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Korea has become the hub of clinical trials in the world. Korea Good Clinical Practice was legislated in 1995, with an amendment in 2001 to adopt ICH-GCP. New Clinical Trial Authorization (CFA) process, which was introduced in 2002 to streamline the regulatory process along with faster study start up, facilitated clinical trials registration in Korea. Following 2002, the number of multinational trials conducted in Korea began to increase rapidly. It was initially centered on late-phase trials, but subsequently moved on to early phase research incorporating translational research and pharmacokinetic (PK) and pharmamlynamic (PD) studies including ethnic difference research. Globally, Seoul National University Hospital Clinical Trials Center (SNUB CTC) is one of the most experienced clinical research facilities. In 2018, 33 phase III studies, 43 phase II studies, and 44 phase I studies were initiated at SNUB CTC oncology team. Oncology phase I clinical trials contributed 42.7% of newly started phase I clinical trials in SNUH CTC in 2018. One of the most important strengths of our oncology team is that SNUH and Seoul National University Bundang Hospital Clinical Trials Center (SNUBH CTC) is working together in one team for all solid tumor types. This collaborative work was very efficient to recruit patients for multi-cohort in early phase trials including basket trial, umbrella trial, and platform trials. One of the main focus of SNUH oncology team is to perform first in human phase I study. We believe target identification and enrichment through translational research is an important process in drug development. SNUH/SNUBH CTC will continue top-notch clinical trials for the global drug development. ; Y

A-kinase anchoring protein 12 (AKAP12) gene is frequently inactivated in human gastric cancer and in several other cancers due to promoter hypermethylation. However, the biological function of AKAP12 in tumorigenesis remains to be identified. Aneuploidy, a hallmark of cancer cells, is often caused by abnormal cell division. In the present study, AKAP12 was found to localize to the cell periphery during interphase and to the actomyosin contractile ring during cytokinesis. Furthermore, AKAP12 depletion using small interfering RNA increased the number of multinucleated cells, and disrupted the completion of cytokinesis. Interestingly, the inhibition of myosin light chain kinase (MLCK), a key regulator of actomyosin contractility, removed AKAP12 from the cell periphery during interphase and from the contractile ring during cytokinesis, suggesting that AKAP12 might be a downstream effector of MLCK. Our findings implicate AKAP12 in the regulation of cytokinesis progression, and suggest a novel role for AKAP12 tumor suppressor. ; This work was supported by a grant from the Korean Ministry of Science & Technology through the National Research Laboratory Program for Cancer Epigenetics, by a Korea Research Foundation Grant funded by the Korean Government (MOEHRD, Basic Research Promotion Fund) (#KRF-2004-217-C00011), and by the BK21 Project for Medicine, Dentistry, and Pharmacy.

A-kinase anchoring protein 12 (AKAP12) is known to function as a scaffold protein and as a putative tumor suppressor. However, little is known about the biological role of AKAP12 in hepatic cells. In this study, we performed micro-array analysis to identify the downstream pathway of AKAP12A, and found that AKAP12A overexpression up-regulates the expressions of several cholesterol-associated genes including HMG-CoA reductase and LDL receptor, which have been reported to be controlled by sterol regulatory element binding protein-2 (SREBP-2). It was found that AKAP12A activates SREBP-2 in hepatic cells, as demonstrated by the presence of its cleavage product, whereas the activation of sterol regulatory element binding protein-1 was not remarkably changed. Moreover, AKAP12A-induced SREBP-2 activation was found to depend on SREBP cleavage-activating protein (SCAP), as inhibition of SCAP by RNAi or sterols blocked SREBP-2 activation in response to AKAP12A overexpression. Interestingly, the hydrophobic amine U18666A caused dramatic movement of AKAP12A from the plasma membrane to cytosol and lysosomal membranes. Moreover, cholesterol depletion from the plasma membrane (using methyl-beta-cyclodextrin) caused a shift of AKAP12A from the plasma membrane to the cytoplasm. Cholesterol binding assay revealed that the N-terminal region of AKAP12A binds directly to cholesterol in vitro. Furthermore, AKAP12A overexpression enhanced [3H]-cholesterol efflux to extracellular acceptors, suggesting that AKAP12A may activate SREBP-2 by increasing cholesterol efflux. In conclusion, the present study suggests that AKAP12A is a novel regulator of cellular cholesterol metabolism. ; This work was supported in part by grants from the Ministry of Science & Technology of Korea through theNational Research Laboratory Program for Cancer Epigenetics, by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD, Basic Research Promotion Fund) (#KRF-2004- 217-C00011), and by BK21 Project for Medicine, Dentistry, and Pharmacy.

Background: Bcl-2 is positively regulated by hormonal receptor pathways in breast cancer. A study was conducted to assess the prognostic significances of clinico-pathologic variables and of ER, PR, p53, c-erbB2, bcl-2, or Ki-67 as markers of relapse in breast cancer patients who had received the identical adjuvant therapy at a single institution. Methods: A cohort of 151 curatively resected stage III breast cancer patients ( M: F = 3: 148, median age 46 years) who had 4 or more positive lymph nodes and received doxorubicin and cyclophosphamide followed by paclitaxel (AC/T) as adjuvant chemotherapy was analyzed for clinico-pathologic characteristics including disease-free survival (DFS) and overall survival ( OS). Patients with positive ER and/or PR expression received 5 years of tamoxifen following AC/T. The protein expressions of biomarkers were assessed immunohistochemically. Results: The median follow-up duration was 36 months, and 37 patients (24.5%) experienced a recurrence. Univariate analyses indicated that the tumor size ( P = 0.038) and the number of involved lymph nodes ( P < 0.001) significantly affected the recurrences. However, the type of surgery, the histology, histologic grade, the presence of endolymphatic emboli, and a close resection margin did not. Moreover, ER positivity ( P = 0.013), bcl-2 positivity ( P = 0.002) and low p53 expression ( P = 0.032) were found to be significantly associated with a prolonged DFS. Furthermore, multivariate analysis identified 10 or more involved lymph nodes (HR 7.366; P < 0.001), negative bcl-2 expression ( HR 2.895; P = 0.030), and c-erbB2 over-expression ( HR 3.535; P = 0.001) as independent indicators of poorer DFS. In addition, bcl-2 expression was found to be significantly correlated with the expressions of ER and PR, and inversely correlated with the expressions of p53, c-erbB2 and Ki-67. Patients with bcl-2 expression had a significantly longer DFS than those without, even in the ER (+) subgroup. Moreover, OS was significantly affected by ER, bcl-2 and c-erbB2. Conclusion: Bcl-2 is an independent prognostic factor of DFS in curatively resected stage III breast cancer patients and appears to be a useful prognostic factor in combination with c-erbB2 and the number of involved lymph nodes. ; This study was supported by a Korean Research Foundation Grant funded by the Korean Government (MOEHRD, Basic Research Promotion Fund) (KRF- 2006-531-E00034) and by a grant from the Korean Health 21 R&D Project, Ministry of Heath & Welfare, Republic of Korea (0412-CR01-0704-0001). We also thank Julian Kanfer, English editor of BioMed Proofreading for her assistance. ; Y

Purpose Neoadjuvant chemotherapy may modify the yield of involved axillary lymph nodes. The purpose of this study was to identify the clinical significance of the involved nodal ratios in patients with stage II/III breast cancer treated with neoadjuvant chemotherapy. Methods Two hundred and five stage II and III breast cancer patients who received neoadjuvant docetaxel/doxorubicin chemotherapy were enrolled in this prospective study. The patients received three cycles of neoadjuvant chemotherapy followed by curative surgery, either breast-conserving surgery or mastectomy with axillary lymph node dissection, and received three additional cycles of docetaxel/doxorubicin chemotherapy as adjuvant. Adjuvant radiotherapy and hormonal therapy were given after adjuvant chemotherapy when indicated. Results The median follow-up duration was 28.9 months. The overall response rate (RR) for neoadjuvant chemotherapy was 77.6%. The mean nodal ratio was 0.29 (range, 0-1.0; nodal ratio a parts per thousand currency sign0.25, 121 [59.0%] vs. > 0.25, 84 [41.0%]). Relapse free survival (RFS) of the patients who had a nodal ratio > 0.25 was significantly shorter (Hazard Ratio (HR) = 2.701, P = 0.001). A nodal ratio > 0.25 was also associated with a shorter overall survival (OS) (HR = 4.109, P = 0.006). However, RFS and OS were not different according to the absolute number of involved nodes (ANIN) (P = 0.166, P = 0.248, respectively). In multivariate analysis, the nodal ratio was an independent prognostic factor for RFS and OS (HR = 4.246, P < 0.001; HR = 7.764, P < 0.001). Conclusion Axillary nodal ratios have an independent prognostic value in stage II/III breast cancer treated with neoadjuvant chemotherapy. Nodal ratio might be a useful tool to identify the patients at high risk of relapse in the neoadjuvant setting. ; This study was supported by a Korean Research Foundation Grant funded by the Korean Government (MOEHRD, Basic Research Promotion Fund) (KRF-2006-531-E00034), a grant from the Seoul National University Hospital Research Fund (05-800- 20050148). ; N