Subtypes Of Epithelial Ovarian Cancer Research Articles

A hybrid stacking classifier with feature selection for handling imbalanced data

Nowadays, cancer has become more alarming. This paper discusses the most significant Ovarian Cancer, Epithelial Ovarian Cancer (EOC), due to the low survival rate. The proposed algorithm for this work is a ‘Multi classifier ShapRFECV based EOC’ (MSRFECV-EOC) subtype analysis technique that utilized the EOC data from the National Centre for Biotechnology Information and Cancer Cell Line Encyclopedia websites for early identification of EOC using Machine Learning Techniques. This approach increases the data size, balances different classes of the data, and cuts down the enormous number of features unrelated to the disease of interest to prevent overfitting. To incorporate these functionalities, in the data preprocessing stage, OC-related gene names were taken from the Cancermine database and other OC-related works. Moreover, OC datasets were merged based on OC genes, and missing values of EOC subtypes were identified and imputed using Iterative Logistic Imputation. Synthetic Minority Oversampling Technique with an Edited Nearest Neighbors approach is applied to the imputed dataset. Next, in the Feature Selection phase, the most significant features for subtypes of EOC were identified by applying the Shapley Additive Explanations based on the Recursive Feature Elimination Cross-Validation (ShapRFECV) algorithm, preserving predefined features while selecting new EOC features. Eventually, an accuracy of 97% was achieved with Optuna-optimized Random Forest, which outperformed the existing models. SHAP plotted the most prominent features behind the classification. The Pickle tool saves much training time by preserving hidden parameter values of the model. In the final phase, by using the Stratified K Fold Stacking Classifier, the accuracy was improved to 98.9%.

High-Grade Serous Ovarian Cancer during Pregnancy: From Diagnosis to Treatment.

Due to the rarity of ovarian cancer diagnosed during pregnancy, the literature on the treatment of subtypes of epithelial ovarian cancer in pregnancy is sparse. The aim of our review was to analyze cases of high-grade serous ovarian cancer in pregnancy. The PubMed and Scopus databases were searched for relevant articles published in English between January 2000 and December 2023. The references of all the relevant reviews found were also checked to avoid omitting eligible studies. Information on the all retrieved cases was extracted and reviewed in detail. The most important detail was the subtype of high-grade serous ovarian cancer, which was referred to as serous adenocarcinoma (grade 2 or grade 3) in older cases. We found eleven cases with relevant details of high-grade serous ovarian cancer diagnosed in pregnancy. Despite the small number of cases we found, our study demonstrated the importance of an accurate initial vaginal ultrasound at the first examination in pregnancy and the safety of diagnostic surgery and chemotherapy in pregnancy. There have not been long-term follow-ups of patients' oncologic and obstetric outcomes. As patients should be comprehensively informed, more detailed case reports or series with longer follow-up periods are needed.

Differentiation of Serous and Non-serous Epithelial Ovarian Cancer by Radiological Imaging

Background: Ovarian cancer has a high incidence and fatality rate, with the most prevalent type is epithelial origin. The serous subtype of epithelial cancer predominates. For therapy selection, it is important to differentiate this subtype by histopathological examination as a gold standard method. Since some patients are not eligible for a biopsy, radiological modalities such as Magnetic Resonance Imaging (MRI) are superior in discriminating tissue compared to computed tomography (CT) or ultrasound. The use of the T1 weighted imaging (T1WI) and T2WI sequences can best differentiate between a cystic and a solid lesion. The goal of this study was to use radiological examination to assist in the identification of ovarian cancer.Methods: This cross-sectional study used secondary data from histopathology and MRI results from patients with ovarian cancer. Data was gathered utilizing electronic medical records in Dr. Sardjito Hospital between January 2017 and May 2022. The following MRI characteristics are evaluated including ascites, papillary projection, solid nodule, signal intensity of solid and cystic components, size, configuration, enhancement of contrast, and bilateral of the lesion.Results: Thirty-eight subjects made up the study’s sample, and 63% of them had serous subtypes. Bilateral lesion suggested a three times greater likelihood that it was serous ovarian cancer (p 0.02; binary logistic regression). Age 50 years old and strong enhancement on contrast was also relevant for separating the serous subtype from other subtypes (enhancement p 0.02; age p 0.044). Conclusions: A bilateral lesion with a significantly enhanced pattern can be seen on the MRI of a serous subtype of epithelial ovarian cancer. The elderly are also more likely to develop this cancer.

Involvement of ferroptosis in eribulin-induced cytotoxicity in ovarian clear cell carcinoma

Ovarian clear cell carcinoma (OCCC) is a unique clinicopathological subtype of epithelial ovarian cancer that is resistant to standard chemotherapy. Eribulin, a microtubule dynamics inhibitor of halichondrin class, has unique effects in the cancer microenvironment such as induction of epithelization and reduction in metastatic potential in breast cancer cells; however, nothing is known about the effect of eribulin and the detailed mechanisms in OCCC. This study aimed to investigate the involvement of ferroptosis and its mechanism in the antitumor activity of eribulin in OCCC cells and a mouse xenograft model. We found that eribulin-induced cell death was reduced by ferroptosis inhibitors; deferoxamine, an iron chelator and ferrostatin-1, a lipid peroxidation inhibitor. Eribulin increased the levels of intracellular iron, reactive oxygen species (ROS), and lipid peroxides, and increased the mitochondrial membrane potential. Eribulin downregulated the expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), and superoxide dismutase (SOD) activity. The combination of eribulin and ML210, a glutathione peroxidase 4-inhibiting ferroptosis inducer, had a synergistic effect on ferroptosis. Taken together, our findings show firstly that eribulin triggers ferroptosis in OCCC and this effect occurs via the suppression of the Nrf2–HO-1 signaling pathway, SOD activity and the promotion of lipid peroxidation. These findings suggest that eribulin-induced ferroptosis is associated with its anti-tumor effect and also could be a potential therapeutic target in OCCC.

Integrated analysis of scRNA-seq and bulk RNA-seq identifies FBXO2 as a candidate biomarker associated with chemoresistance in HGSOC

BackgroundHigh-grade serous ovarian carcinoma (HGSOC) is the most prevalent and aggressive histological subtype of epithelial ovarian cancer. Around 80% of individuals will experience a recurrence within five years because of resistance to chemotherapy, despite initially responding well to platinum-based treatment. Biomarkers associated with chemoresistance are desperately needed in clinical practice. MethodsWe jointly analyzed the transcriptomic profiles of single-cell and bulk datasets of HGSOC to identify cell types associated with chemoresistance. Copy number variation (CNV) inference was performed to identify malignant cells. We subsequently analyzed the expression of candidate biomarkers and their relationship with patients' prognosis. The enrichment analysis and potential biological function of candidate biomarkers were explored. Then, we validated the candidate biomarker using in vitro experiments. ResultsWe identified 8871 malignant epithelial cells in a single-cell RNA sequencing dataset, of which 861 cells were associated with chemoresistance. Among these malignant epithelial cells, FBXO2 (F-box protein 2) is highly expressed in cells related to chemoresistance. Moreover, FBXO2 expression was found to be higher in epithelial cells from chemoresistance samples compared to those from chemosensitivity samples in a separate single-cell RNA sequencing dataset. Patients exhibiting elevated levels of FBXO2 experienced poorer outcomes in terms of both overall survival (OS) and progression-free survival (PFS). FBXO2 could impact chemoresistance by influencing the PI3K-Akt signaling pathway, focal adhesion, and ECM-receptor interactions and regulating tumorigenesis. The 50% maximum inhibitory concentration (IC50) of cisplatin decreased in A2780 and SKOV3 ovarian carcinoma cell lines with silenced FBXO2 during an in vitro experiment. ConclusionsWe determined that FBXO2 is a potential biomarker linked to chemoresistance in HGSOC by combining single-cell RNA-seq and bulk RNA-seq dataset. Our results suggest that FBXO2 could serve as a valuable prognostic marker and potential target for drug development in HGSOC.

Abstract 5479: Spatially resolved molecular features in the tumor-immune microenvironment of germline BRCA1/2 mutated versus BRCA wild type high grade serous ovarian cancers

Abstract High-grade serous ovarian cancer (HGSC) is the most common and aggressive subtype of epithelial ovarian cancer. Importantly, germline mutations in BRCA1/2 give rise to HGSC. Because most HGSC are diagnosed at stage III/IV, outcomes are poor and more effective therapies are needed. Although immune checkpoint inhibitors show promise for a number of cancer types, efficacy has been variable in HGSC. To help provide new clues to the molecular features of HGSC, we set out to elucidate the tumor microenvironment of HGSC using spatial transcriptomics approaches. Specifically, we applied 10x Genomics Visium Spatial Transcriptomics (ST) technology to 48 samples representing primary HGSC tumors from 24 patients, including 15 BRCA1/2 mutated cases and 9 BRCA non-mutated cases. In addition to individual sample analysis, we normalized data from 64,784 total features across all sections and performed an integrated cluster analysis to get an overall picture of the cellular architecture of HGSC, but to also directly investigate differences in the tumor microenvironment based on BRCA mutation status. The resulting 17 integrated clusters were subjected to molecular annotation using GSEA, ESTIMATE, and CIBERSORTx, which revealed feature clusters representing important cell types defined by marker genes. Analysis of the entire dataset identified a primary tumor cluster defined by the expression of known ovarian cancer genes including WFDC2 and “don’t eat me” marker genes CD24 and CD47. However, the predominant tumor cell population in BRCA mutated cases was marked by the expression of MUC1, EPCAM, CLDN3, and CD24, while BRCA non-mutated tumor cell cluster was marked by EFNA1, ID1, LSR, and CD9. Importantly, both groups revealed the presence of a specialized monocyte derived macrophage cluster defined by the expression of LYZ and genes involved in cholesterol metabolism including APOE and APOC1. These lipid-associated macrophages are M2 polarized and shown to be associated with poor outcome. Additional analyses are underway to determine spatial dependencies of various tumor and immunological cell compartments. These data provide novel insights into the HGSC tumor microenvironment that may influence HGSC’s vulnerability to immunological therapies. Citation Format: Jing Qian, Lynda D. Roman, Rania Bassiouni, Seeta Rajpara, Monica Neuman, Varun Khetan, David W. Craig, Joseph W. Carlson, John D. Carpten. Spatially resolved molecular features in the tumor-immune microenvironment of germline BRCA1/2 mutated versus BRCA wild type high grade serous ovarian cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5479.

Abstract 5998: Pharmacological inhibition of the LIF-LIFR autocrine loop reveals vulnerability of ovarian cancer to ferroptosis

Abstract Introduction: Of all gynecologic cancers, epithelial ovarian cancer (OCa) stands out with the highest mortality rates. Despite all efforts, 90% of individuals who receive standard surgical and cytotoxic therapy experience disease recurrence. The potential involvement of leukemia inhibitory factor (LIF) and its receptor (LIFR) in the progression of OCa is still obscure. In this study, we examined the mechanisms by which disruption of LIF/LIFR autocrine loops contributes to the cell death of ovarian cancer cells. Methods: The expression profiles of LIF and LIFR were obtained using 24 distinct OCa model cells, comprising both primary and established cell lines. The effects of EC359 on OCa cells were evaluated using reporter assays, colony formation, cell death, and cell viability. Flow cytometry was utilized to analyze lipid peroxidation. The Agilent Seahorse XF Pro Analyzer was used to calculate the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). Furthermore, flow cytometry was used for the preparation and analysis of lymphocytes. Mechanistic investigations were performed with RT-qPCR and RNA-seq analysis. The efficacy of the LIFR inhibitor EC359 as a targeted therapy was investigated using cell-based xenografts, syngeneic xenografts, patient-derived organoids (PDO), and patient-derived xenograft (PDX) models. Results: Analysis of cancer databases revealed that elevated expression of LIF or LIFR was associated with poor progression-free survival of OCa patients and a predictor of poor response to chemotherapy. Using 24 different primary and established OCa cell lines that represent four subtypes of epithelial OCa, we demonstrated that LIF/LIFR autocrine signaling is active in OCa. Moreover, treatment with EC359, a novel LIFR inhibitor, significantly reduced OCa cell viability and cell survival with an IC50 ranging from 5 to 50 nM. Furthermore, EC359 diminished the stemness of OCa cells. Mechanistic studies using RNA-seq and rescue experiments unveiled that EC359 primarily induced ferroptosis by suppressing the glutathione antioxidant defense system. Using multiple in vitro, ex vivo, and in vivo models including organoids, cell-based xenografts, patient-derived explants, and xenograft tumors, we demonstrated that EC359 dramatically reduced the growth and progression of OCa. Additionally, EC359 therapy considerably improved tumor immunogenicity by robust CD45+ leukocyte tumor infiltration and polarizing tumor-associated macrophages (TAMs) toward M1 phenotype while showing no impact on normal T-, B-, and other immune cells. Conclusions: Collectively, our findings indicate that the LIF/LIFR autocrine loop plays an essential role in OCa progression and that EC359 could be a promising therapeutic agent for OCa. Citation Format: Behnam Ebrahimi, Suryavathi Viswanadhapalli, Uday P. Pratap, Rahul Gopalam, Xue Yang, Prabhakar P. Venkata, Viktor Drel, Bindu Santhamma, Swapna Konda, Xiaonan Li, Alondra L. Rodriguez Sanchez, Hui Yan, Gangadhara R. Sareddy, Zhenming Xu, Brij B. Singh, Philip T. Valente, Yidong Chen, Zhao Lai, Manjeet Rao, Edward R. Kost, Tyler Curiel, Rajeshwar R. Tekmal, Hareesh B. Nair, Ratna K. Vadlamudi. Pharmacological inhibition of the LIF-LIFR autocrine loop reveals vulnerability of ovarian cancer to ferroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5998.

Abstract A107: Characterizing the genomic and immunologic landscape of serous borderline tumors and low-grade serous ovarian cancer

Abstract A107: Characterizing the genomic and immunologic landscape of serous borderline tumors and low-grade serous ovarian cancer

Abstract A114: Robust establishment and expansion of multilineage human fallopian tube organoids in serum-free medium

Abstract High-grade serous ovarian cancer (HGSOC) is the most prevalent subtype of epithelial ovarian cancer. Despite its name, HGSOC originates in the fallopian tube (FT), but metastasizes quickly in the adnexal region and is the most lethal gynecological cancer worldwide. Organoid culture is emerging as a powerful model for studying normal FT cell biology and ovarian cancer. To standardize primary human FT and HGSOC organoid culture, we have developed GyneCult Fallopian Tube Organoid Medium (FTOM), an optimized serum-free medium and a workflow that supports robust and representative FT organoid culture from freshly isolated or cryopreserved primary human FT cells. FT cultures were initiated by seeding 4000 fresh or cryopreserved single cells (8 donors) directly into 20 µL Corning® Matrigel® domes and overlaying them with FT Organoid Medium. Cultures were maintained with full-medium changes every 3 - 4 days and were passaged every 8 - 14 days into new 20 µL Matrigel® droplets, either at a passage ratio of 1:3 or by seeding at 4000 cells per droplet. Cultures were analyzed by immunocytochemistry (ICC) to detect secretory markers keratin 7 (KRT7), oviductal glycoprotein 1 (OVGP1), and PAX8, as well as ciliated cell markers acetylated alpha tubulin (TUBA1A) and FOXJ1. Across all donors, 16 ± 8% (mean ± SD) of dissociated EpCAM+ FT cells formed 50 - 300 µm diameter cystic organoids within 14 days of seeding (n = 8). Cultures can be maintained for at least 5 passages with 14 - 20 cumulative population doublings, at 3 - 4 doublings per passage. ICC analysis confirmed that organoids contained both polarized secretory cells (i.e., KRT7+, OVGP1+, PAX8+) and ciliated cells (i.e. acetylated TUBA1A+, FOXJ1+), indicating multilineage capacity (n = 5). We also tested the compatibility of GyneCult FTOM with culturing HGSOC samples and observed that one of three tumor samples tested generated organoids. These tumour organoids had a solid and irregular shaped morphology and were composed of PAX8+ cells. These cells underwent ≥ 5 cumulative population doublings over 5 passages, with 0.5 - 2 doublings per passage; this performance is consistent with recently published HGSOC organoid culture methods. These results demonstrate that GyneCult Fallopian Tube Organoid Medium is a robust medium for initiating and culturing FT epithelium as organoids, can support HGSOC organoid culture, and is a valuable tool for studying FT biology. Citation Format: Victor Ho, Maggie Chan, Manreet Chehal, Alice Liang, Allen C Eaves, Sharon A Louis, John Stingl. Robust establishment and expansion of multilineage human fallopian tube organoids in serum-free medium [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A114.

Abstract A076: T-cell exhaustion is an independent predictive biomarker of clinical outcome in high grade serous ovarian cancer regardless of homologous recombination deficiency status

Abstract Epithelial ovarian cancer is the most lethal gynecologic malignancy, with 5-year survival rates of 46%. High grade serous carcinoma (HGSC) is the most frequent subtype of epithelial ovarian cancer. Approximately 50% of cases are homologous recombination deficient (HRD). Whereas maintenance treatment by PARP inhibitors has significantly improved the prognosis of patients with HRD tumors, clinical outcome in this malignancy is still poor. Despite the immunogenic nature of HGSC, in which T-cell infiltration correlates to improved clinical outcome following surgery and chemotherapy, the disease exhibits low response rates to immune checkpoint blockade (ICB) monotherapy in advanced line settings. We have previously identified epithelial malignancies including HGSC, CD4 and CD8 populations of tumor-infiltrating and antigen-specific T cells that display features of terminal exhaustion. These populations were key players in the response to anti-PD-1 in patients with epithelial tumors. Here, we set out to characterize tumor-infiltrating T cells in a cohort of 80 HGSC patients treated at our institution from whom we collected tumor samples prior to therapy in which HRD status was assessed. We used multiplex immunofluorescence of FFPE tumor samples to assess infiltration by CD4 and CD8 T cells and multiparametric flow cytometry of frozen viable cell suspensions to assess CD4 and CD8 T-cell exhaustion. The link between biological parameters and clinical outcome was assessed by univariable and multivariable analyses. Assessment of the T-cell infiltrate by immunofluorescence showed no difference in the absolute numbers, per tumor or stroma mm2, of CD8 or CD4 T cells between HRD and homologous recombination proficient (HRP) tumors. Instead, analysis of exhausted CD8 and CD4 T cells showed an increased frequency of terminally exhausted PD-1HighTIM-3+ CD8 T cells in HRD tumors. This population, which expresses the ectonucleotidase CD39, was significantly correlated to the presence of T regulatory cells (Treg), which agreed with previous studies showing comigration of effector and regulatory T cells in ovarian cancer. In addition, terminally exhausted CD4 T cells, expressing the immune checkpoints PD-1 and TIM-3 as well as CD39, were enriched in HRD tumors. Among HRD tumors, no difference was observed between the exhaustion profile in tumors presenting deleterious BRCA1/2 mutations compared to those with other mutations in the homologous recombination pathway. Univariable analyses showed exhaustion parameters to be significant predictors of progression-free survival (PFS). The frequencies of exhausted CD4 and CD8 T cells stood out as predictors of PFS in multivariable analyses. Altogether, these results provide the first evidence of a link between T-cell exhaustion and HRD status and reveal T-cell exhaustion as an independent predictor of disease outcome. They also underline the major role played by the antitumor immune response in HGSC and warrant the development of combination immunotherapies despite the lack of response to ICB monotherapy. Citation Format: Anna Salvioni, Mathilde Del, Marie Michelas, Pierre Vuattoux, Clara-Maria Scarlata, Carlos Martinez-Gomez, Nathalie Van Acker, François-Xavier Frenois, Guillaume Bataillon, Jean-Pierre Delord, Alejandra Martinez, Maha Ayyoub. T-cell exhaustion is an independent predictive biomarker of clinical outcome in high grade serous ovarian cancer regardless of homologous recombination deficiency status [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A076.

Abstract A066: The cytotoxic effects of oxaliplatin and 5-fluorouracil against low-grade serous ovarian cancer cells

Abstract A066: The cytotoxic effects of oxaliplatin and 5-fluorouracil against low-grade serous ovarian cancer cells

Abstract B015: CCDC80 as a novel cell intrinsic tumor suppressor protein in high grade serous ovarian cancer

Abstract B015: CCDC80 as a novel cell intrinsic tumor suppressor protein in high grade serous ovarian cancer

Abstract B058: Targeting mediator kinase CDK8/19 potentiates chemotherapeutic responses, reverses tumor growth, and prolongs survival from ovarian clear cell carcinoma

Abstract Ovarian clear cell carcinomas (OCCC) are a rare histological subtype of epithelial ovarian cancer with known treatment resistance, a feature associated with transcriptional reprogramming. CDK8 and CDK19 Mediator Kinases, which are isoforms of the Mediator Kinase – enzymatic components of a regulatory module that binds to the transcriptional Mediator complex –and not a part of the overall transcription machinery, have been previously reported to modify oncogenic transcription factors. Inhibition of the kinase activity of CDK8/19 was shown to prevent and reverse chemoresistance in other cancers with two CDK8/19 inhibitors currently in clinical trials for non–ovarian cancers. Based on the unmet need for OCCCs, we assessed CDK8/19 expression in a panel of OCCC primary and metastatic tissues and utilized cell line models for investigation into the therapeutic potential of CDK8/19 inhibitors in preventing tumorigenesis and synergizing with existing chemotherapeutics. The synergistic effects of SNX631-6, a preclinical CDK8/19 inhibitor drug candidate, were tested in vitro using three clear cell (ES2, TOV-21-G, RMG1) and one non-clear cell (SKOV3) ovarian carcinoma cell lines. A sub-inhibitory concentration 50 (IC50) concentration of SNX631-6 (500 nM) strongly potentiated effects of cisplatin, carboplatin, and paclitaxel. Additionally, cells demonstrating platinum resistance reverted to platinum sensitivity when exposed to the same concentration of SNX631-6. In vivo antitumor effects and tolerability of oral SNX631-6 were assessed in Foxn1nu homozygous female mice injected subcutaneously with ES2+luc cells. Mice were treated with a vehicle (n=10), intraperitoneal (IP) cisplatin (2 mg/kg) twice weekly (n=9), SNX631-6 medicated diet (330 ppm) orally ad libitum (n=10), or IP cisplatin combined with SNX631 diet (n=10) until tumors reached a predetermined critical volume of 2500mm3. In ES2+luc injected mice, significant tumor growth inhibition relative to vehicle occurred in mice treated with a combination of IP cisplatin and SNX631-6 (p<0.001) or SNX631-6 alone (p<0.01). Additionally, the use of IP cisplatin and SNX631-6 significantly delayed time-to-critical-volume compared to vehicle (p=0.0001). SNX631-6 alone and in combination with IP cisplatin was well tolerated in all mice based on body weight measurements. In summary, SNX631-6 potentiated platinum responses in vitro and demonstrated strong in vivo antitumor effects, including tumor regression, when used as monotherapy and in combination with platinum-based therapy. These data suggest that therapeutically achievable doses of SNX631-6 may provide clinical benefit, prevent tumorigenesis, and reverse platinum resistance in patients with OCCC. Citation Format: Wade Barton, Asha Kumari, Gary School, Zachary Mack, Liz Macias Quintero, Karthik Rangavajhula, Rebecca Arend, Mengqian Chen, Eugenia V. Broude, Karthikeyan Mythreye. Targeting mediator kinase CDK8/19 potentiates chemotherapeutic responses, reverses tumor growth, and prolongs survival from ovarian clear cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B058.

Abstract A074: Maveropepimut-S, a DPX-based immune-educating therapy, combined with Pembrolizumab and Cyclophosphamide in recurrent ovarian cancer, results from the Phase 1/2 PESCO Trial

Abstract A074: Maveropepimut-S, a DPX-based immune-educating therapy, combined with Pembrolizumab and Cyclophosphamide in recurrent ovarian cancer, results from the Phase 1/2 PESCO Trial

Real-world study of lymphadenectomy in patients with advanced epithelial ovarian cancer.

The evidence on the role of retroperitoneal lymphadenectomy is limited to less common histology subtypes of epithelial advanced ovarian cancer. This retrospective cohort study utilized data from the Surveillance, Epidemiology, and End Results Program from January 1, 2010, to December 31, 2019. Patients with stage III-IV epithelial ovarian cancer were included and divided into two groups based on whether they received retroperitoneal lymphadenectomy. The primary outcomes are overall survival (OS) and cause-specific survival (CSS). Among the 10 184 included patients, 5472 patients underwent debulking surgery with retroperitoneal lymphadenectomy, while 4712 patients only underwent debulking surgery. No differences were found in the baseline information between the two groups after propensity score matching. Retroperitoneal lymphadenectomy during debulking surgery was associated with improved 5-year OS (43.41% vs. 37.49%, p < 0.001) and 5-year CSS (46.43% vs. 41.79%, p < 0.001). Subgroup analysis further validate the retroperitoneal lymphadenectomy increased the 5-year OS and CSS in patients with high-grade serous cancer. Although the results were not validated in the less common ovarian cancer (including endometrial cancer, mucinous cancer, low-grade serous cancer, and clear cell cancer), the tendency showed patients with the above four subtypes may benefit from the lymphadenectomy which is restricted for small sample size after propensity score matching. This study revealed that retroperitoneal lymphadenectomy could further improve the survival outcome during debulking surgery in patients with advanced epithelial ovarian cancer. The conclusion was affected by the histology subtypes of ovarian cancer and further studies are needed to validate the conclusion in less common ovarian cancer.

Targeted Mass Spectrometry of Longitudinal Patient Sera Reveals LTBP1 as a Potential Surveillance Biomarker for High-Grade Serous Ovarian Carcinoma.

High-grade serous ovarian carcinoma (HGSC) is the most prevalent subtype of epithelial ovarian cancer. The combination of a high rate of recurrence and novel therapies in HGSC necessitates an accurate assessment of the disease. Currently, HGSC response to treatment and recurrence are monitored via immunoassay of serum levels of the glycoprotein CA125. CA125 levels predictably rise at HGSC recurrence; however, it is likely that the disease is progressing even before it is detectable through CA125. This may explain why treating solely based on CA125 increase has not been associated with improved outcomes. Thus, additional biomarkers that monitor HGSC progression and cancer recurrence are needed. For this purpose, we developed a scheduled parallel reaction monitoring mass spectrometry (PRM-MS) assay for the quantification of four previously identified HGSC-derived glycopeptides (from proteins FGL2, LGALS3BP, LTBP1, and TIMP1). We applied the assay to quantify their longitudinal expression profiles in 212 serum samples taken from 34 HGSC patients during disease progression. Analyses revealed that LTBP1 best-mirrored tumor load, dropping as a result of cancer treatment in 31 out of 34 patients and rising at HGSC recurrence in 28 patients. Additionally, LTBP1 rose earlier during remission than CA125 in 11 out of 25 platinum-sensitive patients with an average lead time of 116.4 days, making LTBP1 a promising candidate for monitoring of HGSC recurrence.

Drug-Resistant Epithelial Ovarian Cancer: Current and Future Perspectives.

Epithelial ovarian cancer (EOC) is a complex disease with diverse histological subtypes, which, based on the aggressiveness and course of disease progression, have recently been broadly grouped into type I (low-grade serous, endometrioid, clear cell, and mucinous) and type II (high-grade serous, high-grade endometrioid, and undifferentiated carcinomas) categories. Despite substantial differences in pathogenesis, genetics, prognosis, and treatment response, clinical diagnosis and management of EOC remain similar across the subtypes. Debulking surgery combined with platinum-taxol-based chemotherapy serves as the initial treatment for High Grade Serous Ovarian Carcinoma (HGSOC), the most prevalent one, and for other subtypes, but most patients exhibit intrinsic or acquired resistance and recur in short duration. Targeted therapies, such as anti-angiogenics (e.g., bevacizumab) and PARP inhibitors (for BRCA-mutated cancers), offer some success, but therapy resistance, through various mechanisms, poses a significant challenge. This comprehensive chapter delves into emerging strategies to address these challenges, highlighting factors like aberrant miRNAs, metabolism, apoptosis evasion, cancer stem cells, and autophagy, which play pivotal roles in mediating resistance and disease relapse in EOC. Beyond standard treatments, the focus of this study extends to alternate targeted agents, including immunotherapies like checkpoint inhibitors, CAR T cells, and vaccines, as well as inhibitors targeting key oncogenic pathways in EOC. Additionally, this chapter covers disease classification, diagnosis, resistance pathways, standard treatments, and clinical data on various emerging approaches, and advocates for a nuanced and personalized approach tailored to individual subtypes and resistance mechanisms, aiming to enhance therapeutic outcomes across the spectrum of EOC subtypes.

Moesin affects the plasma membrane expression and the immune checkpoint function of CD47 in human ovarian clear cell carcinoma

Among major histological subtypes of epithelial ovarian cancer, a higher incidence of ovarian clear cell carcinoma (OCCC) is observed in East Asian populations, particularly in Japan. Despite recent progress in the immune checkpoint inhibitors for a wide variety of cancer cell types, patients with OCCC exhibit considerably low response rates to these drugs. Hence, urgent efforts are needed to develop a novel immunotherapeutic approach for OCCC. CD47, a transmembrane protein, is overexpressed in almost all cancer cells and disrupts macrophage phagocytic activity in cancer cells. Ezrin-Radixin-Moesin (ERM) family member of proteins serve as scaffold proteins by crosslinking certain transmembrane proteins with the actin cytoskeleton, contributing to their plasma membrane localization. Here, we examined the role of ERM family in the plasma membrane localization and functionality of CD47 in OCCC cell lines derived from Japanese women. Confocal laser scanning microscopy analysis showed colocalization of CD47 with all three ERM in the plasma membrane of OCCC cells. RNA interference-mediated gene silencing of moesin, but not others, decreased the plasma membrane expression and immune checkpoint function of CD47, as determined by flow cytometry and in vitro phagocytosis assay using human macrophage-like cells, respectively. Interestingly, clinical database analysis indicated that moesin expression in OCCC was higher than that in other histological subtypes of ovarian cancers, and the expression of CD47 and moesin increased with the cancer stage. In conclusion, moesin is overexpressed in OCCC and may be the predominant scaffold protein responsible for CD47 plasma membrane localization and function in OCCC.

Plasminogen activator inhibitor 1 is associated with high-grade serous ovarian cancer metastasis and is reduced in patients who have received neoadjuvant chemotherapy.

Introduction: High-grade serous ovarian cancer (HGSOC) is the most prevalent and deadliest subtype of epithelial ovarian cancer (EOC), killing over 140,000 people annually. Morbidity and mortality are compounded by a lack of screening methods, and recurrence is common. Plasminogen-activator-inhibitor 1 (PAI-1, the protein product of SERPIN E1) is involved in hemostasis, extracellular matrix (ECM) remodeling, and tumor cell migration and invasion. Overexpression is associated with poor prognosis in EOC. Platelets significantly increase PAI-1 in cancer cells in vitro, and may contribute to the hematogenous metastasis of circulating tumor cells (CTCs). CTCs are viable tumor cells that intravasate and travel through the circulation-often aided by platelets - with the potential to form secondary metastases. Here, we provide evidence that PAI-1 is central to the platelet-cancer cell interactome, and plays a role in the metastatic cascade. Methods: SK-OV-3 cells where PAI-1 had been silenced, treated with healthy donor platelets, and treated with platelet-conditioned medium were used as an in vitro model of metastatic EOC. Gene expression analysis was performed using RNA-Seq data from untreated cells and cells treated with PAI-1 siRNA or negative control, each with and without platelets. Four cohorts of banked patient plasma samples (n = 239) were assayed for PAI-1 by ELISA. Treatment-naïve (TN) whole blood (WB) samples were evaluated for CTCs in conjunction with PAI-1 evaluation in matched plasma. Results and discussion: Significant phenotypic changes occurring when PAI-1 was silenced and when platelets were added to cells were reflected by RNA-seq data, with PAI-1 observed to be central to molecular mechanisms of EOC metastasis. Increased proliferation was observed in cells treated with platelets. Plasma PAI-1 significantly correlated with advanced disease in a TN cohort, and was significantly reduced in a neoadjuvant chemotherapy (NACT) cohort. PAI-1 demonstrated a trend towards significance in overall survival (OS) in the late-stage TN cohort, and correlation between PAI-1 and neutrophils in this cohort was significant. 72.7% (16/22) of TN patients with plasma PAI-1 levels higher than OS cutoff were CTC-positive. These data support a central role for PAI-1 in EOC metastasis, and highlight PAI-1's potential as a biomarker, prognostic indicator, or gauge of treatment response in HGSOC.

Tryptophan metabolism enzymes are potential targets in ovarian clear cell carcinoma.

As the second most prevalent subtype of epithelial ovarian cancers, ovarian clear cell carcinoma (OCCC) is known for its chemoresistance to conventional platinum-based therapy. In this work, we examined the tryptophan (Trp) metabolism enzymes' differential expression in patients with OCCC to assess the potential for personalised treatment. A total of 127 OCCC tissues were used to construct tissue microarrays, and immunohistochemistry (IHC) staining of the Trp enzymes IDO1, IDO2, TDO2 and IL4I1 was performed. The correlations between Trp enzyme expression and clinical characteristics were analysed. Positive IDO1, IDO2, TDO2 and IL4I1 staining was identified in 26.8%, 94.5%, 75.6% and 82.7% of OCCC respectively. IDO1-positive samples were more common in the chemoresistant group than in the platinum-sensitive group (46.7% vs. 19.8%). Moreover, positive expression of IDO1, TDO2 and IL4I1 was related to advanced stage, metastasis, bilateral tumours, endometriosis and tumour rupture (p < 0.05) respectively. Univariate analysis revealed a significant association between bilateral tumours, lymph node metastasis, advanced stage, distant metastasis and aberrant cytology with a poor prognosis for OCCC, while the absence of residual tumour was correlated with a favourable outcome (p < 0.05). However, only bilateral tumours and lymph node metastases were related to a poor prognosis after multivariate analysis. This is the first study to investigate the expression of the Trp enzymes IDO1, IDO2, TDO2 and IL4I1 in OCCC tissues. IDO2, TDO2 and IL4I1 were detected in the majority of OCCC. Clinical traits were correlated with IDO1, IDO2, TDO2 and IL4I1 expression. IDO1 may be used as a therapeutic target given the large percentage of chemoresistant cases with IDO1 expression. These results will aid the development of personalised therapies for OCCC.