PROJECT 3 ABSTRACT Esophageal cancer is a common and deadly disease with inadequate therapies. Systemic therapy remains reliant upon empiric chemotherapy, given alone in the palliative setting and in conjunction with radiation for adjuvant care. The convergence of our rapidly expanding knowledge of the cancer genome and the development of a myriad of targeted agents has created a new and unique opportunity to advance rational, biomarker-driven therapies for esophageal cancer. Our genomic studies of esophageal cancers have identified two dominant classes of targets: highly recurrent amplifications targeting receptor tyrosine kinases, most frequently EGFR and ERBB2 (Her2), and amplified modulators of the cell cycle, Cyclin D1, Cyclin E1 and CDK6. Despite strong genomic rationale for these targets and the available and emerging inhibitors, we lack pre-clinical data to guide the development strategies to exploit these targets. Therefore, we propose to develop strategies to target esophageal cancers harboring targetable genomic alterations of receptor tyrosine kinases and of cell cycle mediators utilizing genomically-characterized model systems in in vitro and in vivo testing of therapeutic agents. We will tests hypotheses regarding means to target tumors, both with single targeted therapies and with rational combinations. Throughout this proposal, we integrate efforts with the other projects in this Project Grant and make extensive use of core resources through this Project and evaluate targeted strategies that for both esophageal squamous cell carcinoma and esophageal adenocarcinoma.
In Aim 1, we propose to evaluate the cell cycle kinase CDK2 as a therapeutic target in esophageal carcinomas by evaluating this target using genetic and pharmacologic tools in esophageal cancer models with genomic lesions that make them more likely dependent upon CDK2, amplifications of genes encoding cyclin D1 and cyclin E1.
In Aim 2, we evaluate distinct classes of small molecule and antibody tyrosine kinase inhibitors in esophageal cancer model systems with genomic alterations leading to oncogenic activation of ERBB family kinases EGFR and ERBB2. Furthermore, in Aim 2 we also test the ability to augment effects of ERBB-directed therapy in esophageal cancer models by combinations with inhibitors of either the MAPK or PI3-K pathway. Finally, in Aim 3 we evaluate the phenomena we have observed that esophageal cancers often harbor genomic aberrations impacting both cell cycle mediators and ERBB-family kinases in the same tumor, suggesting that combining inhibitors of these two sets of targets may be efficacious for these tumors. We therefore propose to characterize the patterns of co-occurrence of these targets in the genomes of these cancers and their co-expression in a large panel of tissue samples. Additionally, we will utilize the example of esophageal cancer models with co-amplification of both EGFR and Cyclin D1 to systematically evaluate distinct methods of combing inhibitors to these pathways. Together, these three aims are designed to pursue specific hypotheses that will allow us to much more rapidly develop new more effective therapeutic strategies for patients with these deadly diseases.
PROJECT 3 NARRATIVE Esophageal cancer is a deadly disease for which new, more effective therapies are desperately needed. Building upon emerging results from the study of biology of esophageal cancer, this proposal aims to develop more effective therapeutic strategies for this disease by systematically testing new drugs that target the key genes that drive esophageal cancers.
|Zhou, Jin; Wu, Zhong; Wong, Gabrielle et al. (2017) CDK4/6 or MAPK blockade enhances efficacy of EGFR inhibition in oesophageal squamous cell carcinoma. Nat Commun 8:13897|
|Whelan, K A; Chandramouleeswaran, P M; Tanaka, K et al. (2017) Autophagy supports generation of cells with high CD44 expression via modulation of oxidative stress and Parkin-mediated mitochondrial clearance. Oncogene 36:4843-4858|
|Whelan, Kelly A; Merves, Jamie F; Giroux, Veronique et al. (2017) Autophagy mediates epithelial cytoprotection in eosinophilic oesophagitis. Gut 66:1197-1207|
|Harmeyer, Kayla M; Facompre, Nicole D; Herlyn, Meenhard et al. (2017) JARID1 Histone Demethylases: Emerging Targets in Cancer. Trends Cancer 3:713-725|
|Facompre, Nicole D; Sahu, Varun; Montone, Kathleen T et al. (2017) Barriers to generating PDX models of HPV-related head and neck cancer. Laryngoscope 127:2777-2783|
|Yoshioka, Masahiro; Ohashi, Shinya; Ida, Tomomi et al. (2017) Distinct effects of EGFR inhibitors on epithelial- and mesenchymal-like esophageal squamous cell carcinoma cells. J Exp Clin Cancer Res 36:101|
|Natsuizaka, Mitsuteru; Whelan, Kelly A; Kagawa, Shingo et al. (2017) Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma. Nat Commun 8:1758|
|Giroux, Véronique; Lento, Ashley A; Islam, Mirazul et al. (2017) Long-lived keratin 15+ esophageal progenitor cells contribute to homeostasis and regeneration. J Clin Invest 127:2378-2391|
|Fichter, Christiane Daniela; Przypadlo, Camilla Maria; Buck, Achim et al. (2017) A new model system identifies epidermal growth factor receptor-human epidermal growth factor receptor 2 (HER2) and HER2-human epidermal growth factor receptor 3 heterodimers as potent inducers of oesophageal epithelial cell invasion. J Pathol 243:481-495|
|Facompre, Nicole D; Harmeyer, Kayla M; Sole, Xavier et al. (2016) JARID1B Enables Transit between Distinct States of the Stem-like Cell Population in Oral Cancers. Cancer Res 76:5538-49|
Showing the most recent 10 out of 149 publications