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BRCA1/2 mutations account for only a small fraction of homologous recombination (HR) deficiency (HRD) cases. Recently developed genomic HRD (gHRD) tests suffer confounding factors that cause low precision in predicting samples that will respond to PARP inhibitors and DNA damaging agents. Here we present molecular and clinical evidence of transcriptional HRD (tHRD) that is based on aberrant transcript usage (aTU) of minor isoforms. Specifically, increased TU of nonfunctional isoforms of DNA repair genes was prevalent in breast and ovarian cancer with gHRD. Functional assays validated the association of aTU with impaired HR activity. Machine learning–based tHRD detection by the transcript usage (TU) pattern of key genes was superior to directly screening for gHRD or BRCA1/2 mutations in accurately predicting responses of cell lines and patients with cancer to PARP inhibitors and genotoxic drugs. This approach demonstrated the capability of tHRD status to reflect functional HR status, including in a cohort of olaparib-treated ovarian cancer with acquired platinum resistance. Diagnostic tests based on tHRD are expected to broaden the clinical utility of PARP inhibitors. Significance: A novel but widespread transcriptional mechanism by which homologous recombination deficiency arises independently of BRCA1/2 mutations can be utilized as a companion diagnostic for PARP inhibitors.

KGOG 3046 is a single-arm phase 2 study evaluating the combination of dual immune checkpoint inhibition (durvalumab [D] and tremelimumab [T]) with neoadjuvant chemotherapy (NAC) for the upfront advanced-stage epithelial ovarian cancer (aEOC). This study enrolled patients with FIGO stage IIIC-IV EOC. Patients were assigned to one of the following neoadjuvant chemo-immunotherapy (NACI): original cohort arm1 (D 1,500 mg q3w + T 75 mg q3w + paclitaxel 175 mg/m2 + carboplatin AUC 5 [3 cycles]) or expansion cohort arm2 (D 1,500 mg q3w + T 300 mg [1 dose] + same chemotherapy as original). Arm2 was initiated after the completion of arm1. After NAC, all patients underwent interval debulking surgery (IDS). After IDS, three cycles of D (1,120 mg) and adjuvant chemotherapy followed by D maintenance (1,120 mg [total 12 cycles]) were administered. During treatment, serial biopsies were performed to explore immunologic changes in tumor microenvironment (TME). The primary endpoint was a 12-month PFS rate. Interim analysis was performed to evaluate outcomes after NAC after all patients underwent IDS. A total of 45 patients were enrolled as follows: arm1 (n=23) and arm2 (n=22). The majority of the patients presented with high-grade serous carcinoma (91.1%) and stage IV disease (77.8%). After NAC, the ORR was 86.7% by RECIST v1.1 (95.7% in arm1 and 81.8% in arm2, P=0.17). At IDS, 30 patients (66.7%) had R0 resection (73.9% in arm1 and 59.1% in arm2, P=0.353). Fourteen patients (31.1%) had a CRS 3 (39.1% in arm1 and 22.7% in arm2, P=0.337) and 5 (11.1%) had a pathologic remission. Skin rashes were the most common adverse events (51.1%) and grade ≥3 events occurred in 3 patients (15.6%), which completely resolved after steroid use. Stromal TIL (P=0.0335), CD8 (P Summary of secondary outcomes D+T75+CT (n=23) D+T300+CT (n=22) P value ORR by RECIST 22 (95.7%) 18 (81.8%) 0.187 ORR by PERCIST 13/14a (92.9%) 16/18a (88.9%) 0.856 R0 at IDS 17 (73.9%) 13 (59.1%) 0.353 CRS3 at IDS 9 (39.1%) 5 (22.7%) 0.337 Pathologic CR 4 (17.4%) 1 (4.5%) 0.348 a, PERCIST was available in 14 (original) and 18 (expansion) cohorts. Citation Format: Junsik Park, Eunhyang Park, Je-Gun Joung, Myong Cheol Lim, Byoung-Gie Kim, Jae Weon Kim, Jung Bok Lee, Sunghoon Kim, Chel Hun Choi, Hee Seung Kim, Sang Yoon Park, Jongsuk Chung, Jung-Yun Lee. A phase II study of durvalumab and tremelimumab with front-line neoadjuvant chemotherapy in patients with advanced-stage ovarian cancer (KGOG 3046/TRU-D) [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 CT010.

BVAC-C is a B cell-based and monocyte-based immuno-therapeutic vaccine transfected with a recombinant human papillomavirus (HPV) 16/18 E6/E7 gene and loaded with alpha-galactosyl ceramide, which is a natural killer T cell ligand. This phase I study sought to determine the tolerability and immunogenicity of BVAC-C in platinum-resistant recurrent cervical cancer patients. Patients with HPV 16-positive or 18-positive recurrent or persistent cervical cancer who had received at least one prior platinum-based combination chemotherapy were enrolled. BVAC-C was injected intravenously three times every four weeks, and dose escalation was planned in a three-patient cohort design at doses of 1×107, 4×107, or 1×108 cells/dose. Eleven patients were enrolled, and six (55%) patients had received two or more lines of platinum-based chemotherapy prior to enrollment. Treatment-related adverse events (TRAEs) were observed in 21 cycles. Most TRAEs were mild fever (n = 6.55%) or myalgia (n = 4.36%). No dose-limiting toxicities occurred. The overall response rate was 11% among nine patients evaluable, and the duration of response was 10 months. Five patients (56%) achieved a stable disease for 4.2-11 months as their best overall response. The median progression-free survival in all patients was 6.8 months (95% CI, 3.2 to infinite months), and the overall survival rate at 6 and 12 months was 89% (95% CI, 71 to 100%) and 65% (95% CI, 39 to 100%), respectively. BVAC-C induced the activation of natural killer T cells, natural killer cells, and HPV 16/18 E6/E7-specific T cells upon vaccination in all patients evaluated. BVAC-C was well tolerated and demonstrated a durable anti-tumor activity with an immune response in HPV 16-positive or 18-positive recurrent cervical carcinoma patients. A Phase 2 efficacy trial is currently underway. Citation Format: Chel Hun Choi, Hyun Jin Choi, Jeong-Won Lee, Eun-Suk Kang, Duck Cho, Byung Kwan Park, Yong-Man Kim, Dae-Yeon Kim, Hyungseok Seo, Myunghwan Park, Wuhyun Kim, Ki-Young Choi, Taegwon Oh, Chang-Yuil Kang, Byoung-Gie Kim. Phase I study of a B cell-based and monocyte-based immunotherapeutic vaccine, BVAC-C, in human papillomavirus type 16- or 18-positive recurrent cervical cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT123.

Purpose: Pembrolizumab was approved for the treatment of patients with relapsed or metastatic cervical cancer with disease progression on or after chemotherapy, whose tumors express PD-L1 (CPS≥1), with a 14.3% objective response rate (ORR) by the U.S. FDA in 2018 (KEYNOTE-158). Combination of pembrolizumab with GX-188E, a DNA vaccine targeting HPV 16 and 18 types is expected to show synergistic anti-tumor effects presumably by antigen-specific CD8+ T cell responses induced by GX-188E DNA vaccine. The objectives of this interim analysis are to assess preliminary anti-tumor efficacy, safety and tolerability. Patients and Design: This is a prospective, open-label, phase II study in patients with advanced, inoperable or metastatic cervical cancer, ECOG PS 0-1, positivity for HPV 16 and/or 18 types who have failed all available standard-of-care (SoC) therapies including surgery, chemotherapy and radiotherapy or who have refused those (≥2 lines). Patients received GX-188E 2 mg intramuscularly, seven times at weeks 1, 2, 4, 7, 13, 19, and 46, with pembrolizumab 200 mg IV every three weeks for up to 2 years or until progression. This interim analysis was performed after obtaining at least one post baseline tumor assessment data from 22 patients (approximately 50% of total patients to be enrolled in Phase II). Results: Among 24 patients treated, 22 patients were evaluable for anti-tumor efficacy. Median age was 52 (range, 27-68) years and 37.5% had ECOG PS 1. As of the Dec 11, 2019 data cutoff, the median follow-up duration was 5.3 months (range; 0.9-16.3 months). ORR was 45.5%, with 5 CRs and 5 PRs. Additionally, one patient had SD at week 14. Median PFS was 4.1 months (range; 1.7-not reached). Median DoR and OS have not been reached. Treatment related AEs occurred in 54.2% of patients with grade 1 or 2 and 12.5% of patients with grade 3-4. The most common treatment related AEs classified by system organ class were gastrointestinal disorders (20.8%) and respiratory, thoracic and mediastinal disorders (16.7%), which were similar to those of pembrolizumab monotherapy. In contrast to pembrolizumab monotherapy, combined therapy showed therapeutic effect in PD-L1 negative tumor. Conclusions: Pembrolizumab combined with GX-188E demonstrated a higher response rate than pembrolizumab monotherapy in patients with cervical cancer showing great synergy regardless of PD-L1 expression. The safety profile was manageable and similar to that of pembrolizumab monotherapy. Further evaluation of anti-tumor response and antigen specific immune response is ongoing in a larger number of patients with and without PD-L1 expression. Citation Format: Sooyoung Hur, Jong Sup Park, Yong-Man Kim, Myong Cheol Lim, Jae Hong No, Byoung-Gie Kim, Jae-Kwan Lee, Chi Heum Cho, Yoon-Jeong Choi, You Suk Suh, Jung Won Woo, Young Chul Sung. Efficacy and safety results of pembrolizumab combined with GX-188E, a therapeutic DNA vaccine administration in patients with HPV 16- and/or 18- positive advanced cervical cancer: Phase II interim analysis results [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT033.

Insulin-like growth factor-binding protein 5 (IGFBP5) plays a role in cell growth, differentiation, and apoptosis. We found that IGFBP5 was markedly downregulated in ovarian cancer tissue, and that its overexpression in cancer cells induced cell death. In this study, we undertook to evaluate the functional significance of each region of IGFBP5 as a tumor suppressor of ovarian cancer. We found that the C-terminal region of IGFBP5 inhibited tumor growth in a 2774 cell xenograft mouse model, and that expression of VEGF, IL-6, and TNF-α were inhibited in 2774 cells stably expressing the C-terminus of IGFBP5. In order to evaluate its effects on tumor suppression, a peptide derived from the C-terminus of IGFBP5 (BP5-C) was synthesized. As a control, a peptide mutated in the IGF-binding site of BP5-C (BP5-Cmut), as well as peptides derived from the IGFBP2 C-terminus and heparin-binding site were also synthesized. Of these peptides, BP5-C and BP5-Cmut inhibited VEGF expression and NF-kB activity. Furthermore, BP5-C inhibited angiogenesis in an in vitro and an ex vivo system, consisting of HUVEC tube formation and rat aortic ring blood vessel sprouting, respectively. The in vivo effect of BP5-C on tumor growth was studied using i.p. injection of ovarian cancer 2774 cells into mice, as well as with a patient-derived xenograft mouse model. BP5-C peptide significantly inhibited tumor growth, angiogenesis, and VEGF expression in both xenograft models. These results suggest that the C-terminus of IGFBP5 exerts an anti-cancer activity by inhibiting angiogenesis via downregulation of VEGF in an IGF-independent manner, and may be considered as a novel angiogenesis inhibitor for the treatment of ovarian cancer. Citation Format: Jeong-Won Lee, Jae Ryoung Hwang, Young-Jae Cho, Yoo-Young Lee, Chel Hun Choi, Duk-Soo Bae, Byoung-Gie Kim. IGFBP5-derived peptide as a novel angiogenesis inhibitor for treatment of ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3384.

Purpose: Recent reports revealed that c-MET activation is associated with epithelial ovarian carcinoma (EOC) and is association with poor prognosis. In this study, we investigated the effects of therapeutic targeting for c-MET in ovarian clear cell carcinoma (OCCC). Experimental Design: Expression levels of c-MET in the epithelial ovarian carcinomas and normal ovarian tissues were evaluated using real-time PCR. To test c-MET inhibitors in CCC cell lines, we performed in vitro experiments including MTT and apoptosis assay. We performed Western blots to evaluate the c-MET expression and down-stream pathway. In addition, we performed in vivo therapy experiments in orthotopic ovarian cancer mice model (RMG1) and patient-derived tumor xenograft (PDX) models of CCC to confirm these effects. Results: The c-MET expression was significantly increased in CCCs compared with serous carcinomas and normal ovarian tissues (P < 0.05). CCC cells treated with c-MET inhibitors (SU11274 or crizotinib) demonstrated significantly decreased cell viability and increased apoptosis. Western blot assay showed that the protein expressions for c-MET signaling pathway were decreased by c-MET inhibitor. Moreover, tumor weight was significant decreased in both in vivo RMG1 and PDX models receiving SU11274 treatment compared with control (P < 0.05). Conclusion: These results show that c-MET inhibitor has the significant anti-tumor effects in ovarian CCC, and suggested that c-MET could have the potential agent in the therapy for this cancer. Citation Format: Jeong-Won Lee, Byoung-Gie Kim, Duk-Soo Bae, Yoo Young Lee. c-MET as a potential target in ovarian clear-cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 697. doi:10.1158/1538-7445.AM2015-697

Purpose: Sphingosine kinase 1 (SK1) is over-expressed in various human cancers with pro-growth effects and its inhibitors has been suggested potential anti-cancer agents. This study was designed to investigate the therapeutic potential of SK1 inhibitor in epithelial ovarian carcinoma (EOC). Experimental design: The expression of SK1 protein was evaluated using immunohistochemistry in patients with EOC. EOC cell lines (A2780, SKOV3ip1, A2780-CP20, SKOV3-TR, ES2 and RMG2) were used in this study to test SK1 siRNA or inhibitors. We used two kinds of SK inhibitor including SK inhibitor (for both SK1 and 2) and FTY720 (specifically inhibiting SK1) to check cell proliferation, apoptosis, angiogenesis and invasion using MTT, FACS, ELISA and wound-healing assay, respectively. Furthermore, in vivo experiments were performed to test the FTY720 on tumor growth in orthotopic EOC mouse model. Results: The expression of SK1 protein in primary EOC tissues was strongly observed in all of patients; however, there was no expression of SK1 protein in the normal ovarian epithelium (n=5). Blocking SK1 by its siRNA or inhibitors significantly affected cell proliferation, apoptosis, angiogenesis and invasion in A2780-PAR and SKOV3ip1 cells. SK1 inhibitors led to decrease of SK enzymatic activity in cells. Furthermore, utilizing the in vivo animal model (A2780-PAR), FTY720 treatment significantly decreased the total tumor weight compared with control (P < 0.05). Conclusions: These results show that therapeutic targeting of SK1 with its inhibitor could have potentials of novel therapeutics for EOC. Citation Format: Jeong-Won Lee, Ji Yoon Ryu, Hye-Kyung Jeon, Young-Ae Park, Young-Jae Cho, Jung-Joo Choi, Yoo-Young Lee, Tae-Joong Kim, Chel Hun Choi, Byoung-Gie Kim, Duk-Soo Bae. Therapeutic targeting for sphingosine kinase 1 in epithelial ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4618. doi:10.1158/1538-7445.AM2014-4618

Renin-Angiotensin system (RAS) is well known for its effect on the cardiovascular homeostasis by regulating arterial pressure. Accumulating evidences have been recently reported its paracrine regulation of tumorigenesis in several cancer types. Angiotensin type II receptor (AGTR) 1 and AGTR2 are the main effecter and known to act as antagonist to each other; AGTR1 plays as oncogene via positively regulating VEGF secretion, cell proliferation and conversely, AGTR2 does as tumor suppressor gene via decreasing not only angiogenesis but cell viability. Accumulating studies have revealed the correlation of these two receptors to the tumorigenesis through analysis of immunohistochemistry and in vitro data. Collectively, molecular targeting for them is being regarded as a novel strategy of cancer therapy. Treatment of either peptide antagonist of AGTR1, sartan or CGP-42112A, AGTR2 agonist has been shown to inhibit tumor progression in several cancer cells. In this study, we investigated the potentials of AGTR as therapeutic target in epithelial ovarian carcinoma. We estimated the expression of AGTR1 and AGTR2 in ovarian cancer cell lines and further tested whether modification of their activity could induce therapeutic effects. We performed MTT assay and ELISA for determining cell proliferation and secretion of VEGF, respectively. The expressions of AGTR1 or AGTR2 were variable but reciprocal among ovarian cancer cell lines. Stimulation of AGTR1 by treatment of angiotensin (Ang) II increased both cell proliferation and VEGF secretion of ovarian cancer cells expressing AGTR1. When the activity of AGTR1 was down-regulated by siRNA or specific antagonists, losartan or those of AGTR2 was up-regulated by plasmid or agonist CGP42112A, AngII mediated oncogenic effects were reduced. Inversing basal activity of AGTR1 and AGTR2 by treatment with losartan or CGP42112A synergistically enhanced decrease of both cell viability and secretion of VEGF in ovarian cancer cells. Moreover, combined treatment induced synergistic decrease of phosphorylation of PLCβ3 that is one of known downstream of AGTR1 and AGTR2, providing evidences that could explain the mechanism by which AGTR1 and AGTR2 could affect tumorigenesis in ovarian cancer cells. Interestingly, these enhancements were also reproduced in HUVEC (human umbilical vein endothelial cell) and by comparison, we found that both individual and combined treatment were more effective in endothelial cells in comparison to the ovarian cancer cells, implying the therapeutic effect of targeting AGTR in tumor microenvironment also. Taken together, these results suggested that dual targeting of AGTR 1 and 2 could be a possible therapeutic strategy in the treatment of epithelial ovarian cancer. Citation Format: Young Ae Park, Jeong-Won Lee, Duk-Soo Bae, Byoung-Gie Kim, Ha-Jeong Kim, Chel Hun Choi. Dual targeting of angiotensin receptors (AGTR1 and AGTR2) as a new therapeutic strategy in epithelial ovarian carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5561. doi:10.1158/1538-7445.AM2013-5561

Purpose: Galectin-1 (Gal-1) is a 14-kDa laminin-binding galectin involved in several biologic events including regulation of tumor proliferation and metastasis. In this study, we investigated the clinical significance of Gal-1 expression and its functional role in cell proliferation and invasion in epithelial ovarian cancer (EOC). Experimental Design: We evaluated the expression of Gal-1 in 52 serous, 11 endometrioid, and 3 mucinous type EOC tumor samples from 66 patients by immunohistochemistry. In vitro experiments were performed to determine the function of Gal-1 in cell survival, proliferation, and invasion in EOC cells using siRNA and anginex, a Gal-1 inhibitor, as well as recombinant Gal-1 protein. Results: Patients with strong Gal-1 peritumoral staining had poorer progression-free survival (PFS) than patients with weak peritumoral staining (P = 0.03). Inhibition of Gal-1 by siRNA or anginex resulted in the inhibition of cell growth and proliferation of HeyA8 and SKOV3ip1 cells. Moreover, the ability of cells to migrate was significantly reduced by treatment of cells with Gal-1 siRNA but was increased by treatment of cells with recombinant Gal-1. When we evaluated the interaction between fibroblasts (H HESC) and cancer cells (A2780-CP20), we found that MMP-2 expression in cancer cells was affected by Gal-1 secreted by fibroblast cells, which suggests that Gal-1 in human fibroblasts might affect the invasive abilities of tumor cells. Conclusion: Our results suggest that Gal-1 expression is a potential prognostic factor for PFS and that Gal-1 could be a novel treatment target in EOC patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2105. doi:1538-7445.AM2012-2105

Backgrounds: Menstrual, reproductive and hormonal factors have been related to ovarian cancer risk, but further quantification of their role in various populations is required. Patients and methods: Cases were 77 women, below age 79, with incident, histologically confirmed epithelial ovarian cancer, and 117 women with, histologically confirmed benign ovarian tumor and controls 776 women, age matched controls The study was conducted from 2009 to 2010 in five hospitals in Seoul, South Korea. Data were obtained through in-person interviews and analysis was conducted using unconditional logistic regression Results: A statistically significant inverse association was observed between parity and ovarian cancer risk and between parity and benign ovarian tumor (Odds ratio [OR] = 0.18; 95% confidence interval [CI] = 0.06-0.50, OR=0.08, CI (0.02-0.30))No consistent association was observed with time since first or last birth, nor with spontaneous or induced abortions Breastfeeding was associated with a significant reduction in risk of ovarian cancer and benign neoplasm. (OR=0.33, CI (0.17-0.68), OR=0.42 CI(0.34-0.94)) Conclusion: This uniquely asian study confirms and further quantities the relation between hormonal and reproductive factors and ovarian cancer.The pattern of risk observed cannot be totally explained by a role of ovulation in ovarian carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 652. doi:1538-7445.AM2012-652

Background: Angiotensin and its receptor, AGTR (Anigiotensin receptor) are known as main effectors molecules of renin-angiotensin system in regulating the physiological processes of the cardiovascular system. Not only do they function as an endocrine system, but they have recently reported to regulate cell proliferation, angiogenesis, invasiveness, and viabilities via inducing intercellular signaling pathways. The aim of this study is to evaluate the role of angiotensin II and AGTR1 on cell survival and proliferation in epithelial ovarian carcinoma cells. Methods: Expressions of AGTR1 were evaluated by immunohistochemistry in epithelial ovarian carcinoma tissues and analyzed the correlation between AGTR1 expression and clinicopathological characteristics of patients. For in vitro test, we checked the level of expression for angiotensin II and AGTR1 in human ovarian cancer cell lines by Western blot. A recombinant angiotensin II and its blocker losartan were treated into the cells. For cell viabilities and proliferations were estimated by MTT assay. Results: Through checking the expression of AGTR1 in human ovarian cancer cells, we selected A2780 and HeyA8 cells for in vitro tests because these cells have relatively high expression. Exogenous treatment of angiotensin II resulted in increased cell growth of both cells. Losartan, specific blocker of AGTR1, diminished the angiotensin II-induced increased cell growth. Moreover, we identified that angiotensin II activated Akt and STAT signaling through AGTR1 and pretreatment of losartan inhibited those activations. Conclusion: In this study, we inquired into the role of angiotensin II-AGTR1 interaction in ovarian cancer. They positively regulate cell survivability and proliferation and activate intercellular signaling involving Akt and STAT via suggesting their oncogenic mechanisms. Moreover, treatment of losartan, showed antiproliferative effect by inhibiting the activations of AGTR1 mediated signaling. These results suggest that AGTR1 inhibitor like as losartan could be a novel therapeutic strategy treating this cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 892. doi:1538-7445.AM2012-892

Objectives: The 67-kDa laminin receptor (67LR) is a non-integrin cell surface receptor with high affinity for laminin, which plays a key role in tumor invasion and metastasis. We investigated the clinical significance of 67LR expression including roles of prognostic marker or therapeutic target in epithelial ovarian carcinoma. Methods: The expression of 67LR was evaluated by immunohistochemistry in 71 patients with ovarian carcinomas including 54 serous, 13 endometrioid and 4 mucinous types. We assessed the correlation of 67LR expression with clinical characteristics including histology, tumor grade, FIGO stage, and survival. In vitro experiment was performed for 67LR with inhibition using siRNA to evalute its role in cell growth control and sensitivity to chemotherapeutic agents in ovary carcinoma cell line. Results: The expression of 67LR protein with mainly membranous location was observed in majority (45/62, 73 %) of the EOCs but not in normal ovarian tissues (P Conclusion: These finding suggest that 67LR expression might be a prognostic marker for survival and it may play possible target for experimental treatment of epithelial ovary carcinoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 301. doi:10.1158/1538-7445.AM2011-301

ABSTRACT Objective: Hypoxia is now established as a key factor influencing the pathophysiology of malignant growth. Hypoxia-induced changes in gene expression are coordinated mainly by the hypoxia-inducible factor-1(HIF-1α) and HIF-2α. The aim of this study was to determine whether HIF-2α expression is associated with survival and response to radiation in cervical cancer. Methods: After reviewing the medical records of 119 patients treated in our institution by primary radiotherapy for stage IIB-IVA cervical cancer, we performed a case-control study. Cases (n = 12) were selected from patients with local recurrence or radiation failure after primary radiation therapy with or without concurrent chemoradiation. For each case, we selected two controls from patients who showed no local recurrence. Using pretreatment paraffin-embedded tissues, we evaluated expression of HIF-2α by immunohistochemistry. Staining was scored based on intensity (Intensity Score (IS) 0- 3) and proportion (Proportion Score (PS) 0-100). Results were analyzed by Student t-test, Mann-Whitney U test, Fisher's exact test, and Cox proportional hazards regression model. Results: HIF-2α expression representing degree of hypoxia has a relationship with poor response to radiotherapy. Conclusion: HIF-2α expression may have an important role in radioresistance in locally advanced cervical cancer. Key Words: Cervical neoplasm, Radiation, HIF-2α, Survival, Hypoxia Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 438.