High expression of maternal embryonic leucine-zipper kinase (MELK) impacts clinical outcomes in patients with ovarian cancer and its inhibition suppresses ovarian cancer cells growth ex vivo

Yuji Ikeda,Sho Sato,Akira Yabuno,Daisuke Shintani,Aiko Ogasawara,Maiko Miwa,Makda Zewde,Takashi Miyamoto,Keiichi Fujiwara,Yusuke Nakamura,Kosei Hasegawa 대한부인종양학회 2020 Journal of Gynecologic Oncology Vol.31 No.6

Objective: Maternal embryonic leucine zipper kinase (MELK) is receiving an attentionas a therapeutic target in various types of cancers. In this study, we aimed to evaluate theprognostic significance of MELK expression in ovarian cancer using clinical samples, andassessed the efficacy of a small molecule MELK inhibitor, OTS167, using patient-derivedovarian cancer cells as well as cell lines. Methods: Expression levels of MELK in 11 ovarian cancer cell lines were confirmed bywestern blotting. Inhibitory concentration of OTS167 was determined by colorimetric assay. MELK messenger RNA (mRNA) expression was evaluated in 228 ovarian cancer patients byquantitative polymerase chain reaction. Growth inhibition of OTS167 was also evaluatedusing freshly-isolated primary ovarian cancer cells including spheroid formation condition. Results: MELK mRNA expression was significantly higher in ovarian cancer than in normalovaries (p<0.001), and high MELK mRNA expression was observed in patients with advancedstage, positive ascites cytology and residual tumor size. Patients with high MELK mRNAexpression showed shorter progression-free survival (p=0.001). Expression of MELK wasalso confirmed in 10 of 11 ovarian cancer cell lines tested, and the half maximal inhibitoryconcentration of MELK inhibitor, OTS167, ranged from 9.3 to 60 nM. Additionally, OTS167showed significant growth inhibitory effect against patient-derived ovarian cancer cells,regardless of their tumor locations, histologic subtypes and stages. Conclusions: We demonstrated MELK as both a prognostic marker and a therapeutic targetfor ovarian cancer using clinical ovarian cancer samples. MELK inhibition by OTS167 may bean effective approach to treat ovarian cancer patients.

암 치료를 위한 항체치료제에 대한 고찰: 면역항암제

유한진(HanJin Yu),홍세영(Seyoung Hong),권미지(Miji Kwon),이지현(Jihyeon Lee),박희호(Hee Ho Park),임광석(Kwang Suk Lim) 한국생물공학회 2020 KSBB Journal Vol.35 No.2

Recently, biopharmaceutical drugs take a big part in the pharmaceutical market with the development of genetic engineering. Therapeutic antibodies, one of the representative biopharmaceuticals, have strong therapeutic efficacy in various diseases such as autoimmune disease, rheumatism and cancer. Antibodies are widely used as targeted delivery systems, diagnostics and therapeutics because of their high specific recognition ability. In addition, the market for therapeutic antibodies is expanding further with the development of new biologic drugs such as biosimilar and biobetter. In particular, cancer immunotherapy has shown excellent efficacy for the treatment of cancer by regulating the immune response. In recent years, antibody-drug conjugates (ADCs), immune checkpoint inhibitors and therapeutic antibodies have been developed by many researchers and pharmaceutical companies and approved by U.S. food and drug administration as a potential strategy for the treatment of cancer. Although cancer immunotherapy has a strong therapeutic efficacy, there are still limitations to overcome such as for the treatment of solid tumor, immunogenicity and resistance. To solve these problems, new biomarkers, bispecific antibodies and combinatorial therapy with chemotherapy are being investigated. In this review, we describe the mechanism of immune response with respect to antibody therapeutics, characteristics of target cancers and discuss the potentials of cancer immunotherapy.

Autophagy in Cervical Cancer: An Emerging Therapeutic Target

Pandey, Saumya,Chandravati, Chandravati Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.10

Cervical cancer is a leading cause of morbidity and mortality in women worldwide. Although the human papillomavirus (HPV) is considered the major causative agent of cervical cancer, yet the viral infection alone is not sufficient for cancer progression. The etiopathogenesis of cervical cancer is indeed complex; a precise understanding of the complex cellular/molecular mechanisms underlying the initiation, progression and/or prevention of the uterine cervix is therefore essential. Autophagy is emerging as an important biological mechanism in targeting human cancers, including cervical cancer. Furthermore, autophagy, a process of cytoplasm and cellular organelle degradation in lysosomes, has been implicated in homeostasis. Autophagic flux may vary depending on the cell/tissue type, thereby altering cell fate under stress conditions leading to cell survival and/or cell death. Autophagy may in turn govern tumor metastasis and subsequent carcinogenesis. Inflammation is a known hallmark of cancer. Vascular insufficiency in tumors, including cervical tissue, leads to depletion of glucose and/or oxygen perturbing the osmotic mileu causing extracellular acidosis in the tumor microenvironment that may eventually result in autophagy. Thus, targeted manipulation of complex autophagic signaling may prove to be an innovative strategy in identification of clinically relevant biomarkers in cervical cancer in the near future.

OIP5 is a highly expressed potential therapeutic target for colorectal and gastric cancers

( Ho Kyung Chun ),( Kyung Sook Chung ),( Hee Cheol Kim ),( Jung Eun Kang ),( Min Ah Kang ),( Jong Tae Kim ),( Eun Hwa Choi ),( Kyeong Eun Jung ),( Moon Hee Kim ),( Eun Young Song ),( Seon Young Kim ) 생화학분자생물학회 2010 BMB Reports Vol.43 No.5

Previously, we reported that overexpression of Opa (Neisseria gonorrhoeae opacity-associated)-interacting protein 5 (OIP5) caused multi-septa formation and growth defects, both of which are considered cancer-related phenotypes. To evaluate OIP5 as a possible cancer therapeutic target, we examined its expression level in 66 colorectal cancer patients. OIP5 was upregulated about 3.7-fold in tumors and over 2-fold in 58 out of 66 colorectal cancer patients. Knockdown of OIP5 expression by small interfering RNA specific to OIP5 (siOIP5) resulted in growth inhibition of colorectal and gastric cancer cell lines. Growth inhibition of SNU638 by siOIP5 caused an increase in sub-G1 DNA content, as measured by flow cytometry, as well as an apoptotic gene expression profile. These results indicate that knockdown of OIP5 may induce apoptosis in cancer cells. Therefore, we suggest that OIP5 might be a potential cancer therapeutic target, although the mechanisms of OIP5-induced carcinogenesis should be elucidated. [BMB reports 2010; 43 (5): 349-354]

폐암 정복을 위한 전방위적 반격

장승훈 대한의사협회 2023 대한의사협회지 Vol.66 No.3

Background: Lung cancer is increasing exponentially as the population ages. To conquer lung cancer, early diagnosis, developing new treatments, and combining multidisciplinary treatment modalities are essential. Current Concepts: Since the national lung cancer screening program for high-risk individuals using low-dose chest computed tomography has launched, the rate of early diagnosis of lung cancer is expected to increase. The development of immune checkpoint inhibitors and target agents is paying off in terms of producing new anticancer drugs. Immune checkpoint inhibitors are administered in combination with existing treatment modalities in various clinical situations, such as for not only patients with metastatic lung cancer but also for those with resectable lung cancer and with surgically unresectable locally advanced disease. These trials dramatically improved survival outcomes. The development of targeted anticancer drugs is also advancing at a rapid pace. The survival rate of patients with lung cancer who have specific gene mutations has greatly improved when targeted anticancer drugs are administered alone or in combination with conventional therapies. Discussion and Conclusion: Early diagnosis of lung cancer and the development of new treatment modalities are greatly improving the prognosis of patients with lung cancer. Attempts to combine conventional and new treatment modalities should continue. It is necessary to discuss changing medical policies for long-term survivors, which will inevitably increase.

식도암의 수술적 치료

박성용 대한의사협회 2024 대한의사협회지 Vol.67 No.2

Background: Esophageal cancer was the seventh most common cancer worldwide in 2020 and the sixth leading cause of cancer-related deaths (544,000 deaths annually), accounting for one-eighteenth of all cancer-related deaths. In Korea, esophageal cancer accounted for 1.0% of all cancer cases, with 2,483 cases diagnosed in 2017, making it the fifteenth most common cancer and the eleventh most common cause of cancer-related deaths. Current Concepts: Esophageal squamous cell cancer (ESCC) is the most prevalent pathology (91.2%) in Korea, typically affecting the upper and middle esophagus. The common causes of ESCC are smoking, drinking, and hot beverages. ESCC lesions confined to the mucosa, such as cTis and cT1a, can be treated with endoscopic resection, but lesions invading the submucosa require esophagectomy. Patients with locally advanced ESCC with lymph node metastasis require neoadjuvant therapy followed by esophagectomy and reconstruction. Esophagectomy is associated with mortality and morbidity rates of 3% and 50%, respectively. Discussion and Conclusion: ESCC is associated with a poorer prognosis compared to those associated with other cancers, and the high mortality and morbidity rates associated with esophagectomy often lead to hesitation toward aggressive treatments. However, recent advances in chemotherapy, radiation therapy, and surgery can offer hope for a cure. Minimally invasive esophagectomy may reduce the rate of fatal complications. The shift from traditional platinum-based chemotherapy to immune checkpoint inhibitors also suggests promise for the treatment outcomes of ESCC.

유전자 발현을 활용한 루테튬 (¹⁷⁷Lu)의 암 치료 효능 검증

김다미,이소영,임재청,최강혁,Da-Mi Kim,So-Young Lee,Jae-Cheong Lim,KangHyuk Choi 한국방사선산업학회 2023 방사선산업학회지 Vol.17 No.4

Lutetium(¹⁷⁷Lu), with its theranostic properties, is one of the most widely used radioisotopes and has a large share of the radiopharmaceutical market due to its many applications and targeted therapeutic research using lutetium-based radiopharmaceuticals. However, lutetium-based radiopharmaceuticals currently approved by the US Food and Drug Administration (FDA) are limited to the indications of gastrointestinal cancer, pancreatic neuroendocrine cancer and metastatic castration-resistant prostate cancer. To overcome these limitations, we aimed to demonstrate the feasibility of expanding the use of lutetium-based radiopharmaceuticals by verifying the availability and therapeutic efficacy of lutetium produced in a research reactor(HANARO). In this study, we confirmed the therapeutic efficacy of lutetium by using cancer cells from different types of cancer. In addition, we selected cancer biomarkers based on characteristics common to various cancer cells and compared and evaluated the therapeutic efficacy of lutetium by regulating the expression of target genes. The results showed that modulation of cancer biomarker gene expression resulted in higher therapeutic efficacy compared to lutetium alone. In conclusion, this study verified the potential use and therapeutic efficacy of lutetium based on the production of a research reactor (HANARO), providing fundamental evidence for the development of lutetium-based radiopharmaceuticals and the expansion of their indications.

Effects of Screening on Gastric Cancer Management: Comparative Analysis of the Results in 2006 and in 2011

Kim, Yun Gyoung,Kong, Seong-Ho,Oh, Seung-Young,Lee, Kyung-Goo,Suh, Yun-Suhk,Yang, Jun-Young,Choi, Jeongmin,Kim, Sang Gyun,Kim, Joo-Sung,Kim, Woo Ho,Lee, Hyuk-Joon,Yang, Han-Kwang The Korean Gastric Cancer Association 2014 Journal of gastric cancer Vol.14 No.2

Purpose: This study aimed to analyze the effect of screening by using endoscopy on the diagnosis and treatment of gastric cancer. Materials and Methods: The clinicopathologic characteristics of gastric cancer were compared in individuals who underwent an endoscopy because of symptoms (non-screening group) or for screening purposes (screening group). The distributions of gastric cancer stages and treatment modalities in 2006 and 2011 were compared. Results: The proportion of patients in the screening group increased from 45.1% in 2006 to 65.4% in 2011 (P<0.001). The proportion of stage I cancers in the entire patient sample also increased (from 60.5% in 2006 to 70.6% in 2011; P=0.029). In 2011, the percentages of patients with cancer stages I, II, III, and IV were 79.9%, 8.2%, 10.9%, and 1.1%, respectively, in the screening group, and 47.9%, 10.8%, 29.8%, and 11.5%, respectively, in the non-screening group. The proportion of laparoscopic and robotic surgeries increased from 9.6% in 2006 to 48.3% in 2011 (P<0.001), and endoscopic submucosal dissection increased from 9.8% in 2006 to 19.1% 2011 (P<0.001). Conclusions: The proportion of patients diagnosed with gastric cancer by using the screening program increased between 2006 and 2011. This increase was associated with a high proportion of early-stage cancer diagnoses and increased use of minimally invasive treatments.

miR-181b as a Potential Molecular Target for Anticancer Therapy of Gastric Neoplasms

Guo, Jian-Xin,Tao, Qing-Song,Lou, Peng-Rong,Chen, Xiao-Chun,Chen, Jun,Yuan, Guang-Bo Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.5

Objective: MicroRNAs (miRNAs) play important roles in carcinogenesis. The aim of the present study was to explore the effects of miR-181b on gastric cancer. Methods: The expression level of miR-181b was quantified by qRT-PCR. MTT, flow cytometry and matrigel invasion assays were used to test proliferation, apoptosis and invasion of miR-181b stable transfected gastric cancer cells. Results: miR-181b was aberrantly overexpressed in gastric cancer cells and primary gastric cancer tissues. Further experiments demonstrated inducible expression of miR-181b by Helicobacter pylori treatment. Cell proliferation, migration and invasion in the gastric cancer cells were significantly increased after miR-181b transfection and apoptotic cells were also increased. Furthermore, overexpression of miR-181b downregulated the protein level of tissue inhibitor of metalloproteinase 3 (TIMP3). Conclusion: The upregulation of miR-181b may play an important role in the progress of gastric cancer and miR-181b maybe a potential molecular target for anticancer therapeutics of gastric cancer.

A Novel Monoclonal Antibody Targets Mucin1 and Attenuates Growth in Pancreatic Cancer Model

Wu, Guang,Maharjan, Sony,Kim, Dongbum,Kim, Jung Nam,Park, Byoung Kwon,Koh, Heeju,Moon, Kyungduk,Lee, Younghee,Kwon, Hyung-Joo MDPI 2018 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.19 No.7

<P>Mucin1 (MUC1) is a highly glycosylated transmembrane protein that plays a crucial role in the lubrication and protection of normal epithelial cells. However, MUC1 has emerged as a potential target for cancer therapy because it is overexpressed and functions in several types of cancers. Recently, we produced a monoclonal antibody (the anti-hMUC1 antibody) specific to the extracellular region of the MUC1 subunit MUC1-C to evaluate the utility of using anti-MUC1 antibodies in pancreatic cancer models. The anti-hMUC1 antibody recognized the MUC1-C protein in pancreatic cancer cells. Based on immunostaining and confocal image analyses, the anti-hMUC1 antibody initially bound to the cell membrane then was internalized in cancer cells that express MUC1. The anti-hMUC1 antibody suppressed epidermal growth factor (EGF)-mediated extracellular signal–regulated kinase (ERK) phosphorylation and cyclin D1 expression. When the anti-hMUC1 antibody was injected into a xenograft mouse model and traced using an in vivo imaging system, we observed that the anti-hMUC1 antibody was localized to MUC1-expressing pancreatic tumors. Importantly, the anti-hMUC1 monoclonal antibody suppressed pancreatic tumor growth in mice. According to immunohistochemistry analysis using a pancreatic cancer tissue array and the anti-hMUC1 antibody, MUC1 was highly expressed in human pancreatic cancer tissues compared to normal tissues. Therefore, we conclude that the anti-hMUC1 antibody specifically targets MUC1 and suppresses its function in pancreatic cancer in vitro and in vivo and can be further developed as a promising targeted therapy to treat pancreatic cancer.</P>