PROJECT 2 ABSTRACT The long-term objective of this Project centers on elucidation of the mechanisms whereby extra-cellular signals are sensed by the cell cycle machinery and regulate cell cycle progression during neoplastic conversion of epithelium. Our current work focus on the mitogenically responsive D-type cyclin, cyclin D1, and more specifically how the aberrant accumulation of cyclin D1 contributes to esophageal cancers and whether our enhanced understanding of cyclin D1 regulation can contribute to new and more effective therapies for this deadly disease. Progress in the characterization of the mechanism of cyclin D1 overexpression in cancer has been hindered by lack of information regarding the nature of the E3 ubiquitin ligase that directs cyclin D1 proteolysis. We have identified the SCF (FBX4-?B crystallin) that controls cyclin D1 ubiquitination and degradation in esophageal cancer. Importantly, the progress we have made during the past 5 years has provided key insights into the mechanisms whereby dysregulated cyclin D/CDK4 activity contributes to the neoplastic conversion of a normal cell and to the ongoing proliferation and survival of esophageal tumor clones. This progress now provides a framework critical for proper utilization, evaluation and interpretation of the effects that can be achieved by treatment of cancer patients with the evolution of highly specific small molecule inhibitors of the cyclin D1/CDK4 kinase. Having developed this framework describing mechanisms of cyclin D1 dysregulation in esophageal cancer (in particular, esophageal squamous cell cancer or ESCC), we are now in an ideal position to translate these novel concepts and in doing so develop effective therapies for a cancer lacking in any significant therapeutic intervention. As direct result of this progress, we now propose an overarching new hypothesis wherein the SCFFBX4-?B crystallin E3 ligase maintains threshold levels of the cyclin D1/CDK4 kinase critical for esophageal cell growth and homeostasis. We further hypothesize that therapeutic strategies targeting the cyclin D1/CDK4 kinase, or key downstream effectors (such as PRMT5), could be of significant therapeutic benefit in the treatment of esophageal cancer. Experiments proposed in this grant will directly determine the physiological contribution of Fbxo4 to the regulation of cyclin D1 accumulation and neoplastic activity in esophageal epithelium (Aim 1);assess the therapeutic efficacy of targeting the catalytic partner for cyclin D1 (CDK4/6) in esophageal cancer (Aim 2);and finally, address the mechanistic contributions of the histone methyltransferase, PRMT5, to the neoplastic activities of cyclin D1/CDK4 in esophageal cancer (Aim 3). Collectively, this unified approach is utilizing mechanistic findings as a platform for new translational/therapeutic strategies in ESCC that have potential applicability to other related cancers, such as head/neck squamous and lung squamous cell cancers. Our mechanistic approaches and translational applications are unified by integrated and synergistic approached with Projects 1 and 3, all supported by the Core Facilities.
PROJECT 2 NARRATIVE Overexpression of cyclin D1 in human esophageal cancer occurs frequently as a consequence of mutations in the machinery that destroys the cyclin D1 protein. In order to develop effective therapies that counter these events, we have identified the critical component of the machinery, Fbxo4, which directs destruction of the cyclin D1 protein. The experiments described in this proposal will evaluate the biological properties of Fbxo4 in esophageal cancer and determine the efficacy of therapeutic approaches that inhibit the catalytic function of cyclin D1CDK4.
|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|
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|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|
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