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.

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]

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.

Suppression of the growth of human colorectal cancer cells by therapeutic stem cells expressing cytosine deaminase and interferon-β via their tumor-tropic effect in cellular and xenograft mouse models

Yi, B.R.,Park, M.A.,Lee, H.R.,Kang, N.H.,Choi, K.J.,Kim, S.U.,Choi, K.C. Elsevier BV 2013 MOLECULAR ONCOLOGY Vol.7 No.3

Genetically engineered stem cells (GESTECs) exhibit a potent therapeutic efficacy via their strong tumor tropism toward cancer cells. In this study, we introduced the human parental neural stem cells, HB1.F3, with the human interferon beta (IFN-β) gene which is a typical cytokine gene that has an antitumor effect and the cytosine deaminase (CD) gene from Escherichia coli (E. coli) that could convert the non-toxic prodrug, 5-fluorocytosine (5-FC), to a toxic metabolite, 5-fluorouracil (5-FU). Two types of stem cells expressing the CD gene (HB1.F3.CD cells) and both the CD and human IFN-β genes (HB1.F3.CD.IFN-β) were generated. The present study was performed to examine the migratory and therapeutic effects of these GESTECs against the colorectal cancer cell line, HT-29. When co-cultured with colorectal cancer cells in the presence of 5-FC, HB1.F3.CD and HB1.F3.CD.IFN-β cells exhibited the cytotoxicity on HT-29 cells via the bystander effect. In particular, HB1.F3.CD.IFN-β cells showed the synergistic cytotoxic activity of 5-FU and IFN-β. We also confirmed the migration ability of HB1.F3.CD and HB1.F3.CD.IFN-β cells toward HT-29 cells by a modified migration assay in vitro, where chemoattractant factors secreted by HT-29 cells attracted the GESTECs. In a xenograft mouse model, the volume of tumor mass was decreased up to 56% in HB1.F3.CD injected mice while the tumor mass was greatly inhibited about 76% in HB1.F3.CD.IFN-β injected mice. The therapeutic treatment by these GESTECs is a novel strategy where the combination of the migration capacity of stem cells as a vector for therapeutic genes towards colorectal cancer and a synergistic antitumor effect of CD and IFN-β genes can selectively target this type of cancer.

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.

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.

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.

자궁경부암과 인 유두종 바이러스 백신 개발

황지영,김도균 東國大學校醫學硏究所 2003 東國醫學 Vol.10 No.2

자궁경부암은 한국 여성에서 발생 빈도가 높으며, 증가 추세인 유방암과 함께 중요한 질환으로 인식되고 있으며, 과학의 발달로 자궁경부암의 원인이 인 유두종 바이러스(human papillomavirus)라는 것이 밝혀진 이래로 자궁경부암은 성병과 같은 감염성 질환(infectious disease)으로 여겨지고 있는데, 이는 한편으로 예방할 수 있는 질환이라고 볼 수 있는 근거가 된다. 자궁경부암을 감소시키기 위하여 원천적으로 자궁경부암의 원인인 HPV 감염을 차단한다는 개념으로 개발된 예방적 백신은 성 생활을 시작하기 전의 젊은 여성들에게 접종을 통해 HRV에 대한 중화 항체를 만들어 HPV가 감염되어도 세포 속으로 침투하기 전에 무력화 시키겠다는 전략이다. 현재, 가장 진전된 예방백신 후보 물질들로 미국 NIH-NCI가 개발 중인 HPV 16 L1-VLP, GSK사의 HPV 16/18 L1, Merck사의 HPV 6/11/16/18 L1, Medigene사의 HPV 16 L1-chymeric VLP, 그리고 NCI의 HPV 16 L1-L2-E2-E7 chymeric VLP등이 있다. 이들 백신 후보 물질들은 모두, 안전성이 높은 것으로 확인되고 높은 면역원성이 증명되었다. 최근 임상실험 중 자궁경부암 예방백신이 곧 현실화될 수 있음을 제시하는 매우 중요한 결과 보고가 2002 년 11월에 있었는데, Merck사가 개발한 백신후보물질의 임상실험으로 HPV 예방효과를 분석하는 것이었다. HPV 감염 검사결과 765명의 위약 그룹에서 41례의 바이러스 지속감염이 확인된 반면, 접종을 한 768명 중에는 단 한 례도 나타나지 않았다는 것이었다. HPV감염에 대한 치료적 백신의 전략은 HPV의 비구조단백질을 목표로 하여 즉, 자궁경부암을 발생시키고, 유지시키는 발암 단백질 유전자인 E6, E7 부분을 면역학적으로 인식하여 무력화 시키겠다는 이론을 바탕으로 하여 E6, E7에 대한 항체 형성과 CTL (cytotoxic T lymphocyte)반응을 유도시킬 수 있도록 하는 것이다. 개발에 성공하면 이미 감염된 사람을 대상으로 훨씬 빠른 공중보건 상의 이익을 가져올 것으로 기대된다. 연구 중인 백신의 모델은 암유전자 E6, E7 등을 목표로 한 재조합융합단백질이나, vaccinia virus, adenovirus, retrovirus등을 vector로 사용하여 제조하거나, DNA vaccine 상태로 직접 투여하는 방법이다. 현재, 연구가 가장 많이 진전된 치료백신 후보 물질들로 Xenova사의 FP L2-E7-E6와 Vaccinia E6-E7, Transgene사의 Vaccinia(MVA)-E6-E7, Stressgen사의 HSP-E7등이 있다. 이와 같은 개발 및 실험 현황으로 볼 때 예방과 치료 목적의 HPV vaccine이 사용될 수 있는 시기가 5년 이내에 도래할 것으로 예상되고 있으며, 향후 우리나라에서도 효과적인 HPV 예방 백신을 사용할 수 있다면 최소 20~30년 이후에는 자궁경부암의 발생은 크게 감소할 수 있을 것으로 생각된다. Uterine cervical cancer has high incidence in Korea along with breast cancer and is regarded as an infectious disease because the scientific advances have provided the evidence of human papillomavirus (HPV) infection as the cause of it, and this suggests that the cervical cancer is a preventable disease. In order to decrease the incidence of cervical cancer, prophylactic vaccine blocking the HPV was developed for young women before actual sexual activity and the aim of this prophylactic vaccine is to make the neutralizing antibodies by injecting the antigenic materials for HPV. Most advanced available prophylactic HPV vaccine candidates are the HPV 16 L1-VLP from NIH-NCI, HPV 16/18 L1 from GSK, HPV 6/11/16/18 L1 from Merck, HPV 16 L1-chymeric VLP from Medigene, and HPV 16 L1-L2-E2-E7 chymeric VLP from NCI, etc... These vaccines are safe, highly immunogenic and well tolerated. From the clinical HPV vaccine trial by Merck company, important result was reported on November of 2002. It was that the 41 cases of 765 women who were injected with placebo appeared to have persistent HPV infection in the HPV-DNA test, while 768 women who were injected with HPV 16 VLP vaccine have all appeared to be free from HPV infection. The aim of therapeutic HPV vaccine is an immunologic recognition of oncoprotein E6/E7 associated with carcinogenesis followed by the formation of antibodies for E6/E7 and inducing the CTL (cytotoxic T lymphocyte) responses. If successful therapeutic vaccine is made, we can expect beneficial effects on public health since there are many patients who have had HPV infection, CIN(cervical intraepithelial neoplasia) or cervical cancer. Models of therapeutic HPV vaccine that are currently in research are the type of recombinant oncoprotein E6/E7, and live viral vectors like vaccinia virus, adenovirus, retrovirus and DNA vaccines. Most advanced available therapeutic HPV vaccine candidates are the FP L2-E7-E6 and Vaccinia E6-E7 from Xenova, Vaccinia(MVA)-E6-E7 from Transgene, and HSP-E7 from Stressgen. Under these circumstances, current researches and trials are expected to bring about the routine usage of prophylactic vaccine for HPV within 5 years, as well as decreasing the incidence of uterine cervical cancer in Korea by using it effectively.

Interleukin-34 cancels anti-tumor immunity by PARP inhibitor

Takayoshi Nakamura,Nabeel Kajihara,Naoki Hama,Takuto Kobayashi,Ryo Otsuka,Nanumi Han,Haruka Wada,Yoshinori Hasegawa,Nao Suzuki,Ken-ichiro Seino 대한부인종양학회 2023 Journal of Gynecologic Oncology Vol.34 No.3

Objective: Breast cancer susceptibility gene 1 (BRCA1)-associated ovarian cancer patients have been treated with A poly (ADP-ribose) polymerase (PARP) inhibitor, extending the progression-free survival; however, they finally acquire therapeutic resistance. Interleukin (IL)-34 has been reported as a poor prognostic factor in several cancers, including ovarian cancer, and it contributes to the therapeutic resistance of chemotherapies. IL-34 may affect the therapeutic effect of PARP inhibitor through the regulation of tumor microenvironment (TME). Methods: In this study, The Cancer Genome Atlas (TCGA) data set was used to evaluate the prognosis of IL-34 and human ovarian serous carcinoma. We also used CRISPR-Cas9 genome editing technology in a mouse model to evaluate the efficacy of PARP inhibitor therapy in the presence or absence of IL-34. Results: We found that IL34 was an independent poor prognostic factor in ovarian serous carcinoma, and its high expression significantly shortens overall survival. Furthermore, in BRCA1-associated ovarian cancer, PARP inhibitor therapy contributes to anti-tumor immunity via the XCR1+ DC-CD8+ T cell axis, however, it is canceled by the presence of IL-34. Conclusion: These results suggest that tumor-derived IL-34 benefits tumors by creating an immunosuppressive TME and conferring PARP inhibitor therapeutic resistance. Thus, we showed the pathological effect of IL-34 and the need for it as a therapeutic target in ovarian cancer.