bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract PR-001: Beta-adrenergic blockade licenses the use of immunotherapy in primary brain tumors and brain metastases
Authors: Lorrey Selena , Wachsmuth Lucas , Price Mackenzie , Neff Corey , Ostrom Quinn , Fecci Peter
Published: March 2024

Immunotherapy is less effective against intracranial metastases compared to extracranial metastases and ineffective against primary brain tumors such as glioblastoma. Brain tumors present a unique challenge to in the context of immunotherapy, as these patients are immunosuppressed not just locally at the tumor, but also outside the CNS. Importantly, systemic immunosuppression observed in brain tumor patients limits the capacity of the immune system to respond to immunotherapy. Through this work we present a novel axis of immunosuppression in patients with intracranial tumors and demonstrate that overactive adrenergic signaling is a major barrier to immunotherapeutic success. Our data indicate that combining beta-adrenergic blockade with immunotherapy provides a survival benefit in the setting of brain tumors, where immunotherapy alone has proven ineffective. We demonstrate that this survival benefit is driven by a remodeling of the tumor microenvironment, increasing NF-kB activity and resulting in an increase in cDC1s and CD8+ T cells, as well as an increase in CD40-CD40L signaling, suggesting the immune system is poised to respond to immunotherapy. Further, we demonstrate that beta-adrenergic blockade can overcome systemic immunosuppression to restore the capacity of T cells to respond to an immune stimulus. Using the SEER-Medicaid database, we retrospectively examined outcomes in patients with melanoma and lung adenocarcinoma brain metastasis who received checkpoint blockade therapy alone vs those concurrently receiving beta-blocker therapy. We found that patients receiving combination therapy showed increased overall survival compared to those receiving checkpoint blockade alone. We then validated these findings in preclinical models of glioma, demonstrating that combining immunotherapy and propranolol, a widely prescribed FDA-approved beta-blocker, extended survival. Moving forward, we proffer that combination therapy with beta-blocker and immunotherapy, particularly checkpoint blockade, represents a promising translational treatment platform for patients with primary or metastatic intracranial malignancies.

Citation Format: Selena Lorrey, Lucas Wachsmuth, Mackenzie Price, Corey Neff, Quinn Ostrom, Peter Fecci. Beta-adrenergic blockade licenses the use of immunotherapy in primary brain tumors and brain metastases [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr PR-001.
Abstract A028: Investigating the role of SOX2 in promoting anchorage-independent survival of ovarian cancer cells
Authors: Kamlapurkar Shriya , Stump Coryn , Karthikeyan Mythreye , Hempel Nadine
Published: March 2024

Ovarian cancer (OVCA) is the most lethal gynecologic malignancy, often detected at an advanced stage. OVCA progression involves transcoelomic metastasis, where tumor cells disseminate into the peritoneal ascites. Malignant cells in the ascites adapt to survive under Anchorage-Independent (A-I) conditions by altering the expression of genes escalating anoikis (A-I cell death) resistance and metastasis. Our lab has shown that OVCA cells manipulate their transcriptomic profile to promote the expression of anoikis resistance genes in A-I. Expression profiling of genes upregulated in A-I revealed the transcription factor SRY-Box Transcription Factor 2 (SOX2) to be highly upregulated in response to OVCA cell detachment. While we have previously demonstrated that SOX2 is necessary for the A-I survival of OVCA cells, the specific mechanism underlying SOX2-dependent A-I survival remains unknown. RNA-sequencing studies performed in the high-grade serous ovarian cancer cell line, OVCAR3, revealed that the Leucine-rich repeat-containing G-protein coupled receptor 5, LGR5, is the most significantly upregulated gene in A-I compared to attached conditions. Importantly, amongst those genes that are upregulated in A-I, LGR5 is significantly downregulated following SOX2 knockdown in A-I. LGR5 is an ‘orphan’ G-protein coupled receptor known to modulate canonical Wnt signaling upon interacting with its ligand R-spondin1 (RSPO1). Time-course experiments in OVCAR3 cells revealed a striking increase in LGR5 expression that peaked after 24 hours in A-I. Furthermore, siRNA mediated knockdown of SOX2 downregulated LGR5 expression only in A-I, suggesting that LGR5 is a potential SOX2 target under A-I conditions. Interestingly, bioinformatics analysis of the existing OVCA datasets from the Cancer Genome Atlas showed increased expression of RSPO1, which correlated with a significant decrease in the overall survival of OVCA patients. Interaction of LGR5 with its ligand RSPO1 is crucial for the receptor to signal through the Wnt pathway to promote cell survival and cancer stemness. Although SOX2 and LGR5 are established markers of cancer stemness in various tumor types, their direct relationship in promoting tumor progression and regulation of OVCA A-I cell survival remains unknown. Our data suggests that increased SOX2 and LGR5 expression could drive OVCA cell survival under A-I conditions. Our current studies focus on understanding the molecular mechanisms behind SOX2-driven regulation of LGR5 and the role of LGR5 in driving OVCA A-I cell survival.

Citation Format: Shriya Kamlapurkar, Coryn Stump, Mythreye Karthikeyan, Nadine Hempel. Investigating the role of SOX2 in promoting anchorage-independent survival of ovarian cancer 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 A028.
Abstract A048: Utero-tubal lavage proteomic analysis: detection of ovarian cancer in BRCA mutation carriers
Authors: Bahar-Shany Keren , Barnabas Georgina D. , Korach Jacob , Jakobson-Setton Ariella , Geiger Tamar , Levanon Keren
Published: March 2024

No current screening methods for high-grade ovarian cancer (HGOC) guarantee effective early detection for high-risk women such as germline BRCA mutation carriers. Therefore, the standard-of-care remains risk-reducing salpingo-oophorectomy (RRSO) around age 40. Proximal liquid biopsy is a promising source of biomarkers, but sensitivity has not yet qualified for clinical implementation. We aimed to develop a proteomic assay based on proximal liquid biopsy, as a decision support tool for monitoring high-risk population. Ninety Israeli BRCA1 or BRCA2 mutation carriers were included in the training set (17 HGOC patients and 73 asymptomatic women), (BEDOCA trial; ClinicalTrials.gov Identifier: NCT03150121). The proteome of the microvesicle fraction of the samples was profiled by mass spectrometry and a classifier was developed using logistic regression. An independent cohort of 98 BRCA mutation carriers was used for validation. Safety information was collected for all women who opted for uterine lavage in a clinic setting. We present a 7-protein diagnostic signature, with AUC >0.97 and a negative predictive value (NPV) of 100% for detecting HGOC. The AUC of the biomarker in the independent validation set was >0.94 and the NPV >99%. The sampling procedure was clinically acceptable, with favorable pain scores and safety. We conclude that the acquisition of Müllerian tract proximal liquid biopsies in women at high-risk for HGOC and the application of the BRCA-specific diagnostic assay demonstrates high sensitivity, specificity, technical feasibility, and safety. A similar classifier for an average-risk population is warranted.

Citation Format: Keren Bahar-Shany, Georgina D. Barnabas, Jacob Korach, Ariella Jakobson-Setton, Tamar Geiger, Keren Levanon. Utero-tubal lavage proteomic analysis: detection of ovarian cancer in BRCA mutation carriers [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 A048.
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

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

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

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<0.05), higher anti-tumorigenic M1-like CCL2 (P<0.05), and lower pro-tumorigenic M2-like mannose receptor (P<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<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

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

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

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

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

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

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.
Abstract B106: A minimal driver pair for a spontaneous high-grade serous ovarian cancer mouse model: Myc and p53-R270H
Authors: Delaney Joe R
Published: March 2024

Genetically engineered mouse models (GEMM) have fundamentally changed how ovarian cancer etiology, early detection, and treatment can be understood. One challenge of the last decade has been to provide evidence for which cells are responsible for the origin of epithelial ovarian cancer. Different promoters, including Pax8, Lgr5, Ogvp1, and others have allowed for expression of transgenes in specific epithelial compartments in mice. Ovgp1 has been shown to be specific for fallopian tube epithelium (FTE), which most HGSOC is now thought to originate from. Pairing Ovgp1 with multiple homozygous deletions of powerful tumor suppressors like Brca1, Trp53, Rb1, and Nf1 yields murine disease after a year of age. However, human tumors do not contain homozygous deletions of these many tumor suppressors. Others have utilized Pax8 to knock out Trp53 and Pten to yield tumors at 3-8 months of age, but human tumors rarely have PTEN knockouts and Pax8 drives kidney and thyroid expression as well. We postulated that it is possible to strictly mimic human HGSOC genetics in a mouse model and nonetheless drive oncogenesis within the lifespan of a mouse. Here, we describe the OvTrpMyc model, Trp53em1Jdel_Tg(Ovgp1-Trp53*R270H-Myc), in which p53-R270H and Myc expression are driven by the Ovgp1 promoter. The transgene was inserted at the endogenous Trp53 locus, predicting that this design would allow for loss of the opposing wild-type chromosome 11 (syntenic to chromosome 17 in humans) to better mimic human HGSOC genetics. This model generated lethal disease at a median of 15.6 months of age. Dissected metastatic tumors were peritoneal and expressed Pax8, consistent with human disease. Immunohistochemical staining of the fallopian tube, ovary, and uterus indicated clear nuclear staining of p53 and Myc on the FTE. Notably, pockets of intraepithelial metastases expressing p53 and Myc were also found on the uterine epithelium. Cells grown ex vivo from uterus or fallopian tube dissections were analyzed for transcriptomes. RNA-seq revealed a clustering of these extracted cancer cells with human HGSOC and p53 mutant serous endometrial cancers. Loss of heterozygosity at the p53 locus was universal in these ex vivo grown cancer cells, as was extensive aneuploidy. The OvTrpMyc model requires only a single transgene for its breeding strategy, better enabling cancer detection, prevention, and treatment experiments. Taken together, the OvTrpMyc model of p53-R270H mutation and Myc expression driven by Ovgp1 is sufficient to recapitulate cancer hallmarks of HGSOC and, surprisingly, p53 mutant serous uterine cancer as well.

Citation Format: Joe R Delaney. A minimal driver pair for a spontaneous high-grade serous ovarian cancer mouse model: Myc and p53-R270H [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 B106.
Abstract B108: Zinc finger protein 217 (ZNF217) promotes ovarian cancer metastasis through interaction with estrogen
Authors: Wardrup Kathryn , Padmanabhan Achuth
Published: March 2024

ZNF217 is a transcription factor located at chromosomal region 20q13.2 which is frequently amplified in many human cancers, including ovarian. Consistently, ZNF217 mRNA is overexpressed in epithelial ovarian cancer and is negatively correlated with 5-year survival predictions. Despite this connection, little is known about the role of ZNF217 in the development of epithelial ovarian cancer. To explore the role of ZNF217 in this context, we generated ovarian cancer cell lines that stably overexpress ZNF217 to prolife in vitro pro-metastatic phenotypes. We found that increased expression of ZNF217 led to increases in cell proliferation, cell migration, adhesion, and transwell invasion. Subsequent gene expression analysis revealed alterations consistent with the induction of epithelial to mesenchymal transition (EMT). Depleting ZNF217 resulted in abrogation of these phenotypes. Consistent with these in vitro data, both intraperitoneal and ovary intrabursal xenograft models demonstrated that increased levels of ZNF217 rapidly enhanced the rate of tumorigenesis in vivo. RNA sequencing analyses revealed significant alterations in expression of genes involved in estrogen signaling, such as ESR1 and ESR2. We found that in vitro the presence of 17β-estradiol synergistically increased cell proliferation and invasion when compared to cells in media lacking estrogens. In vivo, ovariectomized mice supplemented with a subcutaneous slow release 17β-estradiol tablet in combination with high-ZNF217 expressing cells displayed an increased rate of tumorigenesis and an increase in disease severity as compared to controls lacking estrogens. The findings reveal a novel transcription factor that is key in promoting ovarian cancer progression and metastasis and highlights a functional role for estrogen in promoting ZNF217-driven metastasis.

Citation Format: Kathryn Wardrup, Achuth Padmanabhan. Zinc finger protein 217 (ZNF217) promotes ovarian cancer metastasis through interaction with estrogen [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 B108.
Abstract IA001: Placing our bets to make a difference
Authors: Bowtell David D.
Published: March 2024

The presentation will focus genomics of high grade serous ovarian cancer (HGSC). I will briefly describe TRACEBACK, a study aimed at identifying deceased high-risk mutation carriers, and how a novel approach to patient ascertainment and testing may serve as a model for other familial cancer diseases. I will discuss some of key questions and directions arising from our studies of end-stage BRCA-related HGSC using samples collected through a rapid autopsy program. The major focus of the presentation will be on analyses of patients with exceptionally poor or favorable overall survival, including a cohort of BRCA1/2 patients with an unusually poor response to treatment and survival, and HGSC patients who survive more than 10 years following their diagnosis.

Citation Format: David D. Bowtell. Placing our bets to make a difference [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 IA001.
Abstract IA005: Regional combating of immunosuppressive forces in the ovarian tumor microenvironment
Authors: Powell Daniel J.
Published: March 2024

The accumulation of intraepithelial T cells in ovarian cancer is prognostic for increased survival while the accumulation of immunosuppressive cells, such as tumor associated macrophages, are associated with poor outcomes. These clinical findings provide the rationale for the development of immunotherapeutic approaches that locally augment T cell responses while circumventing immunosuppressive forces. Clinical trials of systemic immunotherapy have shown encouraging clinical responses in a subset of treated patients; however tumor regression does not occur in most treated patients, some patients experience immune related adverse effects and patients with immunologically cold tumors are unlikely to respond. One central objective of researchers is to understand the basis of natural immune recognition and to use this knowledge to rationally bolster anti-tumor immunity. One modality to augment anti-cancer immunity is to administer adoptive T cell therapy (ACT), thereby increasing the net number of tumor-reactive T cells in a patient. While ACT is effective and approved for the treatment of various hematological cancers, there is no approved immunotherapeutic agent for the treatment of ovarian cancer, including ACT. With significant advances in synthetic biology and large-scale cell manufacturing, it is now possible to generate patient-specific T cell products that specifically recognize and kill antigen expressing cancer cells; to outfit those T cells with supraphysiological properties that overcome immunosuppressive forces in the tumor microenvironment; and to safely promote local recruitment of endogenous T cell responses to markedly enhance the overall immune response against ovarian cancer. Using these techniques, overexpressed antigens can be targeted, immunosuppressive tumor associated macrophages can be selectively eliminated, the tumor microenvironment can be polarized to an inflammatory state, endogenous T cell recruited, and T cells made to proliferate robustly at the tumor site in response to tumor recognition. This knowledge and these approaches provide a guidepost and the infrastructure to begin creating safe and effective immunotherapy for ovarian cancer.

Citation Format: Daniel J. Powell. Regional combating of immunosuppressive forces in the ovarian tumor microenvironment [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 IA005.
Abstract IA006: Friend or foe: Reevaluating the therapeutic potential of monocytes and tumor-associated macrophages in ovarian cancer
Authors: Yeku Oladapo
Published: March 2024

The hostile tumor microenvironment in ovarian cancer is an active deterrent to the efficacy of immunotherapeutic agents such as immune checkpoint inhibitors, Chimeric Antigen Receptor (CAR) T-cells, and Bispecific T-cell Engagers (BiTEs). Tumor-associated macrophages (TAMs) and Myeloid-Derived Suppressor Cells (MDSCs) have been shown to promote an immunosuppressive metabolic and cytokine tumor microenvironment that is detrimental to cytotoxic effector T-cell activity in ovarian cancer. These immunosuppressive cells are also associated with poor prognostic outcomes. The ideal approach to modulating TAMs and MDSCs is unknown. Data from preclinical models support reprogramming these cells to a more inflammatory phenotype or removing them from the tumor microenvironment entirely. However, neither approach has translated to clinical benefits. We have previously demonstrated that CAR-T cells modified to secrete IL-18 exerted their therapeutic effects partly via polarization of bone marrow macrophages towards an M1 phenotype. We also found that the depletion of TAMs improved CAR-T cell efficiency, even when these CAR-T cells were co-modified to secrete IL-12. Because of the propensity for monocytes to be recruited to the ovarian cancer tumor microenvironment, we evaluated the efficacy of monocytes genetically modified to secrete BiTEs. First, we designed and evaluated BiTEs that recognize the retained portion of MUC16 (Muc16-ecto) and CD3+ T-cells and showed that these BiTEs were efficacious in vitro and in vivo in a xenograft model of ovarian cancer. We validated that monocytes transduced to secrete Muc16-specific BiTEs (Mono-BiTEs) could effectively lyse tumor cells in vitro and suppress xenograft ovarian cancer cells in vivo. Adding IFN-alpha and IFN-gamma to Mono-BiTEs significantly improved Mono-BiTEs antitumor efficacy over BiTE therapy or unmodified monocyte therapy alone. Adoptive cell therapy with genetically engineered autologous monocytes could provide an alternative approach to reprograming or eliminating myeloid-derived cells in ovarian cancer.

Citation Format: Oladapo Yeku. Friend or foe: Reevaluating the therapeutic potential of monocytes and tumor-associated macrophages 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 IA006.
Abstract IA009: Epigenetic approaches to endometriosis-associated ovarian cancer
Authors: Zhang Rugang
Published: March 2024

The past decade has brought unprecedented progress in understanding the genetics of epithelial ovarian cancer (EOC), but cures remain elusive due to the lack of insights into mechanisms that can be leveraged to develop new therapies. EOC is genetically heterogeneous and, therefore, it is imperative that therapeutic strategies become personalized by targeting distinct molecular subsets of EOC. Despite the importance of epigenetic regulators in EOC, the mechanism of action for these epigenetic regulators and the associated vulnerabilities exposed by their dysregulations have remained elusive for most of them. Here we will discuss our recent work on how to leverage epigenetic mechanisms to address unmet clinical needs in endometriosis-associated ovarian cancer through integrated approaches.

Citation Format: Rugang Zhang. Epigenetic approaches to endometriosis-associated 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 IA009.
Table S2 from Next-generation Multi-target Stool DNA Panel Accurately Detects Colorectal Cancer and Advanced Precancerous Lesions
Authors: Gagrat Zubin D. , Krockenberger Martin , Bhattacharya Abhik , Gagrat Bridget Z. , Leduc Christine M. , Matter Michael B. , Fourrier Keith D. , Mahoney Douglas W. , Edwards V David K. , Lidgard Graham P. , Limburg Paul J. , Johnson Scott C. , Domanico Michael J. , Kisiel John B.
Published: March 2024

Table S2: Subject demographics for the marker selection study for novel multi-target stool DNA panel.
Figure S3 from Next-generation Multi-target Stool DNA Panel Accurately Detects Colorectal Cancer and Advanced Precancerous Lesions
Authors: Gagrat Zubin D. , Krockenberger Martin , Bhattacharya Abhik , Gagrat Bridget Z. , Leduc Christine M. , Matter Michael B. , Fourrier Keith D. , Mahoney Douglas W. , Edwards V David K. , Lidgard Graham P. , Limburg Paul J. , Johnson Scott C. , Domanico Michael J. , Kisiel John B.
Published: March 2024

Figure S3: Performance of novel multi-target stool DNA panel at fixed 90% specificity in the marker selection study; (A) Colorectal cancer (CRC) by stage and (B) advanced precancerous lesion (APL) by type; HGD, high-grade dysplasia; SSL, sessile serrated lesion
Figure S2 from Next-generation Multi-target Stool DNA Panel Accurately Detects Colorectal Cancer and Advanced Precancerous Lesions
Authors: Gagrat Zubin D. , Krockenberger Martin , Bhattacharya Abhik , Gagrat Bridget Z. , Leduc Christine M. , Matter Michael B. , Fourrier Keith D. , Mahoney Douglas W. , Edwards V David K. , Lidgard Graham P. , Limburg Paul J. , Johnson Scott C. , Domanico Michael J. , Kisiel John B.
Published: March 2024

Figure S2: Novel multi-target stool DNA Receiver Operator Characteristics curves for the marker selection study; CRC, colorectal cancer; APL, advanced precancerous lesion; AUC, area under the curve
Supplementary Figure S1 from Engaging Communities in Cancer Prevention and Control Activity Prioritization through a Statewide Needs Assessment: A Case Study from Nebraska
Authors: Watanabe-Galloway Shinobu , Napit Krishtee , McCullough Jordan , Luma Lady Beverly , Kabayundo Josiane , Carritt Nicole L. , Schabloske Laura , Robinson Tamara , Rohde Jolene , Champion Victoria , LoConte Noelle K. , Ratnapradipa Kendra L.
Published: March 2024

Supplementary Figure S1: Infographic on cancer burden tailored toward African Americans
Figure S9 from Neutralizing Antibodies Impair the Oncolytic Efficacy of Reovirus but Permit Effective Combination with T cell–Based Immunotherapies
Authors: Groeneveldt Christianne , Kinderman Priscilla , Griffioen Lisa , Rensing Olivia , Labrie Camilla , van den Wollenberg Diana J.M. , Hoeben Rob C. , Coffey Matt , Loghmani Houra , Verdegaal Els M.E. , Welters Marij J.P. , van der Burg Sjoerd H. , van Hall Thorbald , van Montfoort Nadine
Published: March 2024

Figure S9. Intratumoral T-cell influx after Reo treatment in μMT or C57BL/6J mice.