Bo Hwa Sohn

Significant Association of Oncogene YAP1 with Poor Prognosis and Cetuximab Resistance in Colorectal Cancer Patients

Purpose: Activation of YAP1, a novel oncogene in the Hippo pathway, has been observed in many cancers, including colorectal cancer. We investigated whether activation of YAP1 is significantly associated with prognosis or treatment outcomes in colorectal cancer. Experimental Design: A gene expression signature reflecting YAP1 activation was identified in colorectal cancer cells, and patients with colorectal cancer were stratified into two groups according to this signature: activated YAP1 colorectal cancer (AYCC) or inactivated YAP1 colorectal cancer (IYCC). Stratified patients in five test cohorts were evaluated to determine the effect of the signature on colorectal cancer prognosis and response to cetuximab treatment. Results: The activated YAP1 signature was associated with poor prognosis for colorectal cancer in four independent patient cohorts with stage I–III disease (total n = 1,028). In a multivariate analysis, the impact of the YAP1 signature on disease-free survival was independent of other clinical variables [hazard ratio (HR), 1.63; 95% confidence interval (CI), 1.25–2.13; P < 0.001]. In patients with stage IV colorectal cancer and wild-type KRAS, IYCC patients had a better disease control rate and progression-free survival (PFS) after cetuximab monotherapy than did AYCC patients; however, in patients with KRAS mutations, PFS duration after cetuximab monotherapy was not different between IYCC and AYCC patients. In multivariate analysis, the effect of YAP1 activation on PFS was independent of KRAS mutation status and other clinical variables (HR, 1.82; 95% CI, 1.05–3.16; P = 0.03). Conclusions: Activation of YAP1 is highly associated with poor prognosis for colorectal cancer and may be useful in identifying patients with metastatic colorectal cancer resistant to cetuximab. Clin Cancer Res; 21(2); 357–64. ©2014 AACR.

Genomic Predictors for Recurrence Patterns of Hepatocellular Carcinoma: Model Derivation and Validation

In this study, Lee and colleagues develop a genomic predictor that can identify patients at high risk for late recurrence of hepatocellular carcinoma (HCC) and provided new biomarkers for risk stratification.

Clinical Significance of Four Molecular Subtypes of Gastric Cancer Identified by The Cancer Genome Atlas Project

Purpose: The Cancer Genome Atlas (TCGA) project recently uncovered four molecular subtypes of gastric cancer: Epstein–Barr virus (EBV), microsatellite instability (MSI), genomically stable (GS), and chromosomal instability (CIN). However, their clinical significances are currently unknown. We aimed to investigate the relationship between subtypes and prognosis of patients with gastric cancer. Experimental Design: Gene expression data from a TCGA cohort (n = 262) were used to develop a subtype prediction model, and the association of each subtype with survival and benefit from adjuvant chemotherapy was tested in 2 other cohorts (n = 267 and 432). An integrated risk assessment model (TCGA risk score) was also developed. Results: EBV subtype was associated with the best prognosis, and GS subtype was associated with the worst prognosis. Patients with MSI and CIN subtypes had poorer overall survival than those with EBV subtype but better overall survival than those with GS subtype (P = 0.004 and 0.03 in two cohorts, respectively). In multivariate Cox regression analyses, TCGA risk score was an independent prognostic factor [HR, 1.5; 95% confidence interval (CI), 1.2–1.9; P = 0.001]. Patients with the CIN subtype experienced the greatest benefit from adjuvant chemotherapy (HR, 0.39; 95% CI, 0.16–0.94; P = 0.03) and those with the GS subtype had the least benefit from adjuvant chemotherapy (HR, 0.83; 95% CI, 0.36–1.89; P = 0.65). Conclusions: Our prediction model successfully stratified patients by survival and adjuvant chemotherapy outcomes. Further development of the prediction model is warranted. Clin Cancer Res; 23(15); 4441–9. ©2017 AACR.

Inactivation of Hippo Pathway Is Significantly Associated with Poor Prognosis in Hepatocellular Carcinoma

Purpose: The Hippo pathway is a tumor suppressor in the liver. However, the clinical significance of Hippo pathway inactivation in HCC is not clearly defined. We analyzed genomic data from human and mouse tissues to determine clinical relevance of Hippo pathway inactivation in HCC. Experimental Design: We analyzed gene expression data from Mst1/2−/− and Sav1−/− mice and identified a 610-gene expression signature reflecting Hippo pathway inactivation in the liver [silence of Hippo (SOH) signature]. By integrating gene expression data from mouse models with those from human HCC tissues, we developed a prediction model that could identify HCC patients with an inactivated Hippo pathway and used it to test its significance in HCC patients, via univariate and multivariate Cox analyses. Results: HCC patients (National Cancer Institute cohort, n = 113) with the SOH signature had a significantly poorer prognosis than those without the SOH signature [P < 0.001 for overall survival (OS)]. The significant association of the signature with poor prognosis was further validated in the Korean (n = 100, P = 0.006 for OS) and Fudan University cohorts (n = 242, P = 0.001 for OS). On multivariate analysis, the signature was an independent predictor of recurrence-free survival (HR, 1.6; 95% confidence interval, 1.12–2.28: P = 0.008). We also demonstrated significant concordance between the SOH HCC subtype and the hepatic stem cell HCC subtype that had been identified in a previous study (P < 0.001). Conclusions: Inactivation of the Hippo pathway in HCC is significantly associated with poor prognosis. Clin Cancer Res; 22(5); 1256–64. ©2015 AACR.

Tat‐activating regulatory DNA‐binding protein regulates glycolysis in hepatocellular carcinoma by regulating the platelet isoform of phosphofructokinase through microRNA 520

Metabolic changes are common features of many cancer cells and are frequently associated with the clinical outcome of patients with various cancers, including hepatocellular carcinoma (HCC). Thus, aberrant metabolic pathways in cancer cells are attractive targets for cancer therapy. However, our understanding of cancer‐specific regulatory mechanisms of cell metabolism is still very limited. We found that Tat‐activating regulatory DNA‐binding protein (TARDBP) is a novel regulator of glycolysis in HCC cells. TARDBP regulates expression of the platelet isoform of phosphofructokinase (PFKP), the rate‐limiting enzyme of glycolysis that catalyzes the irreversible conversion of fructose‐6‐phosphate to fructose‐1,6‐bisphosphate. Silencing of TARDBP expression in multiple HCC cell lines leads to impaired glucose metabolism and inhibition of in vitro and in vivo growth of HCC cells. Notably, the microRNA 520 (miR‐520) family is an intermediate regulator of TARDBP‐mediated regulation of glycolysis. Mechanistically, TARDBP suppressed expression of the miR‐520 family, which, in turn, inhibited expression of PFKP. We further showed that expression of TARDBP is significantly associated with the overall survival of patients with HCC. Conclusion: Our study provides new mechanistic insights into the regulation of glycolysis in HCC cells and reveals TARDBP as a potential therapeutic target for HCC. (HEPATOLOGY 2013;)

Yes-associated protein 1 and transcriptional coactivator with PDZ-binding motif activate the mammalian target of rapamycin complex 1 pathway by regulating amino acid transporters in hepatocellular carcinoma

Metabolic activation is a common feature of many cancer cells and is frequently associated with the clinical outcomes of various cancers, including hepatocellular carcinoma. Thus, aberrantly activated metabolic pathways in cancer cells are attractive targets for cancer therapy. Yes‐associated protein 1 (YAP1) and transcriptional coactivator with PDZ‐binding motif (TAZ) are oncogenic downstream effectors of the Hippo tumor suppressor pathway, which is frequently inactivated in many cancers. Our study revealed that YAP1/TAZ regulates amino acid metabolism by up‐regulating expression of the amino acid transporters solute carrier family 38 member 1 (SLC38A1) and solute carrier family 7 member 5 (SLC7A5). Subsequently, increased uptake of amino acids by the transporters (SLC38A1 and SLC7A5) activates mammalian target of rapamycin complex 1 (mTORC1), a master regulator of cell growth, and stimulates cell proliferation. We also show that high expression of SLC38A1 and SLC7A5 is significantly associated with shorter survival in hepatocellular carcinoma patients. Furthermore, inhibition of the transporters and mTORC1 significantly blocks YAP1/TAZ‐mediated tumorigenesis in the liver. These findings elucidate regulatory networks connecting the Hippo pathway to mTORC1 through amino acid metabolism and the mechanisms potential clinical implications for treating hepatocellular carcinoma. Conclusion: YAP1 and TAZ regulate cancer metabolism and mTORC1 through regulation of amino acid transportation, and two amino acid transporters, SLC38A1 and SLC7A5, might be important therapeutic targets. (Hepatology 2016;63:159–172)

Development and Validation of a Prognostic Gene-Expression Signature for Lung Adenocarcinoma

Although several prognostic signatures have been developed in lung cancer, their application in clinical practice has been limited because they have not been validated in multiple independent data sets. Moreover, the lack of common genes between the signatures makes it difficult to know what biological process may be reflected or measured by the signature. By using classical data exploration approach with gene expression data from patients with lung adenocarcinoma (n = 186), we uncovered two distinct subgroups of lung adenocarcinoma and identified prognostic 193-gene gene expression signature associated with two subgroups. The signature was validated in 4 independent lung adenocarcinoma cohorts, including 556 patients. In multivariate analysis, the signature was an independent predictor of overall survival (hazard ratio, 2.4; 95% confidence interval, 1.2 to 4.8; p = 0.01). An integrated analysis of the signature revealed that E2F1 plays key roles in regulating genes in the signature. Subset analysis demonstrated that the gene signature could identify high-risk patients in early stage (stage I disease), and patients who would have benefit of adjuvant chemotherapy. Thus, our study provided evidence for molecular basis of clinically relevant two distinct two subtypes of lung adenocarcinoma.

YAP1 and TAZ Activates mTORC1 Pathway by Regulating Amino Acid Transporters in hepatocellular carcinoma

Metabolic activation is a common feature of many cancer cells and is frequently associated with the clinical outcomes of various cancers, including hepatocellular carcinoma. Thus, aberrantly activated metabolic pathways in cancer cells are attractive targets for cancer therapy. Yes‐associated protein 1 (YAP1) and transcriptional coactivator with PDZ‐binding motif (TAZ) are oncogenic downstream effectors of the Hippo tumor suppressor pathway, which is frequently inactivated in many cancers. Our study revealed that YAP1/TAZ regulates amino acid metabolism by up‐regulating expression of the amino acid transporters solute carrier family 38 member 1 (SLC38A1) and solute carrier family 7 member 5 (SLC7A5). Subsequently, increased uptake of amino acids by the transporters (SLC38A1 and SLC7A5) activates mammalian target of rapamycin complex 1 (mTORC1), a master regulator of cell growth, and stimulates cell proliferation. We also show that high expression of SLC38A1 and SLC7A5 is significantly associated with shorter survival in hepatocellular carcinoma patients. Furthermore, inhibition of the transporters and mTORC1 significantly blocks YAP1/TAZ‐mediated tumorigenesis in the liver. These findings elucidate regulatory networks connecting the Hippo pathway to mTORC1 through amino acid metabolism and the mechanisms potential clinical implications for treating hepatocellular carcinoma. Conclusion: YAP1 and TAZ regulate cancer metabolism and mTORC1 through regulation of amino acid transportation, and two amino acid transporters, SLC38A1 and SLC7A5, might be important therapeutic targets. (Hepatology 2016;63:159–172)

Comparison of Prognostic Genomic Predictors in Colorectal Cancer

Background Although several prognostic genomic predictors have been identified from independent studies, it remains unclear whether these predictors are actually concordant with respect to their predictions for individual patients and which predictor performs best. We compared five prognostic genomic predictors, the V7RHS, the ColoGuideEx, the Meta163, the OncoDX, and the MDA114, in terms of predicting disease-free survival in two independent cohorts of patients with colorectal cancer. Study Design Using original classification algorithms, we tested the predictions of five genomic predictors for disease-free survival in two cohorts of patients with colorectal cancer (n = 229 and n = 168) and evaluated concordance of predictors in predicting outcomes for individual patients. Results We found that only two predictors, OncoDX and MDA114, demonstrated robust performance in identifying patients with poor prognosis in 2 independent cohorts. These two predictors also had modest but significant concordance of predicted outcome (r>0.3, P<0.001 in both cohorts). Conclusions Further validation of developed genomic predictors is necessary. Despite the limited number of genes shared by OncoDX and MDA114, individual-patient outcomes predicted by these two predictors were significantly concordant.

Biologic Effects of Platelet-Derived Growth Factor Receptor α Blockade in Uterine Cancer

Purpose: Platelet-derived growth factor receptor α (PDGFRα) expression is frequently observed in many kinds of cancer and is a candidate for therapeutic targeting. This preclinical study evaluated the biologic significance of PDGFRα and PDGFRα blockade (using a fully humanized monoclonal antibody, 3G3) in uterine cancer. Experimental Design: Expression of PDGFRα was examined in uterine cancer clinical samples and cell lines, and biologic effects of PDGFRα inhibition were evaluated using in vitro (cell viability, apoptosis, and invasion) and in vivo (orthotopic) models of uterine cancer. Results: PDGFRα was highly expressed and activated in uterine cancer samples and cell lines. Treatment with 3G3 resulted in substantial inhibition of PDGFRα phosphorylation and of downstream signaling molecules AKT and mitogen-activated protein kinase (MAPK). Cell viability and invasive potential of uterine cancer cells were also inhibited by 3G3 treatment. In orthotopic mouse models of uterine cancer, 3G3 monotherapy had significant antitumor effects in the PDGFRα-positive models (Hec-1A, Ishikawa, Spec-2) but not in the PDGFRα-negative model (OVCA432). Greater therapeutic effects were observed for 3G3 in combination with chemotherapy than for either drug alone in the PDGFRα-positive models. The antitumor effects of therapy were related to increased apoptosis and decreased proliferation and angiogenesis. Conclusions: These findings identify PDGFRα as an attractive target for therapeutic development in uterine cancer. Clin Cancer Res; 20(10); 2740–50. ©2014 AACR.