bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A050: MicroRNA as biomarkers in early detection and personalized treatment in ovarian cancer: Development of a personalized prevention consortium
Authors: Fortner Renée Turzanski , Langseth Hilde 
Published: March 2024

Abstract
Epithelial ovarian cancer (EOC) has poor survival given no effective early detection strategies and non-specific early disease symptoms. We have formed a consortium with European and American partners to provide the necessary validation of a microRNA (miRNA) panel for earlier detection of EOC using serum samples and data from prospective cohorts, paired with clinical data and biospecimens. Our objectives are to validate a serologic miRNA panel that, together with CA125, would have sufficient diagnostic discrimination to be used as a tool that, complementary to imaging, would allow early identification and direction of patients with suspected malignancy to personalized gyn-oncological care. We will validate serum miRNA profiles as biomarkers for early detection in samples collected from cases ⇐3 years prior to EOC diagnosis and matched controls and characterize sources of variation in miRNA profiles and their impact on discrimination. Evaluate miRNA profiles in the clinical setting and the discrimination between EOC cases and women with (i) benign ovarian tumors in blood samples collected prior to diagnostic surgery and (ii) underlying comorbidities (including other cancer types). Further, we will evaluate serum miRNA profiles as predictors of recurrence and will compare tumor tissue and serum miRNA profiles. Develop and optimize protocols for data integration and methods for algorithm development. Direct in silico validation, including miRNA and CA125 levels, and clinical and epidemiologic data. Address Ethical, Legal and Social Aspects (ELSA), including activities in key stakeholder groups. Challenges in health data privacy and sharing, including for development of an artificial intelligence model, will be addressed, as will the definition of a “healthy” population with respect to miRNA profiles for EOC. The consortium was launched in 2023, with the first findings expected in 2024. Beyond the initial direct aims of the consortium, expanded aims on further promising markers are envisaged.
Citation Format: Renée Turzanski Fortner, Hilde Langseth. MicroRNA as biomarkers in early detection and personalized treatment in ovarian cancer: Development of a personalized prevention consortium [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 A050.
Abstract A053: Understanding geospatial relationships in ovarian cancer risk
Authors: Wang Victoria , Hart Jaime , Elias Kevin 
Published: March 2024

Abstract
To examine the geographic distribution of ovarian cancer cases in the New England area and identify potential case clusters. Methods: This was a case-control study utilizing 1580 ovarian cancer patients from a single healthcare system (MGB). Using electronic health record (EHR) review, patient primary addresses were geocoded. To account for spatial distribution confounded by access to the MGB health system, 1750 patients from the MGB biobank system were geocoded as controls. Generalized additive models were used to determine the spatial patterning of cases and controls, controlled for age and race. Geospatial analysis was performed using ArcGIS software and R. Results: 3325 patients (1576 ovarian cancer patients, 1749 biobank controls) were successfully geocoded. Distribution of ovarian cancer cases and biobank patient controls were similar (average nearest neighbor distance 6337m vs 5623 m). Among the cohort of patients in New England (defined as MA, ME, NH, VT, RI, CT), there were 1476 ovarian cancer patients and 1663 biobank control patients. Use of a generalized additive model demonstrated higher incidence of ovarian cancer in Western CT, western MA, VT, and southern ME. These data are similar to SEER reported county-level incidence of late-stage ovarian cancer. Conclusions: Understanding the geospatial distribution of ovarian cancer cases can highlight potential clusters of higher incidences of disease. Causal relationships have yet to be established and require future investigation, but these data suggest spatially patterned exposures are worth examination.
Citation Format: Victoria Wang, Jaime Hart, Kevin Elias. Understanding geospatial relationships in ovarian cancer risk [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 A053.
Abstract A100: Entinostat alters the M1/M2 ratio in ascites compared to tumors derived from an ID8 murine model of ovarian cancer
Authors: Gupta Vijayalaxmi , Roby Katherine , Miceska SImona , Wilson Andrew , Yull Fiona , Crispens Marta , Zhang Wendy , Khabele Dineo 
Published: March 2024

Abstract
Poly ADP ribose inhibitors (PARPi) are most effective in ovarian cancer tumors with homologous recombination (HR) deficiency. Our group has shown that histone deacetylase inhibitors (HDACi) sensitize HR proficient ovarian cancer cells to PARPi. Our current efforts are directed towards understanding how this therapeutic regimen alters tumor-associated macrophages (TAMs) in murine models of high grade serous ovarian cancer. To investigate the effects of Ola combined with Ent, we used HR-proficient ID8 P53 wild-type and ID8 P53−/− syngeneic murine models. Mice were randomized into 4 groups: control, Ola, Ent and Ola+Ent. Mice (Ent and Ola+Ent) were pre-treated with 15 mg/kg entinostat or vehicle (Ola and Ola+Ent) for one week via oral gavage and then treated with vehicle/Ent/Ola (100 mg/kg)/Ola+Ent for two weeks. Mice were sacrificed 24 h after the last dose to harvest tumors and ascites. Tumors were processed for histology to determine cell proliferation (Ki67) and immune cell markers (CCL2, M1 and M2-like macrophages). Ascites fluid was processed for flow cytometric analysis of immune cells. Tumors from parental ID8 P53 wild type mice showed significantly lower cell proliferation marker Ki67 (P&lt;0.05), higher anti-tumorigenic M1-like CCL2 (P&lt;0.05), and lower pro-tumorigenic M2-like mannose receptor (P&lt;0.05) in Ent and Ola+Ent groups compared to vehicle and Ola. Ascites showed no significant change in anti-tumorigenic M1-like macrophages, but significantly increased pro-tumorigenic M2-like macrophages (P&lt;0.005). Arginase-1, another marker of M1 macrophage, assessed by IF also confirmed significant decrease in pro-tumorigenic M2-like macrophage in Ent and Ola+Ent treated mice tumors. Additional immune cell markers identified in ascites are being analyzed. To summarize, in ID8 syngeneic mouse models, Ola and Ent treatment exerted anti-tumorigenic effects in tumors but potentially pro-tumorigenic effects in ascites. In conclusion, concomitant targeting of tumor TAMs and ascites TAMs may be a therapeutic regimen to investigate in the future.
Citation Format: Vijayalaxmi Gupta, Katherine Roby, SImona Miceska, Andrew Wilson, Fiona Yull, Marta Crispens, Wendy Zhang, Dineo Khabele. Entinostat alters the M1/M2 ratio in ascites compared to tumors derived from an ID8 murine model of ovarian cancer [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 A100.
Abstract A110: Targeting methionine metabolism inhibits ovarian cancer stem cells
Authors: Zhang Shu , Metcalfe Tara X. , Hassel Christiane A. , O'Hagan Heather M. , Nephew Kenneth P. 
Published: March 2024

Abstract
Ovarian cancer (OC) is the leading cause of gynecologic cancer death. Platinum (Pt)- based chemotherapy can reprogram cancer cells to ovarian cancer stem cells (OCSCs) and contribute to disease recurrence. In the current study, we demonstrated that platinum drugs can enrich for OCSCs. In high grade serous ovarian cancer (HGSOC) cell lines, cisplatin treatment (IC50 for 16hrs) increased the percentage of cells with high aldehyde dehydrogenase (ALDH+) activity, a known OCSCs marker, and altered methionine (Met) metabolism. Extracellular Met uptake is converted to S-adenosyl-methionine (SAM) by methionine adenosyltransferase 2A (MAT2A), the rate-limiting enzyme of Met utilization. Short-term cisplatin treatment decreased SAM level and increased expression of MAT2A. It has been reported that CSCs have a high-flux metabolic state and are dependent on Met metabolism. We observed higher MAT2A expression in ALDH+ cells compared to the whole cell population, and Met depletion blocked the cisplatin-induced increase in %ALDH+ cells and spheroid formation ability. Furthermore, both MAT2A siRNA knockdown and the MAT2A inhibitor FIDAS-5 prevented cisplatin-induced increase in %ALDH+ cells, suggesting that blocking Met metabolism phenotypically inhibited the platinum enrichment of OCSCs. MAT2A inhibition also downregulated Cyclin E and arrested HGSOC cells in G1/S phase, indicating that a lower level of Met utilization re-established G1/S checkpoint in p53-mutant OC. As SAM is the universal methyl-group donor, it was of interest to examine whether the observed cisplatin-induced alterations in SAM level resulted in changes in DNA methylation. Methylation specific-PCR analysis demonstrated that siMAT2A or FIDAS-5 treatment of HGSOC cells inhibited cisplatin-induced hypermethylation of CpG islands of BRCA1 and ALDH1L1, a folate metabolic enzyme of which promoter hypermethylation is associated to tumor progression. Collectively, these results demonstrated a crucial role of Met metabolism in cisplatin-induced OCSCs enrichment. MAT2A has been recognized as a therapeutic target for the treatment of solid tumors and Met inhibition by targeting MAT2A could represent a therapeutic approach for inhibiting CSC in ovarian cancer.
Citation Format: Shu Zhang, Tara X. Metcalfe, Christiane A. Hassel, Heather M. O'Hagan, Kenneth P. Nephew. Targeting methionine metabolism inhibits ovarian cancer stem cells [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 A110.
Abstract B017: Understanding the impact of transporter heterogeneity on the efficacy of PARP inhibitors
Authors: Moncayo Carmen Ramirez , Zhang Guanying , Barr Alexis , Wu Vincen , Fotopoulou Christina , Cunnea Paula , Hall Zoe , Fets Louise 
Published: March 2024

Abstract
While PARP inhibitors have undoubtedly enhanced the prognosis of high-grade serous ovarian cancer (HGSOC) patients, variability in response and acquired drug resistance remain persistent hurdles undermining these drugs' effectiveness. One of the multiple mechanisms of resistance ascribed to PARP inhibitors involves transporter-dependent detoxification, facilitated by the overexpression of the multidrug-resistant protein MDR1, which couples ATP hydrolysis to drug efflux. Conversely, the Solute Carrier (SLC) family of transporters plays a role in the cellular uptake of multiple therapeutic compounds, whereby the presence and abundance of the relevant transporter at the plasma membrane may dictate intracellular concentration of the drug, with subsequent clinical implications. Despite these findings, our understanding of PARP inhibitor drug uptake mechanisms, and how heterogeneity of transporter expression limits drug efficacy, remains limited. To better understand this, we employed a combination of cell-based high-content microscopy assays and multimodal molecular tissue imaging techniques to investigate the heterogeneity in response to PARP inhibitors and their relationship to drug distribution. Mass spectrometry imaging of human HGSOC tumor explants demonstrated intra-tumor heterogeneity in PARP inhibitor uptake within clinical samples. Even at the single cell level, heterogeneity in PARP inhibitor uptake was observed, and this was seen to correlate with levels of DNA damage, suggesting that differences in drug distribution may limit PARP inhibitor response and contribute to acquired drug resistance. Taken together, this data suggests that diverse transporter signatures in cancer could contribute to patient-to-patient variability in PARP inhibitor response. The identification of the molecular determinants of the heterogeneity hitherto described might contribute towards a better understanding of drug sensitivity and acquired drug resistance, with the idea of improving patient stratification in the context of personalized medicine.
Citation Format: Carmen Ramirez Moncayo, Guanying Zhang, Alexis Barr, Vincen Wu, Christina Fotopoulou, Paula Cunnea, Zoe Hall, Louise Fets. Understanding the impact of transporter heterogeneity on the efficacy of PARP inhibitors [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 B017.
Abstract B021: A phase 1 dose escalation study of lapatinib and paclitaxel in recurrent ovarian cancer
Authors: Cao Connie D. , McCorkle Joseph R. , Yan Donglin , Jayswal Rani , Miller Rachel W. , Dietrich Charles S. , Ueland Frederick R. , Kolesar Jill M 
Published: March 2024

Abstract
Objectives: Paclitaxel is a commonly used chemotherapy agent for women with recurrent ovarian cancer; however, its efficacy is limited by the development of ABCB1-mediated drug resistance. Lapatinib is an EGFR and HER2 inhibitor approved for treating breast cancer but without single agent activity in ovarian cancer. Lapatinib is also an ABCB1 inhibitor, and we hypothesize that lapatinib overcomes ABCB1-mediated paclitaxel resistance in previously treated ovarian cancer patients. Methods: This phase 1 dose escalation study used a Bayesian optimal interval (BOIN) design to determine the recommended phase 2 dose of the combination of paclitaxel and lapatinib. Secondary endpoints were to assess adverse effects, determine the objective response rate, and assess pharmacokinetics. Eligible patients had ovarian, peritoneal, or fallopian tube cancer and had recurred within 12 months of platinum-based chemotherapy. Patients received three weekly paclitaxel doses of 80 mg/m2 in 28-day cycles. Patients were pretreated with escalating doses of lapatinib twice daily in the 48 hours preceding paclitaxel for up to 3 cycles starting with the second paclitaxel dose of cycle 1. Three lapatinib doses were evaluated, escalating from 750 to 2000 mg orally twice daily. Results: Fifteen of nineteen patients were eligible and evaluable for toxicity and 12 have completed study therapy and are evaluable for response. All were female, the median age was 66, and the median number of prior therapies was 3. Three patients were treated at dose level 1, six at dose level 2, and seven at dose level 3. One patient treated at dose level 3 was not evaluable for dose-limiting toxicity (DLT). There was one DLT in dose level 2 (diarrhea) and another in dose level 3 (elevated liver function tests), with a posterior DLT estimate of 0.17, 95% Credible Interval of (0.01, 0.53) for dose level 3. The most common grade 1-2 adverse effects were diarrhea (75%) and neutropenia (43.8%). Among the 12 patients evaluable for efficacy, there were two partial responses and one stable disease for an objective response rate of 16% and a disease control rate of 25% in this heavily pretreated population. Conclusion: The combination of paclitaxel and lapatinib is safe and with an efficacy signal. The recommended phase 2 dose of the combination is 80 mg/m2 of weekly paclitaxel combined with 2000 mg bid of lapatinib two days before the paclitaxel dose.
Citation Format: Connie D. Cao, Joseph R. McCorkle, Donglin Yan, Rani Jayswal, Rachel W. Miller, Charles S. Dietrich, Frederick R. Ueland, Jill M Kolesar. A phase 1 dose escalation study of lapatinib and paclitaxel in recurrent ovarian cancer [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 B021.
Abstract B034: Targeting the HER family/Src pathways in ovarian cancer
Authors: Conlon Neil T. , Mörhle Elena , Collins Denis M. , Crown John 
Published: March 2024

Abstract
Background: Targeting EGFR and HER2 has been highly successful across several cancer types, but has been underexplored in ovarian cancer (OC), with several studies suggesting EGFR and HER2 is commonly over-expressed in epithelial OC. The irreversible pan-HER inhibitor neratinib has demonstrated clinical activity in HER2-mutant and HER2-overexpressing cancers and we have previously shown that neratinib plus the multi-kinase inhibitor dasatinib is highly synergistic in ovarian and breast cancers. Targeting the Src family kinases has involved the use of broad multi-kinase inhibitors such as dasatinib and bosutinib. However, NXP-900 is a novel orally bioavailable small molecule selective inhibitor of Src family kinases that may have synergistic efficacy with reduced off-target effects. The aim of this study was to investigate the potential of NXP-900 in combination with the pan-HER inhibitor neratinib in OC. Methods: The anti-proliferative effects of Src inhibitors, dasatinib (multi-kinase) or NXP-900 (Src selective), plus neratinib were tested in SKOV3, OVCAR3, PEO1 and IGROV-1 cell lines. Synergism was assessed using Combenefit software with the Loewe additivity model. Induction of caspase 3/7 activation, a marker of apoptosis, and the effects on cell migration with single agent and combination treatment were assessed using the Incucyte S3 imaging system. Downstream signaling alteration were investigated by Western blotting. Results: The combination of neratinib with either dasatinib or NXP-900 was highly synergistic across the cell lines. NXP-900 had little anti-proliferative activity as a single agent but significantly enhanced the effect of neratinib at nanomolar concentrations. Dasatinib showed potent single agent activity and synergies with neratinib across cell lines. SKOV3 cell line displayed the greatest synergy with both combinations and was selected for further characterization. Src inhibition alone inhibited cell migration, and further migration suppression was observed with the addition of neratinib. The combination stimulated apoptosis induction and resulted in on-target signaling inhibition in SKOV3 cells. Conclusions: This pre-clinical study showed that inhibition of the HER family and Src family kinases may have a strong anti-proliferative effect in OC models.
Citation Format: Neil T. Conlon, Elena Mörhle, Denis M. Collins, John Crown. Targeting the HER family/Src pathways in ovarian cancer [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 B034.
Abstract B063: Vascular senescence associated cell migration inducing hyaluronidase-1 production promotes ovarian cancer migration and tumorigenesis
Authors: Kumari Asha , Clark Peyton , Monavarian Mehri , Macias Liz Quintero , Arend Rebecca , Margaroli Camilla , Sewell Loftin Mary Kathryn , Karthikeyan Mythreye 
Published: March 2024

Abstract
Ovarian cancer is the most lethal gynecological cancer, typically diagnosed at advanced stages in post-menopausal women. The ovaries, which are a metastatic site of tumor growth for all ovarian cancers, are subjected to rapid changes in the vasculature upon the onset of menopause. Notably, we find that onset of menopause stimulates tumor growth in the ovaries, a key organ site involved in multiple ovarian cancers. In a corollary manner, vasculature is a primary therapeutic target for the management of advanced ovarian cancers indicating the significance of tumor angiogenesis in diseases progression and metastasis. Given the association between aging, endothelial senescence and angiogenesis, and our findings on the in vivo effect of menopause on tumor burden, we hypothesized that pre-existing senescent endothelial cells in ovaries as a result of follicle regression serve as a chemoattractant for tumor cells into the ovary leading to increased ovarian cancer cell migration and tumor growth. Using unbiased proteomics in conjunction with a novel 3D microphysiolological system along with studies using the ID8p53-/-ovarian cancer models we defined the effects of vascular senescence on ovarian tumor burden. We also identified cell migration inducing hyaluronidase 1 (CEMIP-1) as a vascular senescence factor. Notably, we observed that CEMIP is present in exosomes and regulates tumor cell migration and tumor burden changes in ovarian cancer models. Our findings demonstrate an active role for the changes in the ovarian vasculature with age, mediated potentially via cell migration inducing hyaluronidase 1 (CEMIP).
Citation Format: Asha Kumari, Peyton Clark, Mehri Monavarian, Liz Quintero Macias, Rebecca Arend, Camilla Margaroli, Mary Kathryn Sewell Loftin, Mythreye Karthikeyan. Vascular senescence associated cell migration inducing hyaluronidase-1 production promotes ovarian cancer migration and tumorigenesis [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 B063.
Abstract B098: Impact of dexamethasone on chemotherapy response in ovarian cancer
Authors: Venkatachalam Annapoorna , Correia Cristina , Mcgehee Cordelia , Finstuen-Magro Sarah , Schneider Paula A. , Hurley Rachel , Peterson Kevin L. , Heinzen Ethan , Larson Melissa C. , Hou Xiaonon , Oberg Ann L. , Weroha Saravut , Kaufmann Scott H. 
Published: March 2024

Abstract
Background: Ovarian cancer ranks fifth in cancer deaths among women. The gold standard of care for advanced disease includes cytoreductive surgery along with adjuvant or neoadjuvant platinum/taxane-based chemotherapy. Although response to this treatment is high, chemotherapy-induced nausea and vomiting due to platinum agents and allergic reactions due to both agents are common. For nearly half a century, the glucocorticoid (GC) dexamethasone (DEX) has been administered as part of supportive care. However, there have periodically been questions about the possible deleterious effects of DEX on chemotherapy response, especially in solid tumors. Methods: Platinum-sensitive, glucocorticoid receptor (GRa) expressing ovarian cancer cells were exposed to DEX prior to chemotherapy and clonogenic survival was assessed. The effects of DEX on cell cycle and apoptosis were assessed by flow cytometry. Changes in the tumor cell transcriptome after acute DEX treatment were determined by RNA sequencing. Mice bearing orthotopic ovarian cancer patient-derived xenografts (PDXs) were treated with chemotherapy ± DEX to assess changes in chemotherapy response in vivo. Findings: DEX pre-treatment decreased platinum cytotoxicity in ovarian cancer cell lines in vitro and diminished platinum response in some PDXs analyzed for chemotherapy response ex vivo. RNA-seq analysis revealed changes in transcripts encoding proteins involved in platinum detoxification and TNFa pro-survival signaling. In ovarian cancer PDXs, DEX decreased platinum response in one model and had limited impact on both platinum and platinum/taxane chemotherapy in three distinct studies. Interpretation: DEX appears to modulate chemotherapy response in some settings in vitro and ex-vivo. The impact of DEX on chemotherapy response in vivo appears to be limited. However, further investigation of this question in vivo in non-immunosuppressed murine models appears warranted.
Citation Format: Annapoorna Venkatachalam, Cristina Correia, Cordelia Mcgehee, Sarah Finstuen-Magro, Paula A. Schneider, Rachel Hurley, Kevin L. Peterson, Ethan Heinzen, Melissa C. Larson, Xiaonon Hou, Ann L. Oberg, Saravut Weroha, Scott H. Kaufmann. Impact of dexamethasone on chemotherapy response in ovarian cancer [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 B098.