Colorectal cancer (CRC) represents a leading cause of cancer death in the US and worldwide, and its development is driven by mutational activation of Wnt, RAS/RAF/ERK and PI3K/AKT/mTOR signaling. However, targeting individual driver in CRC has limited success. Wnt, mTOR and ERK signaling converges to deregulate eIF4F and lead to translate key oncogenic targets including c-Myc. Interestingly, phosphorylated eIF4E (S209, or p-eIF4E) is dispensable for development or global translation, but required for transformation and optimal tumorigenesis in some models. The underlying causes and significance of elevated p-eIF4E in human cancer and oncogenic translation remains largely unknown. Our novel preliminary data and recent publications supports a critical role of p-eIF4E in human and mouse colon cancer development, and in regulating colon cancer proliferation via ATF4-mediated metabolic and stress adaptation. Pharmacological targeting of eIF4E/4F induces endoplasmic reticulum stress and CRC cell death in culture and in vivo. The central hypothesis of the project is that phosphorylated eIF4E drives colon cancer initiation and progression through ATF4-dependent metabolic and stress reprogramming and serves as an actionable and druggable vulnerability. We will test this hypothesis in three specific Aims. SA1. Define the role of eiF4E phosphorylation in colon cancer development. SA2. Elucidate the mechanisms of p-eIF4E-dependent oncogenesis in colon cancer. SA3. Target eIF4F/4E in colon cancer therapy. The proposed work will develop and employ innovative tools, including phosphorylation defective eIF4E cancer cells and mice, clinical samples, and highly mechanistic and comprehensive approaches to define the role of p-eIF4E in colon cancer biology and therapy. If successful, our work will provide a better understanding of oncogenic translation in protective stress and metabolic adaptation, as well as strategies to target this addiction for therapy. These findings will likely have important implications in treating other cancers with hyperactive Wnt and RAS/RAF for which no effective therapy currently exists.

Public Health Relevance

(PUBLIC HEALTH RELEVANCE) Colorectal cancer (CRC) represents a leading cause of cancer death in the US and worldwide. Developing targeted therapies for colon cancer has thus far been impeded by a lack of agents able to target the gate keeper mutation of APC loss or Wnt hyperactivation, and by the well-documented elaborate network of feedback activation of survival pathways triggered by mutant KRAS/BRAF. The proposed work will explore the convergence of these alterations on oncogenic translation and on metabolic and stress adaptation as an actionable and druggable vulnerability. The proposed work will develop and employ innovative tools and a highly mechanistic and translational approach to define the role of p-eIF4E, not eIF4E or global translation, in colon cancer biology and therapy. These studies are likely to advance basic understanding of colon cancer development, and discover potential biomarkers and novel drug combinations for treating advanced colon cancer and other cancers with hyperactivated Wnt and mutant RAS/RAF, for which no therapy currently exists.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA215481-02
Application #
9618672
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Forry, Suzanne L
Project Start
2018-01-01
Project End
2022-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Pathology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Fletcher, Rochelle; Wang, Yi-Jun; Schoen, Robert E et al. (2018) Colorectal cancer prevention: Immune modulation taking the stage. Biochim Biophys Acta Rev Cancer 1869:138-148
Wang, Yi-Jun; Fletcher, Rochelle; Yu, Jian et al. (2018) Immunogenic effects of chemotherapy-induced tumor cell death. Genes Dis 5:194-203
Chen, Dongshi; Tong, Jingshan; Yang, Liheng et al. (2018) PUMA amplifies necroptosis signaling by activating cytosolic DNA sensors. Proc Natl Acad Sci U S A 115:3930-3935
Tong, Jingshan; Zheng, Xingnan; Tan, Xiao et al. (2018) Mcl-1 Phosphorylation without Degradation Mediates Sensitivity to HDAC Inhibitors by Liberating BH3-Only Proteins. Cancer Res 78:4704-4715