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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA098101-11
Application #
8741116
Study Section
Special Emphasis Panel (ZCA1-RPRB-O (M1))
Project Start
2002-12-01
Project End
2019-06-30
Budget Start
2014-08-01
Budget End
2015-06-30
Support Year
11
Fiscal Year
2014
Total Cost
$287,668
Indirect Cost
$81,331
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Wong, Gabrielle S; Zhou, Jin; Liu, Jie Bin et al. (2018) Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition. Nat Med 24:968-977
Karakasheva, Tatiana A; Dominguez, George A; Hashimoto, Ayumi et al. (2018) CD38+ M-MDSC expansion characterizes a subset of advanced colorectal cancer patients. JCI Insight 3:
Liu, Yang; Sethi, Nilay S; Hinoue, Toshinori et al. (2018) Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas. Cancer Cell 33:721-735.e8
Facompre, Nicole D; Harmeyer, Kayla M; Sahu, Varun et al. (2018) Targeting JARID1B's demethylase activity blocks a subset of its functions in oral cancer. Oncotarget 9:8985-8998
Deng, Jiehui; Wang, Eric S; Jenkins, Russell W et al. (2018) CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation. Cancer Discov 8:216-233
Karakasheva, Tatiana A; Lin, Eric W; Tang, Qiaosi et al. (2018) IL-6 Mediates Cross-Talk between Tumor Cells and Activated Fibroblasts in the Tumor Microenvironment. Cancer Res 78:4957-4970
Kasagi, Yuta; Chandramouleeswaran, Prasanna M; Whelan, Kelly A et al. (2018) The Esophageal Organoid System Reveals Functional Interplay Between Notch and Cytokines in Reactive Epithelial Changes. Cell Mol Gastroenterol Hepatol 5:333-352
Pectasides, Eirini; Stachler, Matthew D; Derks, Sarah et al. (2018) Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma. Cancer Discov 8:37-48
Campbell, Joshua D; Yau, Christina; Bowlby, Reanne et al. (2018) Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas. Cell Rep 23:194-212.e6
Whelan, Kelly A; Muir, Amanda B; Nakagawa, Hiroshi (2018) Esophageal 3D Culture Systems as Modeling Tools in Esophageal Epithelial Pathobiology and Personalized Medicine. Cell Mol Gastroenterol Hepatol 5:461-478

Showing the most recent 10 out of 173 publications