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1. Plasmids, shRNAs and miRNA. 2. Promoter reporter constructs. 3. 3Â'UTR reporter constructs and site-directed mutagenesis. 4. Viral production and infection. 5. Reagents 6. Transient transfection and reporter gene assay. 7. Real-time quantitative PCR. 8. Quantification of mature miRNA. 9. ChIP assay. 10. mRNA microarray analysis. 11. EpiTect Methyl q-PCR Assay. 12. Mice genotype. 13. PLD activity assay. 14. In vitro limiting dilution assays (LDAs). 15. Additive statistical analysis.

The RB1/E2F1 signaling pathway is frequently deregulated in colorectal cancer and has been suggested to intersect with Wnt/β-catenin and PI3K/Akt pathways, but molecular evidence for this link is lacking. In this study, we demonstrate that phospholipase D1 (PLD1), a transcriptional target of β-catenin/TCF4, orchestrates functional interactions between these pathways during intestinal tumor development. Overexpression of PLD1 in intestinal epithelial cells protected cells from apoptosis induced by PLD1 ablation in the Apcmin/+ mouse model of intestinal tumorigenesis. Mechanistic investigations revealed that genetic and pharmacologic targeting of PLD1 promote the E2F1-dependent apoptotic program via both miR-192/4465–mediated downregulation of RB1 and inhibition of Akt–TopBP1 pathways. Moreover, the miRNA–RB1 axis and Akt pathway also contributed to the PLD1-mediated self-renewal capacity of colon cancer–initiating cells. Finally, PLD1-driven E2F1 target gene expression positively correlated with tumor stage in patients with colorectal cancer. Overall, our findings suggest that PLD1 mediates cross-talk between multiple major signaling pathways to promote the survival and malignancy of colon cancer cells and may therefore represent an ideal signaling node for therapeutic targeting. Cancer Res; 77(1); 142–52. ©2016 AACR.

Legend for supplementary figures.

Supplementary Table S1. Primer sets for Q-RT-PCR. Supplementary Table S2. Sequences of the promoter-specific primers used in ChIP assay Supplementary Table S3. Primer sets for mice genotype Supplementary Table S4. Factors of multivariates variables, gender, age, organ, tumor stage, and the protein pairs using Cox's proportional hazards model.

Background Resistance to PARP inhibitor occurs frequently and diversely in spite of germline/somatic BRCA mutations. Receptor tyrosine kinase cMET, which is frequently overexpressed in EOC associates with PARP1 activity and cell survival pathway. We investigated whether the combination of PARP inhibitor and cMET inhibitor could overcome PARP inhibitor resistance in resistant patient-derived xenografts (PDXs). Methods We established acquired resistant and innate resistant PDXs, which have BRCA mutation and cMET overexpression. These resistant models were used for evaluation of combined treatment of PARP inhibitor and cMET inhibitor. Resistant PDXs were treated with Vehicle, Olapairb, Savolitinib, Combination treatment. Results In acquired resistant PDXs, tumor growth rate were highly increased in vehicle group than the sensitive PDXs. Contrary to sensitive group, combination treatment was more efficient to inhibit tumor growth rather than olaparib single treatment. In the innate resistant PDXs were more tolerated to olapairb than the acquired resistant PDXs. As the acquired resistant PDXs, combination treatment was most efficient to inhibited tumor growth. Conclusion In this study, cMET inhibition sensitized the tumor with PARP inbihitor resistance to PARP inhibitor. These results indicated that savolitinib could have synerge with the combined treatment of PARP inhibitors for EOC patients with PARP inhibitor resistant.

Dendritic cell (DC)-based immunotherapies have been shown to be a potential treatment option for various cancers; however, the exact strategies in ovarian cancer remain unknown. Here, we report the effectiveness of mouse CD8α+ DCs derived from bone marrow hematopoietic stem cells (BM-HSCs), equivalent to human CD141+ DCs, which have proven to be a highly superior subset. Mono-DCs from monocytes and stem-DCs from HSCs were characterized by CD11c+ CD80+ CD86+ and CD8α+ Clec9a+ expression, respectively. Despite a lower dose compared with Mono-DCs, mice treated with pulsed Stem-DCs showed a reduced amount of ascitic fluid and lower body weights compared with those of vehicle-treated mice. These mice treated with pulsed stem-DCs appeared to have fewer tumor implants, which were usually confined in the epithelium of tumor-invaded organs. All mice treated with DCs showed longer survival than the vehicle group, especially in the medium/high dose pulsed Stem-DC treatment groups. Moreover, the stem-DC-treated group demonstrated a low proportion of myeloid-derived suppressor cells and regulatory T cells, high interleukin-12 and interferon-γ levels, and accumulation of several tumor-infiltrating lymphocytes. Together, these results indicate that mouse CD8α+ DCs derived from BM-HSCs decrease tumor progression and enhance antitumor immune responses against murine ovarian cancer, suggesting that better DC vaccines can be used as an effective immunotherapy in EOC treatment. Further studies are necessary to develop potent DC vaccines using human CD141+ DCs.

Objectives: Dendritic cell (DC) based immunotherapies have been shown to be a potential treatment option for various cancers; however, the exact strategies in ovarian cancer remain unknown. This study aimed to evaluate the effectiveness of mouse CD8α+ dendritic cells (DCs), corresponding to human CD141+ DCs, derived from bone marrow (BM) hematopoietic stem cells (HSCs) in a syngeneic and orthotopic mouse ovarian cancer model. Methods: Stem-DCs from HSCs and Mono-DCs from monocytes were generated from the bone marrow mononuclear cells (BM-MNCs) of C57BL/6 mice in condition of pulsing with ID8 tumor cell lysates. C57BL/6 mice were intraperitoneally injected with 5 × 106 ID8 cells. They were treated with vehicle, low/medium/high dose pulsed Stem-DCs, Mono-DCs, and unpulsed Stem-DCs. At 8 to 9 weeks, the treated mice were sacrificed, and tumor responses and immune responses, such as lymphocyte proliferation and cytokine secretion, were analyzed. Results: Mono-DCs and Stem-DCs were characterized by CD11c+CD80+CD86+ and CD8α+Clec9a+ expression, respectively. They were confirmed by the secretion of immunostimulatory cytokines, such as interleukin (IL)-12 and interferon (IFN)-γ, and T cell proliferation was observed after maturation. Despite a lower dose compared with Mono-DCs, mice treated with pulsed Stem-DCs showed a reduced amount of ascitic fluid and lower body weights compared with those of vehicle treated mice (P = 0.0021 and P = 0.0092, respectively). These mice treated with pulsed Stem-DCs appeared to have fewer tumor implants which were usually confined in the epithelium of ovaries, diaphragm and peritoneum. All mice injected with DCs demonstrated longer survival than the vehicle group (P = 0.0187), especially the medium/high dose pulsed Stem-DC treatment groups. Moreover, these favorable tumor responses were associated with a low proportion of myeloid-derived suppressor cells (MDSCs) and regulatory T cells, high IL-12 and IFN-γ levels, and accumulation of several tumor-infiltrating lymphocytes. Conclusions: We demonstrated that mouse CD8α+ DCs derived from BM HSCs could decrease tumor progression and enhance antitumor immune responses against murine ovarian cancer. Further studies are necessary to develop potent DC vaccines using human CD141+ DCs. Citation Format: Shin-Wha Lee, Dasol Oh, Hyunah Lee, Kyung-Won Lee, Min-Je Kim, Sung Wan Kang, Young-Jae Lee, HyunSoo Kim, Yong-Man Kim. CD8α+ dendritic cells potentiate the antitumor and immune activities against murine ovarian cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6798.

Background: High-risk human papillomavirus (HPV) type 16 is the major etiological agent found in more than 60% of patients with cervical cancer and associated with cancer development and progression. Persistent expression HPV E6 and E7 oncoproteins are essential for the initiation and maintenance of cervical cancer. The therapeutic approaches targeting HPV E6 and E7 have been proved to be highly efficient in killing malignant cells. The suppression of HPV 16 E6/E7 expression by the short interfering RNA (siRNA) was more effective in combination therapy with cisplatin (CDDP) for cervical cancer. ENB101-LNP is an ionizable lipid nanoparticles (LNPs) encapsulating siRNA against E6/E7 of HPV 16 for delivery to the tumor cells. Methods: To investigate the anticancer efficacy and mechanism of ENB101-LNP combined with cisplatin in cervical cancer; the xenograft model was generated by the injection of CaSki cells subcutaneously into BALB/c nude mice. Mice were randomly divided into six groups: 1) blank control; 2) 1mg/kg ENB101-LNP; 3) 3mg/kg ENB101-LNP; 4) CDDP; 5) 1mg/kg ENB101-LNP-CDDP; 6) 3mg/kg ENB101-LNP-CDDP. ENB101-LNP was treated with intravenous injection three times weekly for 3 weeks and CDDP was treated with IP injection once a week for 3 weeks. Tumor growth curves were plotted to calculate the tumor inhibition rate. Mice were sacrificed one week after the last treatment and the tumor tissues were investigated using histopathology, immunohistochemical staining and western blotting. Results: Compared with the control and the other treatment groups, the tumor growth was significantly inhibited (P < 0.05). The tumor inhibition rate was 29.7% in 1mg/kg ENB101-LNP group, 29.6% in 3mg/kg ENB101-LNP group, 34.0% in CDDP group, 47.0% in 1mg/kg ENB101-LNP-CDDP group. At the dose of 3mg ENB101-LNP/kg combined with CDDP exhibited superior antitumor efficacy, the tumor inhibition rate was 68.8%. The successful ENB101-LNP mediated knockdown (with up to 80%) of HPV16 E6/E7 in tumors of both 1mg/kg and 3mg/kg groups was confirmed by RT-PCR. The ENB101-LNP increased p53 and p21 expression in tumors compared to control and CDDP alone groups and combination treatment with CDDP showed decreased expression of PD-L1 expression compared to CDDP alone group. The treatment of ENB101-LNP and combination with CDDP showed significant increase in apoptotic cells compared to control and single-agent groups respectively. Conclusions: The ENB101-LNP inhibiting E6 and E7 of HPV 16 in combination with CDDP showed promising anticancer activity in the cervical cancer cells xenograft mouse model. Citation Format: Sung Wan Kang, Shin-Wha Lee, Ji-young Lee, Ok Ju Kang, Hyejeong Kim, Yisak Kim, Yong-Man Kim. Evaluation of anti-cancer efficacy of lipid nanoparticles containing siRNA against HPV16 E6 and E7 combined with cisplatin in xenograft model of cervical cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3779.

PURPOSE Here, we compared the operative and perioperative outcomes between robot-assisted laparoscopic myomectomy (RALM) and abdominal myomectomy (AM) in patients with large (>10 cm) or heavy myomas (>250 g). MATERIALS AND METHODS We included 278 patients who underwent multi-port RALM (n=126) or AM (n=151) for large or heavy myomas in a tertiary care hospital between April 2019 and June 2020. The t-test, chi-square, Bonferroni's test, and multiple linear regression were used. RESULTS No differences were observed in age, body mass index, parity, or history of pelvic surgery between the two groups. Myoma diameters were not different (10.8±2.52 cm vs. 11.2±3.0 cm, p=0.233), but myomas were lighter in the RALM group than in the AM group (444.6±283.14 g vs. 604.68±368.35 g, respectively, p=0.001). The RALM group had a higher proportion of subserosal myomas, fewer myomas, fewer large myomas over >3 cm, lighter myomas, and longer total operating time. However, the RALM group also had shorter hospital stay and fewer short-term complications. Estimated blood loss (EBL) was not different between the two groups. The number of removed myomas was the most significant factor (coefficient=10.89, p

Study Objective To investigate the prognostic factors and impact of minimally invasive surgery (MIS) in surgically treated early-stage high-grade (HG) neuroendocrine cervical carcinoma (NECC). Design Retrospective cohort study. Setting Asan Medical Center, Seoul, Korea. Patients Patients with International Federation of Obstetrics and Gynecology (2009) stages IB1 to IIA HG NECC. Interventions All patients underwent radical hysterectomy (RH) with a laparotomy or an MIS approach. Measurements and Main Results Between 1993 and 2017, 47 patients with International Federation of Obstetrics and Gynecology stages IB1 to IIA1 HG NECC were initially treated with RH. Clinicopathologic variables of patients were retrospectively reviewed from electronic medical records. The median follow-up period was 28.2 months (interquartile range, 17.1–42). Stage IB1 disease was the most common (70.2%). Twenty-nine patients (61.7%) underwent RH by MIS. The overall survival (OS) and disease-free survival (DFS) rates were 63.8% and 38.3%, respectively. Lymph node metastasis and resection margin involvement were significant risk factors for DFS (hazard ratio [HR], 2.227; 95% confidence interval [CI], 1.018–4.871; p =.045 and HR, 6.494; 95% CI, 1.415–29.809; p =.016, respectively) and OS (HR, 3.236; 95% CI, 1.188–8.815; p =.022 and HR, 12.710; 95% CI, 1.128–143.152; p =.040, respectively). The Kaplan-Meier survival curves revealed no significant differences in OS and DFS between the laparotomy and MIS groups (50% vs 72.4% log-rank p =.196, 38.9% vs 37.9% p =.975). Conclusion Lymph node metastasis and resection margin involvement were poor prognostic factors of survival outcomes in initially surgically treated early-stage HG NECC. No difference was observed in the survival outcomes between the MIS and laparotomy approaches.

본고는 한국의 민주화 과정에서 대중의 인식과 선호가 외교정책 결정 과정에 어떠한 영향을 끼치는지 살펴보았다. 특히 한국 민주주의에서 점점 뚜렷해지는 좌우 진영논리와 그로 인한 여론의 양분화와 정치화가 외교정책의 딜레마로 이어진 대표적인 세 가지 사례, 즉 i) 2008년 광우병 파동과 촛불시위로 인한 한미협상 결과; ii) 2015년 한일 ‘위안부합의’에 대한 여론의 반대와 그 결과; 그리고 iii) 2017년 THAAD 배치와 그에 따른 중국과의 관계에 대한 상충되는 주장을 비교 고찰하였다. 이들 사례를 통해 살펴볼 수 있듯이, 극도로 정치화･양분화된 여론 및 잘못된 포퓰리즘에 기반한 전략은 국익을 최우선시 해야하는 한국 외교에 커다란 걸림돌이 되어왔다. 따라서 정치지도자는 국익에 근거한 엄격한 외교정책원칙을 준수하며 불안정하고 자칫 감정에 치우칠 수 있는 여론에 휘둘리지 않는 인지적 분별력과 강단이 필요하다. 이와 동시에 민주적 책임을 진 지도자는 국민의 일상에 지대한 영향을 미칠 외교정책을 결정하기 전에 시민사회와의 ‘건설적인’ 대화를 지속해야 한다. 대중적 또는 당파적 선호 때문에 쉽게 흔들리지 않는 책임감 있고, 반응하고, 합법적인 외교정책을 수립·이행하기 위해 정부는 여론을 존중하고 국민은 국익이 무엇인지 이해하고 우선시하는 상호 윈-윈(win-win) 접근이 중요하다.

There are few studies between postoperative neutrophil to lymphocyte ratio (NLR) and survival in cervical cancer. We compared postoperative changes in NLR according to surgical methods and analyzed the effect of these changes on 5-year mortality of cervical cancer patients. A total of 929 patients were assigned to either the laparoscopic radical hysterectomy (LRH) (n = 721) or open radical hysterectomy (ORH) (n = 208) group. Propensity score matching analysis compared the postoperative NLR changes between the two groups, and multivariate logistic regression analysis evaluated the association between NLR changes and 5-year mortality. Surgical outcomes between the two groups were also compared. In the LRH group, NLR changes at postoperative day (POD) 0 and POD 1 were significantly lower than in the ORH group after matching (NLR change at POD 0, 10.4 vs. 14.3, p &lt, 0.001, NLR change at POD 1, 3.5 vs. 5.4, p &lt, 0.001). In multivariate logistic regression analysis, postoperative NLR change was not associated with 5-year mortality (2nd quartile: OR 1.55, 95% CI 0.56–4.29, p = 0.401, 3rd quartile: OR 0.90, 95% CI 0.29–2.82, p = 0.869, 4th quartile: OR 1.40, 95% CI 0.48–3.61, p = 0.598), whereas preoperative NLR was associated with 5-year mortality (OR 1.23, 95% CI 1.06–1.43, p = 0.005). After matching, there were no significant differences in surgical outcomes between the two groups. There were significantly fewer postoperative changes of NLR in the LRH group. However, the extent of these NLR changes was not associated with 5-year mortality. By contrast, preoperative NLR was associated with 5-year mortality.

Immunoprofiling has an established impact on the prognosis of several cancers, however, its role and definition in high-grade serous ovarian cancer (HGSOC) are mostly unknown. This study is to investigate immunoprofiling which could be a prognostic factor in HGSOC. We produced tumor microarrays of 187 patients diagnosed with HGSOC. We performed a multiplexed immunofluorescence staining using Opal Multiplex IHC kit and quantitative analysis with Vectra-Inform system. The expression intensities of programmed death-ligand 1 (PD-L1), CD4, CD8, CD20, FoxP3, and CK in whole tumor tissues were evaluated. The enrolled patients showed general characteristics, mostly FIGO stage III/IV and responsive to chemotherapy. Each immune marker showed diverse positive densities, and each tumor sample represented its immune characteristics as an inflamed tumor or noninflamed tumor. No marker was associated with survival as a single one. Interestingly, high ratios of CD8 to FoxP3 and CD8 to PD-L1 were related to the favorable overall survival (77 vs. 39 months, 84 vs. 47 months, respectively), and CD8 to PD-L1 ratio was also a significant prognostic factor (HR 0.621, 95% CI 0.420–0.917, p = 0.017) along with well-known clinical prognostic factors. Additionally, CD8 to PD-L1 ratio was found to be higher in the chemosensitive group (p = 0.034). In conclusion, the relative expression levels of CD8, FoxP3, and PD-L1 were significantly related to the clinical outcome of patients with HGSOC, which could be a kind of significant immunoprofiling of ovarian cancer patients to apply for treatment.

We aimed to compare the perioperative outcomes of single-incision robotic myomectomy (SIRM) and multiport robotic myomectomy (MPRM) and provide surgical tips. We retrospectively analyzed the medical records of 462 patients with symptomatic leiomyoma who underwent MPRM or SIRM between March 2019 and April 2021. Demographic characteristics and surgical outcomes, including the&nbsp, total operative time (OT), estimated blood loss (EBL), and surgical complication rate, were compared between the two groups. Patients in the SIRM group had lower a body mass index and rate of previous pelvic surgery and were younger than those in the MPRM group. The myoma type was not different between groups, however, the MPRM group had larger, and more myomas than the SIRM group. After propensity score matching, these variables were not significantly different between the groups. The total OT, EBL, difference in hemoglobin levels, transfusion rate, and postoperative fever were not different between the groups. No postoperative complications occurred in the SIRM group. In the MPRM group, one patient needed conversion to laparotomy, and two patients had postoperative complications (umbilical incisional hernia and acute kidney injury). In conclusion, both MPRM and SIRM are feasible and effective surgical options for symptomatic myomas with cosmetic benefits and minimal risk of laparotomy conversion.

Objective To assess the clinical usefulness and diagnostic accuracy of ultrasonographic measurement of endometrial thickness (ET) in women with endometrial hyperplasia or cancer (EH+). Methods This retrospective cohort study included 29,995 consecutive women who underwent transvaginal ultrasonography (TVS) for an incidental finding of a thickened endometrium at the health screening and promotion center at Asan Medical Center between 2006 and 2010. Among 959 patients with endometrial abnormalities, 92 patients were included in this study. A total of 867 patients were excluded: 416 were lost to follow-up; 263 did not undergo endometrial biopsy; 155 had endometrial polyps; 17 had submucosal myomas; and 16 had insufficient tissue samples. Endometrial histology was the reference standard for calculating accuracy. Results Of the 92 patients, 78 (84.8%) had normal pathology, while 14 (15.2%) had endometrial pathology (EH+), including 5 patients (35.7%) with simple hyperplasia without atypia, 3 (21.4%) with complex hyperplasia, and 6 (42.9%) with endometrial carcinoma, all stage Ia. The area under the receiver-operating characteristic curve was 0.75 (95% confidence interval [CI], 0.593-0.906). The cut-off value for ET was 8 mm, indicating that TVS ET had a fair accuracy in diagnosing carcinoma, had a sensitivity of 100% (95% CI, 62.9-100.0%) and a specificity of 24.3% (95% CI, 15.2-36.3%). Conclusion TVS is useful for detecting EH+, with a cut-off value for ET of 8 mm having a high sensitivity for detecting endometrial pathologies and the ability to identify women highly unlikely to have EH+, thereby avoiding more invasive endometrial biopsy.

2018년 초부터 시작된 국제사회의 북한 비핵화 협상 국면에서 북 · 미협상이 남 · 북협상과 함께 한 축을 구성하게 됨에 따라 미국에 대한 ‘정책공공외교’의 중요성이 최근 더욱 주목받고 있다. 한국은 한편으로는 미국 여론 주도층의 입장을 청취하면서 미국 정책결정자들의 의중을 파악하여야 한다. 다른 한편으로는 한국의 입장을 미국 여론 주도층에게 이해시키고, 그들을 통해 한국의 입장을 미국 정책결정자에게 설득하는 것이 필요하다. 이러한 맥락에서 본 연구는 먼저 정책공공외교가 공공외교의 영역에서 위상이 더욱 높아지고 있음을 살펴보고, 대미 정책공공외교의 대상과 주체를 파악한다. 이어 현시점에서 한국이 주력해야 할 대미 정책공공외교의 목표 및 우선순위를 설정하고, 대미 정책공공외교 효과를 증대시키기 위한 추진 방향을 제시한다.

Background We aimed to review the burden and the potential impact of human papillomavirus (HPV) vaccines on HPV-related diseases in the Republic of Korea and to discuss cervical cancer prevention practices in this country. Methods Cancer burden statistics were retrieved from GLOBOCAN-2018 and Statistics Korea. HPV disease burden was assessed via systematic review. Vaccine types relative contribution (RC) was estimated using data from an international project using formalin-fixed paraffin-embedded specimens. Results Despite a downtrend in cervical cancer in recent years, Korean rates remain high. In contrast, oropharyngeal cancer incidence has gradually increased and other anogenital cancers remain rare. In Korea, HPV prevalence in general population is around 20%. In cervical cancer, RC of HPVs 16/18 (74.0%) increased to 92.0% when including HPVs 31/33/45/52/58. Limited information was available for other HPV-related cancer sites. Regarding prevention, since the inclusion of the HPV vaccine into the National Immunization Program, almost half (49%) of the target cohort in 2016 had received the first dose of vaccine. Further, percentage of women screened with pap has increased from 41.1%-2009 to 53.0%-2016. Conclusions HPV-related disease burden in Korea is significant. Results suggest that the combination of effective and high coverage HPV vaccination and screening programmes could substantially impact on HPV-related disease in Korea., Highlights • HPV-related disease burden (cancer and genital warts) in Korea is significant. • HPV16 is the most frequent genotype, causing itself more than 60% of HPV-related cancers. • HPV vaccine types 16/18/31/33/45/52/58/6/11 cause 92.0% of cervical cancers. • HPV vaccines could significantly impact on the HPV-related disease burden.

PKO(Peacekeeping Operation)는 많은 국가에서 주요 외교정책으로 부상한 공공외교(public diplomacy) 관점에서도 중요하다. 왜냐하면 군의 활동이 자국 안보수호를 넘어 해외파병을 통해 세계평화증진에 공동의 책임을 갖고 기여하는 방향으로 확대되는 추이인데, PKO 기여를 통해 대상국 국민의 마음을 사고 상호 소통하는 과정으로서의 ‘안보공공외교’에 대한 인식이 높아졌기 때문이다. 여기서 안보공공외교란 국가 간 군사적 유대와 안보협력을 통한 자국의 외교안보역량 제고 및 글로벌 평화구축 달성을 위해 타국의 대중 및 외교안보정책을 수행하는 개인과 집단의 신뢰와 공감대를 확보하는 외교활동을 일컫는다. 그러나 군 중심으로 이루어져야할 PKO에 있어 민간인 역할이나 현지인들을 상대로 한 소프트파워 제고를 지나치게 강조할 경우 효과적인 임무수행이 어렵다. 따라서 글로벌 공익과 자국의 이익을 조화롭게 고려하여 ‘열린 국익’의 관점에서 하드파워와 소프트파워를 상황에 맞게 적절히 투사하는 PKO 정책수립이 필요하다. 따라서 한국의 PKO 활동을 추진하는 과정에서 명심할 것은 정치적이고 안보지향적인 특정 국익만을 주요 목적으로 하는 파병은 결코 성공적일 수도 인정받을 수도 없는 국제평화활동이라는 점이다. 도움을 절실하게 필요로 하는 힘든 상황의 국가와 국민들을 돕는 것에 우선순위를 부여하고 그들의 필요에 가장 잘 부합하는 방식으로 접근할 때 도덕성과 효과성 모두 확보할 수 있고, 보다 장기적으로 국익의 측면에서도 큰 효과를 거둘 수 있다.

Many studies have reported the efficacy of poly (ADP-ribose) polymerase (PARP) inhibitors in patients with epithelial ovarian cancer (EOC) with or without both germline/somatic BRCA mutations. However, resistance to PARP inhibitor occurs frequently in patients with advanced stage and recurrent. The receptor tyrosine kinase cMET, which is frequently overexpressed in EOC associates with PARP1 activity and cell survival pathway. Therefore, we investigated whether the combination of olaparib and savolitinib, a novel cMET inhibitor, could overcome PARP inhibitor resistance on resistant patient-derived xenografts (PDXs). Tumor tissues were obtained from patients with EOC operated at department of obstetrics and gynecology, Asan medical center, Seoul, South Korea. BRCA1 or BRCA2 mutated and cMET overexpressed tumors were selected and used for animal experiments. The tumor tissues were subcutaneous transplanted into right flank of NOD-scid IL2Rgammanull (NSG) mice. 60~90 days after transplantation, olaparib was administrated (80~100 mg/kg, daily, P.O.). Tumors were inhibited until volume decreased to 0~50 mm3. When the tumor volume was reached under 50 mm3, administration was stopped and tumors were allowed to regrowth. After tumor regrowth, to confirm resistance, administrated concentration of the olaparib was gradually increased 40 to 100 mg/kg (daily, P.O.). The resistant tumors were harvested and re-transplanted into 40 NSG mice. When tumor volumes reached at 100 mm3, mice were divided into 4 groups (Vehicle, Olapairb, Savolitinib, Combination) and olaparib (100 mg/kg, daily, P.O.) and savolitinib (25 mg/kg, daily, P.O.) were administrated. We established acquired resistant and innate resistant PDXs, which have BRCA mutation and cMET overexpression. These resistant models were used for evaluation of combined treatment of PARP inhibitor and cMET inhibitor. In case of the olaparib sensitive PDXs, tumor growth was suppressed to a similar level in combination group and olaparib single treatment group. Single treatment of cMET inhibitor also showed little inhibition in tumor growth. In case of the acquired resistant PDXs, tumor growth rate were highly increased in vehicle group than the sensitive PDXs. Contrary to sensitive group, combination treatment was more efficient to inhibit tumor growth rather than olaparib single treatment. The innate resistant PDXs were more tolerated to olapairb than the acquired resistant PDXs. Similar to acquired resistant PDXs, innate PDXs also showed rapid tumor growth in vehicle. As the acquired resistant PDXs, combination treatment was most efficient to inhibited tumor growth. In this study, cMET inhibition sensitized the resistant tumor to PARP inhibitor. These results indicated that savolitinib, novel cMET inhibitor, could have synergy with the PARP inhibitor for patients with PARP inhibitor resistant ovarian cancer. Citation Format: Min-Je Kim, Shin-Wha Lee, Young-Jae Lee, Su-Bin Park, Dong-Woo Kang, Yong-Man Kim. Combining PARP inhibitor with cMET Inhibition overcomes PARP inhibitor resistance in epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6185.