The Problem: It is estimated that about 1,200 new cases of adenoid cystic carcinoma (ACC) are diagnosed each year in the United States. These tumors are characterized by relentless growth and frequent recurrence. As a consequence, the 15-year survival rate for these patients is unacceptably low (40%). Since no drug has been approved for ACC, the primary treatment still is radical surgery, which is typically associated with high morbidity and poor quality of life. The lack of cell lines and mouse models has been identified as major roadblocks for the discovery of new therapies for ACC. Improvements in the survival of patients with ACC are likely to come from studies performed in animal models that mimic the human tumor microenvironment and enable the discovery of safe and effective mechanism-based therapies for this malignancy. Hypothesis: We recently developed a method to generate human ACC cell lines that is consisted of culturing cells retrieved from surgical specimens for 7-10 days in ultra-low attachment plates. Temporary exposure to non-adherent conditions eliminates stromal cells by anoikis and purifies cultures of tumorigenic ACC. Here, we will use our new ACC cell lines to develop a method for generation of xenograft tumors with humanized vasculature that is optimized for developmental therapeutics studies. The ACC xenograft model will be used to evaluate the effect of novel small molecule inhibitors of the MDM2/Bcl-2 signaling axis in pre-clinical trials. Notably, the oncoproteins MDM2 and Bcl-2 protect tumor cells against apoptosis, correlate with the aggressiveness of ACC, and are likely involved in resistance to chemotherapy. The underlying hypothesis of this work is that therapeutic inhibition of the MDM2/Bcl-2 signaling axis sensitizes adenoid cystic carcinomas to chemotherapy in pre-clinical models of ACC. To address this hypothesis, we propose the following aims:
Specific Aim #1 : To develop and characterize a xenograft model of adenoid cystic carcinoma with humanized vasculature that is suitable for pre-clinical trials.
Specific Aim #2 : To define the effect of therapeutic inhibition of the MDM2/Bcl-2 signaling axis on adenoid cystic carcinoma growth, angiogenesis, and recurrence.
Specific Aim #3 : To determine the effect of therapeutic inhibition of the MDM2/Bcl-2 signaling axis on adenoid cystic carcinoma resistance to a conventional chemotherapeutic drug (Cisplatin). Significance: This proposal is centered on mechanistic studies and pre-clinical trials with novel small molecule inhibitors of the MDM2/Bcl-2 pathway using a unique xenograft model of ACC with humanized vasculature. Small molecule inhibitors of MDM2 and Bcl-2 have been well tolerated by patients in Phase I and II trials. Therefore, successful outcome of the studies proposed here can rapidly be followed by a clinical trial testing these drugs in patients with ACC. Our research team is fully committed to the development of a mechanism- based therapy that will enhance the survival and quality of life of patients with adenoid cystic carcinoma.
The development of safe and effective therapies for adenoid cystic carcinoma has been hindered by the lack of appropriate experimental animal models. This proposal is focused on the development and characterization a new mouse model of adenoid cystic carcinoma, and on the evaluation of novel drugs that target the oncogenic proteins MDM2 and Bcl-2 in these tumors. Our ultimate goal is to develop a mechanism-based therapy that prolongs the survival and enhances the quality of life of patients with adenoid cystic carcinoma.
|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|
|Swiecicki, Paul L; Bellile, Emily; Sacco, Assuntina G et al. (2016) A phase II trial of the BCL-2 homolog domain 3 mimetic AT-101 in combination with docetaxel for recurrent, locally advanced, or metastatic head and neck cancer. Invest New Drugs 34:481-9|
|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|
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