. Oncotarget 7:7993-8005|
|Kim, Hong S; Pearson, Alexander T; NÃ¶r, Jacques E (2016) Isolation and Characterization of Cancer Stem Cells from Primary Head and Neck Squamous Cell Carcinoma Tumors. Methods Mol Biol 1395:241-9|
|Warner, Kristy A; NÃ¶r, Felipe; Acasigua, Gerson A et al. (2016) Targeting MDM2 for Treatment of Adenoid Cystic Carcinoma. Clin Cancer Res 22:3550-9|
|Nor, Felipe; Warner, Kristy; Zhang, Zhaocheng et al. (2016) Therapeutic inhibition of the MDM2-p53 interaction prevents recurrence of adenoid cystic carcinomas. Clin Cancer Res :|
|Acasigua, Gerson A; Warner, Kristy A; NÃ¶r, Felipe et al. (2015) BH3-mimetic small molecule inhibits the growth and recurrence of adenoid cystic carcinoma. Oral Oncol 51:839-47|
|Adams, April; Warner, Kristy; Pearson, Alexander T et al. (2015) ALDH/CD44 identifies uniquely tumorigenic cancer stem cells in salivary gland mucoepidermoid carcinomas. Oncotarget 6:26633-50|
|Mochizuki, Daiki; Adams, April; Warner, Kristy A et al. (2015) Anti-tumor effect of inhibition of IL-6 signaling in mucoepidermoid carcinoma. Oncotarget 6:22822-35|
|Zhang, Zhaocheng; Dong, Zhihong; Lauxen, Isabel S et al. (2014) Endothelial cell-secreted EGF induces epithelial to mesenchymal transition and endows head and neck cancer cells with stem-like phenotype. Cancer Res 74:2869-81|
|Krishnamurthy, Sudha; Warner, Kristy A; Dong, Zhihong et al. (2014) Endothelial interleukin-6 defines the tumorigenic potential of primary human cancer stem cells. Stem Cells 32:2845-57|
|NÃ¶r, Carolina; Zhang, Zhaocheng; Warner, Kristy A et al. (2014) Cisplatin induces Bmi-1 and enhances the stem cell fraction in head and neck cancer. Neoplasia 16:137-46|
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