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.
|Kim, Yong-Mi; Gang, Eun-Ji; Kahn, Michael (2017) CBP/Catenin antagonists: Targeting LSCs' Achilles heel. Exp Hematol 52:1-11|
|Zhao, Yi; Wu, Kaijin; Nguyen, Cu et al. (2017) Small molecule p300/catenin antagonist enhances hematopoietic recovery after radiation. PLoS One 12:e0177245|
|Duchartre, Yann; Kim, Yong-Mi; Kahn, Michael (2016) The Wnt signaling pathway in cancer. Crit Rev Oncol Hematol 99:141-9|
|He, Lina; Gubbins, James; Peng, Zhechu et al. (2016) Activation of hepatic stellate cell in Pten null liver injury model. Fibrogenesis Tissue Repair 9:8|
|Zhao, Y; Masiello, D; McMillian, M et al. (2016) CBP/catenin antagonist safely eliminates drug-resistant leukemia-initiating cells. Oncogene 35:3705-17|
|Okazaki, Satoshi; Loupakis, Fotios; Stintzing, Sebastian et al. (2016) Clinical Significance of TLR1 I602S Polymorphism for Patients with Metastatic Colorectal Cancer Treated with FOLFIRI plus Bevacizumab. Mol Cancer Ther 15:1740-5|
|Thomas, Paul D; Kahn, Michael (2016) Kat3 coactivators in somatic stem cells and cancer stem cells: biological roles, evolution, and pharmacologic manipulation. Cell Biol Toxicol 32:61-81|
|Miyamoto, Yuji; Hanna, Diana L; Zhang, Wu et al. (2016) Molecular Pathways: Cachexia Signaling-A Targeted Approach to Cancer Treatment. Clin Cancer Res 22:3999-4004|
|Stremitzer, S; Zhang, W; Yang, D et al. (2015) Variations in genes involved in dormancy associated with outcome in patients with resected colorectal liver metastases. Ann Oncol 26:1728-33|
|Sunakawa, Y; Stintzing, S; Cao, S et al. (2015) Variations in genes regulating tumor-associated macrophages (TAMs) to predict outcomes of bevacizumab-based treatment in patients with metastatic colorectal cancer: results from TRIBE and FIRE3 trials. Ann Oncol 26:2450-6|
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