Drug Design Targeting T-Cell Factor-Driven Epithelial–Mesenchymal Transition as a Therapeutic Strategy for Colorectal Cancer

Abraham, Adedoyin D.; Esquer, Hector; Zhou, Qiong; Tomlinson, Nicholas; Hamill, Brayden D; Abbott, Joshua M.; Li, Linfeng; Pike, Laura A.; Rinaldetti, Sébastien; Ramirez, Dominique; Lunghofer, Paul J.; Gomez, Jose D.; Schaack, Jerome; Nemkov, Travis; D’Alessandro, Angelo; Hansen, Kirk C.; Gustafson, Daniel L.; Messersmith, Wells A.; LaBarbera, Daniel V.

doi:10.1021/acs.jmedchem.9b01065

Cited by 15 publications

(23 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Subsequently, by constructing a PPI network of differential RBPs, further single-factor and multi-factor Cox regression analysis obtained out 6 Hub RBPs (EXO1, TOP2A, RUVBL1, NXT1, PANCSIN2, WDR4) which are related to prognosis. Con rmed in research that the expression of EXO1 [38,39], RUVBL1 [40], TOP2A [41] are related to the progression of colorectal cancers, which is consistent with the prediction results of our constructed model. Next, based on the 6 Hub RBPs coding genes in the TCGA training set, through multi-factor Cox proportional hazard regression analysis, we established a proportional hazard model for predicting the prognosis of rectal cancer.…”

Section: Discussionsupporting

confidence: 90%

A Prognostic Model Constructed Based on Rna Binding Protein to Predict the Prognosis of Patients With Rectal Cancer

Zhou¹,

Wu²,

Li³

et al. 2021

Preprint

View full text Add to dashboard Cite

Background: The incidence of rectal cancer in young people is increasing, and there has been a problem of poor prognosis in recent years. Many studies have shown that RNA binding protein (RBP) is related to the progression of various malignant tumors. However, the role of RBPs in rectal cancer is poorly understood. New prognostic models are urgently needed.Materials and methods: In the study, we used the RBPTD database, The Cancer Genome Atlas (TCGA) database and the transcription data information and corresponding clinical information of rectal cancer patients in the Gene Expression Omnibus (GEO) database to screen out RBPs that are differentially expressed in tumor tissues and normal tissues. Subsequently, we analyzed the prognostic value of these RBPs using bioinformatics methods. In order to screen the key RBP in the occurrence of rectal tumors and establish a prognostic risk score model. The use of survival analysis shows that assessing the relationship between key RBPs and the patient's overall survival rate. In the TCGA cohort, the prognostic model was further tested. At the same time, the nomogram of the 6 RBP mRNAs in the TCGA cohort was constructed, and the ROC curve was used for verification. Finally, q-PCR was performed on clinical samples to verify the expression of hub genes.Results: The new 6RBP (EXO1, TOP2A, RUVBL1, NXT1, PACSIN2, WDR4) prognostic model was established to predict the prognosis of rectal cancer. The ROC curve showed good results in the training cohort and validation cohort. The new 6RBP (EXO1, TOP2A, RUVBL1, NXT1, PACSIN2, WDR4) prognostic model was established to predict the prognosis of rectal cancer. The ROC curve showed good survival prediction in both the training cohort and the validation cohort. The constructed nomogram has certain guiding significance for clinical decision-making. In addition, GSEA analysis revealed potential biological functions. The q-PCR verification results showed the consistency with the construction of the prognostic model.Conclusions: We constructed a six RBPs prognostic model and a nomogram to predict the prognosis of patients with rectal cancer, and performed q-PCR expression testing through clinical samples, which may help clinical decision-making.

show abstract

Section: Discussionsupporting

confidence: 90%

A Prognostic Model Constructed Based on Rna Binding Protein to Predict the Prognosis of Patients With Rectal Cancer

Zhou¹,

Wu²,

Li³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Moreover, we and others have shown that TCF transcription functions as a master regulator of epithelial-to-mesenchymal transition (EMT; refs. [22][23][24], a process that can transform relatively benign epithelial tumor cells into mesenchymal cells with increased cancer stem cell (CSC) stemness and other malignant properties that drive metastatic colorectal cancer (25). Currently, no drug has been clinically approved that target the Wnt/TCF pathway (26).…”

Section: Introductionmentioning

confidence: 99%

First-in-Class Inhibitors of Oncogenic CHD1L with Preclinical Activity against Colorectal Cancer

Abbott

Zhou

Esquer

et al. 2020

Molecular Cancer Therapeutics

Self Cite

View full text Add to dashboard Cite

Since the discovery of CHD1L in 2008, it has emerged as an oncogene implicated in the pathology and poor prognosis of a variety of cancers, including gastrointestinal cancers. However, a mechanistic understanding of CHD1L as a driver of colorectal cancer has been limited. Until now, there have been no reported inhibitors of CHD1L, also limiting its development as a molecular target. We sought to characterize the clinicopathologic link between CHD1L and colorectal cancer, determine the mechanism(s) by which CHD1L drives malignant colorectal cancer, and discover the first inhibitors with potential for novel treatments for colorectal cancer. The clinicopathologic characteristics associated with CHD1L expression were evaluated using microarray data from 585 patients with colorectal cancer. Further analysis of microarray data indicated that CHD1L may function through the Wnt/TCF pathway. Thus, we conducted knockdown and overexpression studies with CHD1L to determine its role in Wnt/TCF-driven epithelial-to-mesenchymal transition (EMT). We performed high-throughput screening (HTS) to identify the first CHD1L inhibitors. The mechanism of action, antitumor efficacy, and drug-like properties of lead CHD1L inhibitors were determined using biochemical assays, cell models, tumor organoids, patientderived tumor organoids, and in vivo pharmacokinetics and pharmacodynamics. Lead CHD1L inhibitors display potent in vitro antitumor activity by reversing TCF-driven EMT. The best lead CHD1L inhibitor possesses drug-like properties in pharmacokinetic/pharmacodynamic mouse models. This work validates CHD1L as a druggable target and establishes a novel therapeutic strategy for the treatment of colorectal cancer.

show abstract

“…353046, Corning, Corning, NY) at 300,000 cells/well. The pretreatment group was treated in the six-well-plate format for 24 h at 10 mM and 1 mM with a TOP2A inhibitor 4-(2-benzofuranyl)-8hydroxy-7-(3-(morpholin-4-yl)-propanamido)quinoline (compound 61), 14 while the other groups were treated with vehicle. Cells were then detached, pooled, and seeded in quadruplicates into CellCarrier Ultra 96-well plates (Per-kinElmer) at an initial concentration of 2500 cells/well in 100 mL volume, then twofold serial dilutions were performed across the plate to a final concentration of 1 cell/ well.…”

Section: D Limiting Dilution Assays and Topoisomerase-iia (Top2a) Inmentioning

confidence: 99%

“…The extreme limiting dilution of SW620 colorectal cancer cells showed a cell-concentration-dependent response to treatment with a TOP2A inhibitor (compound 61), which we recently reported to possess anticancer activity by inhibiting TOP2A-mediated T-cell factor/lymphoid enhancerbinding factor (TCF/LEF) transcription. 14,15 In colorectal cancer, we and others have characterized TCF/LEF transcription as a master regulator of the epithelial-tomesenchymal transition (EMT) promoting CSC stemness. [14][15][16][17] Serially diluted SW620 cells stained with Hoechst 33342 allowed for digitally masked colonies to obtain colony count, colony surface area, and confluence measurements.…”

Section: High-content Analysis Of Colonies Reveals a Cell-concentratimentioning

confidence: 99%

“…14,15 In colorectal cancer, we and others have characterized TCF/LEF transcription as a master regulator of the epithelial-tomesenchymal transition (EMT) promoting CSC stemness. [14][15][16][17] Serially diluted SW620 cells stained with Hoechst 33342 allowed for digitally masked colonies to obtain colony count, colony surface area, and confluence measurements. Figure 1 shows representative images of SW620 cells serially diluted to 78 cells per well.…”

Section: High-content Analysis Of Colonies Reveals a Cell-concentratimentioning

confidence: 99%

See 1 more Smart Citation

Advanced High-Content-Screening Applications of Clonogenicity in Cancer

et al. 2020

Self Cite

View full text Add to dashboard Cite

Drug Design Targeting T-Cell Factor-Driven Epithelial–Mesenchymal Transition as a Therapeutic Strategy for Colorectal Cancer

Cited by 15 publications

References 51 publications

A Prognostic Model Constructed Based on Rna Binding Protein to Predict the Prognosis of Patients With Rectal Cancer

A Prognostic Model Constructed Based on Rna Binding Protein to Predict the Prognosis of Patients With Rectal Cancer

First-in-Class Inhibitors of Oncogenic CHD1L with Preclinical Activity against Colorectal Cancer

Advanced High-Content-Screening Applications of Clonogenicity in Cancer

Contact Info

Product

Resources

About