Eighty to ninety percent of colorectal cancers involve aberrant activation of the Wnt/-catenin signaling pathway, which is associated with tumor initiation, proliferation, progression and poor prognosis. Wnt signaling, in particular the nuclear functions of -catenin have also been shown to be important in the maintenance, proliferation and differentiation of both embryonic and adult somatic stem cells. Our pharmacogenomic studies clearly demonstrate that the coactivators CBP and p300 have distinct functions in regulating the expression of Wnt/-catenin regulated genes including survivin, EGFR, VEGF, EphB2, S100A4,CD44, connexin 43 and cyclin D1, which play important roles in initiation, proliferation, angiogenesis, metastasis and drug resistance. We have developed and validated a model that posits that CBP/-catenin-mediated transcription is critical for proliferation without differentiation (e.g. in cancer and stem cells) whereas a switch of coactivator usage to p300/-catenin is the essential first step to initiate differentiation with a more limited proliferative capacity. Our central hypothesis is that increased CBP/-catenin/TCF4 driven transcription at the expense of p300/-catenin/TCF4-mediated transcription is associated with colon cancer development, and is essential for tumor relapse, drug resistance, metastases and poor prognosis in patients with colon cancer. Importantly, we have developed the first specific small molecule antagonists of the CBP/-catenin interaction, ICG-001 and C82/C88 (aka PRI-724), which disrupt a subset of Wnt/-catenin driven transcription. We propose to test our hypothesis both pre-clinically in vitro and in vivo and clinically in a randomized phase II trial in combinatin with FOLFOX/Bevacizumab in patients with newly diagnosed metastatic colorectal cancer.

Public Health Relevance

The Wnt signaling pathway is critical for the development and progression of the majority of colon cancers. Targeting this pathway should provide a novel strategy for the treatment of patients with metastatic colon cancer. This proposal incorporates a bench to bedside Phase II clinical trial using novel small molecule agents in combination with FOLFOX/bevcaziumab, which the Principal Investigator's lab developed.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA166161-05
Application #
9249500
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Timmer, William C
Project Start
2013-04-01
Project End
2018-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
5
Fiscal Year
2017
Total Cost
$397,592
Indirect Cost
$156,627
Name
University of Southern California
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90033
Zhao, Yi; Wu, Kaijin; Wu, Yongfeng et al. (2018) Characterization of Imatinib Resistant CML Leukemic Stem/Initiating Cells and Their Sensitivity to CBP/Catenin Antagonists. Curr Mol Pharmacol 11:113-121
Tokunaga, Ryuma; Zhang, Wu; Naseem, Madiha et al. (2018) CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation - A target for novel cancer therapy. Cancer Treat Rev 63:40-47
Schirripa, Marta; Zhang, Wu; Heinemann, Volker et al. (2017) Single nucleotide polymorphisms in the IGF-IRS pathway are associated with outcome in mCRC patients enrolled in the FIRE-3 trial. Int J Cancer 141:383-392
Trosko, James E; Lenz, Heinz-Josef (2017) What roles do colon stem cells and gap junctions play in the left and right location of origin of colorectal cancers? J Cell Commun Signal 11:79-87
Duchartre, Yann; Kim, Yong-Mi; Kahn, Michael (2017) Pharmacologic Manipulation of Wnt Signaling and Cancer Stem Cells. Methods Mol Biol 1613:463-478
Puccini, Alberto; Lenz, Heinz-Josef (2017) New perspectives for colorectal cancer. Oncotarget 8:41782-41783
Berger, M D; Stintzing, S; Heinemann, V et al. (2017) Impact of genetic variations in the MAPK signaling pathway on outcome in metastatic colorectal cancer patients treated with first-line FOLFIRI and bevacizumab: data from FIRE-3 and TRIBE trials. Ann Oncol 28:2780-2785
Suenaga, M; Schirripa, M; Cao, S et al. (2017) Genetic variants of DNA repair-related genes predict efficacy of TAS-102 in patients with refractory metastatic colorectal cancer. Ann Oncol 28:1015-1022
Okazaki, Satoshi; Schirripa, Marta; Loupakis, Fotios et al. (2017) Tandem repeat variation near the HIC1 (hypermethylated in cancer 1) promoter predicts outcome of oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Cancer 123:4506-4514
Puccini, Alberto; Berger, Martin D; Naseem, Madiha et al. (2017) Colorectal cancer: epigenetic alterations and their clinical implications. Biochim Biophys Acta Rev Cancer 1868:439-448

Showing the most recent 10 out of 31 publications