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.
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.
|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|
|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|
|Okazaki, Satoshi; Stintzing, Sebastian; Sunakawa, Yu et al. (2017) Predictive value of TLR7 polymorphism for cetuximab-based chemotherapy in patients with metastatic colorectal cancer. Int J Cancer 141:1222-1230|
|Kim, Yong-Mi; Gang, Eun-Ji; Kahn, Michael (2017) CBP/Catenin antagonists: Targeting LSCs' Achilles heel. Exp Hematol 52:1-11|
|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|
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