bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A014: A valid second line therapy for high grade serous ovarian cancer
Authors: Rizzolio Flavio , Mauceri Matteo , Perina Tiziana , Saorin Gloria , Caligiuri Isabella , Canzonieri Vincenzo , Cemazar Maja , Kamensek Urska , Kranic Simona Brezar
Published: March 2024

High-grade serous ovarian cancer (HGSOC) requires more effective second-line therapies as current options are limited. Maintenance therapy with PARP inhibitors has improved therapeutic efficacy, but there are no viable options after tumor recurrence. Since 2018, our research group has been investigating the significance of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) in OC (Russo Spena et al., 2018). In 2019, we developed a potent and reversible PIN1 inhibitor called VS10 (Russo Spena et al., 2019). To enhance drug delivery efficiency, we produced VS10 nanocrystals using Pluronic F127 and coated them with albumin, resulting in VS10AF nanocrystals. The new nanodrug was characterized using various techniques, including transmission electron microscopy (TEM), dynamic light scattering (DLS), zeta potential measurements, Fourier-transform infrared spectroscopy (FT-IR), and X-ray diffraction (XRD). Subsequent in vitro and in vivo experiments were conducted, including determining the IC50 values through dose-response curves and evaluating synergistic effects. In vivo efficacy and toxicity were assessed using nude mice injected subcutaneously with OVCAR5 cells. The water dispersion of VS10AF demonstrated four times higher solubility compared to VS10 alone, and TEM and XRD analyses confirmed the crystalline nature of the nanoparticles. VS10 release from the drug delivery system exhibited optimal kinetics observed within five days. Both VS10AF and VS10 showed comparable in vitro IC50 values, and synergistic effects were observed when combined with doxorubicin or liposomal doxorubicin. Moreover, in vivo studies demonstrated that the combination of VS10AF and liposomal doxorubicin effectively reduced tumor growth. After first-line chemotherapy, ovarian cancer patients have limited treatment options. PIN1 represents a promising therapeutic target in HGSOC due to its regulation of multiple oncogenes and tumor suppressors. Our findings suggest that VS10AF could serve as an effective PIN1 inhibitor and synergize with second-line chemotherapy drugs such as doxorubicin or liposomal doxorubicin. Furthermore, the excellent safety profile of VS10AF observed in vivo supports its potential for further clinical development.

Citation Format: Flavio Rizzolio, Matteo Mauceri, Tiziana Perina, Gloria Saorin, Isabella Caligiuri, Vincenzo Canzonieri, Maja Cemazar, Urska Kamensek, Simona Brezar Kranic. A valid second line therapy for high grade serous 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 A014.
Abstract A069: High-resolution volumetric imaging of primary and metastatic high-grade serous ovarian cancer explants
Authors: Connor Adele E. , Lysaght Joanne , Brennan Donal J. , Simpson Jeremy C. , Perry Antoinette S.
Published: March 2024

Introduction: As high-grade serous ovarian cancer (HGSOC) rarely shows symptoms, most patients present with metastases. Tumor heterogeneity between metastases may impede a patient’s response to therapy and thus impact survival. We aim to decipher the heterobiology of HGSOC lesions using high-resolution imaging of patient-derived explants (PDEs), to determine the differential treatment response between primary and metastatic tumors. Methods: PAX8, CK7, RAD51, γH2AX, Ki67, cPARP, and CD3 were chosen to enumerate tumor and T cells, and their activity. Antibodies were optimized in monolayer and spheroid cultures of HGSOC cell lines, COV318 and OVCAR4. CD3 was optimized in FFPE human tonsillitis tissue. Primary and metastatic HGSOC explants were cultured for 48h followed by 24h fixation. Several immunostaining and optical clearing protocols were tested on PDEs, which were imaged using a fully automated confocal high-content screening system. Results: Immunostaining and automated image analysis facilitated the identification of individual nuclei within PDEs without Refractive Index (RI) matching or optical clearing. However, high background impeded further image analysis, preventing the quantification of certain antibodies. Glycerol-based RI matching and ScaleS tissue clearing were implemented to try and overcome this. However, neither generated sufficiently high-quality images for analysis. A novel Clearing-enhanced 3D (Ce3D) immunostaining system recently developed for high-quality multiplex fluorescence microscopy of large tissue volumes was tested. While individual nuclei were recognized, as well as RAD51 foci and CK7 cytoskeleton staining, image analysis was still impeded due to high background. Conclusions: Protocols without RI matching and optical clearing can stain large, complex structures such as PDEs. However, high background impedes image analysis suggesting the need for optical clearing and RI matching. The inclusion of various RI matching and/or optical clearing steps failed to overcome high background staining. Further work is ongoing to refine immunostaining, RI matching, optical clearing, and mounting of PDEs to allow the quantification of all antibodies.

Citation Format: Adele E. Connor, Joanne Lysaght, Donal J. Brennan, Jeremy C. Simpson, Antoinette S. Perry. High-resolution volumetric imaging of primary and metastatic high-grade serous ovarian cancer explants [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 A069.
Abstract A079: G-CSF released from ovulation recruits and activates neutrophils in the peritoneum to aid transformation, seeding, and invasion of high-grade serous carcinoma
Authors: Huang Hsuan Shun , Chu Tang-Yuan
Published: March 2024

The incidence and mortality burden of ovarian high-grade serous carcinoma (HGSC) is increasing rapidly in Taiwan and many urbanized countries. The etiology of HGSC, especially that responsible for the rapid and advanced seeding of the tumor in the peritoneum, which causes late diagnosis and poor prognosis, is elusive. Epidemiological and molecular studies have demonstrated incessant ovulation is the main culprit of ovarian cancer. Our previous studies also elucidated some transforming factors in the ovulatory follicular fluid (FF). We unveiled the oncogenic activities of ovulation on the malignant transformation of fallopian tube fimbria epithelial cells (FTEC), the primary origin of HGSC. We hypothesized that ovulation could also promote the intraperitoneal spreading of tube originated HGSC. First, in both human and mouse specimens, we observed a dramatic influx of neutrophils in the peritoneal fluid during ovulation after LH surge. Ovulatory FF from IVF women, when injected to the mouse peritoneum cavity, readily induced neutrophil influx and activated neutrophil extracellular trap (NET) formation (NETosis). Among the different neutrophil activators in FF, we found G-CSF is responsible for the ROS and PAD4 increases and histone citrullination in NETosis. This FF-GCSF-induced NETosis increases anchoring independent growth (AIG), cell adhesions, and matrigel invasion of STIC-mimicking FTEC and HGSC cells. Interestingly, while the AIG-promoting activity of the ovulation-activated NET showed cell autonomous, the adhesion and invasion activities were non-autonomous conferred by the conditioned medium of the activated neutrophils. Shown by a FF plus tumor cell i.p. coinjection mouse xenograft model, intraperitoneal seeding was increased by the coinjection and was inhibited by the inhibitor (GSK) of NETosis. Taken together, we disclosed an unprecedented intraperitoneal neutrophil influx/activation activity of ovulation. This activity, presumably acting as an antimicrobial to prevent ascending infection during fertilization, is utilized to aid the peritoneal seedings of tubal-origin HGSC.

Citation Format: Hsuan Shun Huang, Tang-Yuan Chu. G-CSF released from ovulation recruits and activates neutrophils in the peritoneum to aid transformation, seeding, and invasion of high-grade serous 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 A079.
Abstract A082: Targeting sterol regulatory element binding protein 1 (SREBP1) improves response to standard-of-care chemotherapy and alters the tumor microenvironment in pre-clinical models of obesity and ovarian cancer
Authors: Stack M. Sharon , Liu Yueying , Yang Jing , Hilliard Tyvette S. , Wang Zhikun , Johnson Jeff , Wang Wanrui , Dominique Gena , Harper Elizabeth I. , Stavrou Nicholas M. , Juncker-Jensen Anna
Published: March 2024

Obesity is a recognized non-infectious pandemic that increases ovarian cancer (OvCa) incidence, enhances metastatic success and reduces survival. We have previously demonstrated a link between obesity and OvCa metastatic success in a diet-induced obesity (DIO) mouse model (Liu et al. Can.Res. 2015; 75:5046). DIO also elevated expression and nuclear localization of sterol regulatory element binding protein 1 (SREBP1), a master regulator of de novo lipogenesis and lipid homeostasis. A follow-up study using DIO models showed a significantly diminished response to standard-of-care (SOC) paclitaxel/carboplatin chemotherapy in high fat diet (HFD) mice relative to low fat diet (LFD) controls (Liu et al., J.Exp.Clin.Can.Res. 2023; 42:165). Both studies showed an effect of DIO on tumor fibrosis and immune landscape and these changes were also observed in the ovarian cancer tumors of women with high body mass index. In the current study, we have evaluated the effect of inhibitors of SREBP1 processing, in combination with SOC chemotherapy, in the context of DIO in pre-clinical models of OvCa. Our results show significantly diminished post-treatment tumor recurrence in HFD mice receiving SOC chemotherapy plus an SREBP1 processing inhibitor, with concomitant alterations in the peritoneal immune landscape. Together these data suggest that the reported negative impact of obesity on OvCa patient survival may be due obesity-induced changes in lipid regulatory factors (SREBP1) and the tumor microenvironment (immune landscape, fibrosis) that alter chemosensitivity. These data demonstrate a contribution of host obesity to ovarian tumor progression and therapeutic response and support future combination strategies targeting SREBP1, immune cells and/or fibrosis in the obese host.

Citation Format: M. Sharon Stack, Yueying Liu, Jing Yang, Tyvette S. Hilliard, Zhikun Wang, Jeff Johnson, Wanrui Wang, Gena Dominique, Elizabeth I. Harper, Nicholas M. Stavrou, Anna Juncker-Jensen. Targeting sterol regulatory element binding protein 1 (SREBP1) improves response to standard-of-care chemotherapy and alters the tumor microenvironment in pre-clinical models of obesity and 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 A082.
Abstract A093: Investigating alterations in metabolic profile of ovarian carcinoma associated mesenchymal stem cells
Authors: Baruwal Roja , Frisbie Leonard G. , Coffman Lan
Published: March 2024

Ovarian cancer causes more deaths than any other gynecologic cancer. Although aerobic glycolysis has been a hallmark of cancer metabolism, it has been found that ovarian cancer (OvCa) cells are metabolically plastic, also utilizing oxidative phosphorylation (OXPHOS) as an active metabolic pathway for their rapid proliferation and metastasis. A growing body of evidence also shows that cancer cells not only reprogram their own metabolism but also metabolically remodel the tumor microenvironment to meet their ever-increasing energy demand. Our lab has previously demonstrated that OvCa cells epigenetically reprogram their resident tissue mesenchymal stromal/stem cells (MSCs) to develop a cancer-supportive phenotype. These cancer-associated mesenchymal stem cells (CA-MSCs) support OvCa progression through several mechanisms, including enhanced metastasis. Recent work by our lab showed these CA-MSCs enhance metastasis by donating their mitochondria to metabolically vulnerable OvCa cells and increasing OvCa cell OXPHOS. While we have demonstrated the impact of CA-MSC mitochondrial transfer to OvCa cells, what changes are happening in the CA-MSC that allow them to transfer mitochondria to OvCa cells is still unknown. Gene set enrichment analysis performed on RNA sequencing data comparing patient derived CA-MSCs to normal MSCs revealed that OXPHOS is one of the top enriched pathways in CA-MSCs. Furthermore, the cell mito stress test comparing mitochondrial respiratory profile of patient derived normal MSCs and CA-MSCs demonstrated that CA-MSCs have significantly increased mitochondrial respiratory capacity compared to normal MSCs. Uncovering the metabolic profile of ovarian CA-MSCs for the first time, our data demonstrates that ovarian cancer alter the metabolism of the CA-MSC towards OXPHOS. Our current studies are focused on understanding the role of enhanced CA-MSC OXPHOS in mitochondrial transfer to OvCa cells and OvCa metastasis.

Citation Format: Roja Baruwal, Leonard G. Frisbie, Lan Coffman. Investigating alterations in metabolic profile of ovarian carcinoma associated mesenchymal 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 A093.
Abstract A102: ROR2/Wnt5a signaling regulates directional cell migration and early tumor cell invasion in ovarian cancer
Authors: Grither Whitney R. , Baker Breanna , Morikis Vasilios A. , Fuh Katherine C. , Longmore Gregoery D
Published: March 2024

Adhesion to and clearance of the mesothelial monolayer are key events in the early metastatic seeding of ovarian cancer. To identify mediators of ovarian cancer cell adhesion and invasion, we developed and conducted a cellular, high-throughput genetic screen using a human kinome siRNA library. Through this screen, we identified ROR2 as a driver of ovarian cancer adhesion and invasion. ROR2 is a receptor tyrosine kinase that interacts with Wnt5a ligand to activate non-canonical Wnt signaling and has been previously shown to be upregulated in ovarian cancer tissue. However, no prior study has evaluated the mechanistic role of ROR2 in ovarian cancer. Using in vitro adhesion and mesothelial clearance assays, we show that ROR2 promotes ovarian cancer cell adhesion and clearance of the mesothelial monolayer, key early steps in ovarian cancer metastasis. Further, we show that depletion of ROR2 reduces metastatic tumor burden in a syngeneic mouse model of ovarian cancer. Additionally, using a microfluidic device capable of producing stable fluid gradients, we demonstrate that ROR2 expression in ovarian cancer cells serves to drive directed cell migration of tumor cells, preferentially to areas of high Wnt5a ligand. As Wnt5a has been previously shown to be produced and upregulated in the mesothelial cells of the ovarian cancer microenvironment, these findings represent a novel role for ROR2 to promote the homing of ovarian tumor cells to the mesothelial lined metastatic niche by using Wnt5a as a chemotactic cue. These findings support the role of ROR2 as a critical factor contributing to the steps of ovarian cancer metastasis. Therapeutic targeting of the ROR2/Wnt5a signaling axis could provide a means of improving treatment for patients with advanced ovarian cancer.

Citation Format: Whitney R. Grither, Breanna Baker, Vasilios A. Morikis, Katherine C. Fuh, Gregoery D Longmore. ROR2/Wnt5a signaling regulates directional cell migration and early tumor cell invasion 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 A102.
Abstract B028: Unraveling the role of matrix metalloproteinase 3 (mmp3) in cisplatin resistance of ovarian cancer
Authors: Rivera-Serrano Mariela , Vivas-Mejía Pablo E.
Published: March 2024

Seventy percent of women with ovarian cancer will develop chemotherapy-resistance to cisplatin. Regardless of the advancements in technology, mortality rates for ovarian cancer have declined only slightly in the last forty years. Therefore, novel and effective second-line therapies for women with ovarian cancer are urgently needed. Previously we showed that Matrix Metalloproteinase 3 (MMP3) expression is upregulated in cisplatin resistant when compared with cisplatin sensitive cells. However, the contribution of MMP3 to cisplatin resistance have not been studied previously. Western blots, ELISAs, and real-time RT-PCR confirmed that the protein and mRNA levels are higher in cisplatin resistant as compared with cisplatin sensitive cells. MMP3 expression levels were also increased by cisplatin treatment of cisplatin resistant cells. Additionally, interrogation of the Kaplan-Meier plotter database showed that ovarian cancer patients with low MMP3 levels live longer than patients with higher MMP3 levels. To understand the impact of targeting MMP3, we employed commercially available chemical inhibitors and small-interference RNA (siRNA) in cell viability, colony formation, invasion, and RNAseq experiments. Notably, MMP3-targeted siRNA significantly reduced cell viability, proliferation, and invasion, particularly when combined with cisplatin treatment. However, the MMP3 chemical inhibitor did not exhibit significant biological effects. RNAseq analysis revealed 415 differentially expressed genes (DEGs) between MMP3-siRNA and negative control (NC)-siRNA groups, as well as 440 DEGs between MMP3-siRNA + cisplatin and NC-siRNA + cisplatin groups. Functional enrichment analysis using Metascape via Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) identified genes associated with potassium and aquaporin mediated transport, clathryn-mediated endocytosis, cell cycle, metabolic processes, cellular response to stress, and extracellular matrix organization. These findings highlight the role of MMP3 upregulation in promoting cisplatin resistance.

Citation Format: Mariela Rivera-Serrano, Pablo E. Vivas-Mejía. Unraveling the role of matrix metalloproteinase 3 (mmp3) in cisplatin resistance 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 B028.
Abstract B031: The PLK1 inhibitor Volasertib as a treatment for HSF1 and MYC coamplified ovarian cancer
Authors: O'Malley Matthew , Williams Imade W. , Walker Bobby , Ray Haimanti , Nephew Kenneth P. , Carpenter Richard
Published: March 2024

Ovarian cancer is a disease that afflicts 1 in 78 women. This disease only has a 5-year relative survival rate of 49% due to the fact that the first line chemotherapy for this disease, platinum-based chemotherapy with taxanes, has an 80% recurrence rate. To improve the treatment for this disease, it would be wise to find biomarkers of sensitivity to other drugs. Using publicly available data from The Cancer Genome Project, our lab has shown that 36% of High Grade Serous Ovarian Cancers (HGSOC) have gene amplifications for both Cellular Myelocytomatosis (MYC) and Heat Shock Factor 1 (HSF1) genes. These genes encode for transcription factors and are known to contribute to malignant disease in multiple cancer types, including ovarian cancer. Evidence indicates that MYC and HSF1 are both essential to HGSOC cells with co-amplification of these genes, that MYC and HSF1 transcriptional activities are highly correlated in patient tumors, and the two transcription factors have a protein-protein interaction, all suggesting these two transcription factors cooperate to drive this subset of HGSOC tumors. Many drugs have been developed to inhibit MYC or HSF1 though they have not shown success in clinical development. We aimed to decrease the activity of these proteins by targeting polo-like kinase 1 (PLK1), a kinase that phosphorylates and regulates both MYC and HSF1 proteins. Active PLK1 levels were highly correlated with MYC and HSF1 protein levels and inhibition of PLK1 with volasertib reduced MYC and HSF1 protein levels and transcriptional activity. Furthermore, volasertib was found to have 155-fold greater potency in HGSOC cells with MYC-HSF1 co-amplification compared to cells without these genes amplified. The increased potency of volasertib in MYC-HSF1 co-amplified cells were also observed in clonogenic growth and spheroid models. Together, these data indicate that MYC and HSF1 cooperate in HGSOC when these genes are amplified and targeting a common kinase between them in PLK1 disrupts this cooperation. Furthermore, MYC and HSF1 co-amplification may serve as a biomarker for volasertib through a personalized medicine approach to treat HGSOC patients.

Citation Format: Matthew O'Malley, Imade W. Williams, Bobby Walker, Haimanti Ray, Kenneth P. Nephew, Richard Carpenter. The PLK1 inhibitor Volasertib as a treatment for HSF1 and MYC coamplified 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 B031.
Abstract B042: Feasibility of an electronic medical records based ovarian cancer symptom screening patient questionnaire
Authors: Behbakht Kian , Nguyen Cam , Rotholz Stephen , Guntupalli Saketh , Goff Barbara , Bitler Benjamin
Published: March 2024

Objectives: Symptoms occur in 75% of women with early-stage ovarian cancer and are also common in the absence of cancer. We report the feasibility and results of a prospective four-question symptom screen applied to a gynecology preventive care visit. Methods: Starting February 2021, a patient-facing questionnaire was added to the electronic medical records for women requesting routine gynecology visit. The question asks patients if they have had any of the following symptoms for more than two weeks duration in the prior year: bloating, difficulty eating or feeling full soon after eating, pelvic or abdominal pain, or trouble with urination. In September 2021, the response “No symptoms” was added. Questionnaire responses, medical history and work up performed +/- 3 months of the preventive gynecologic visit were extracted from electronic medical records, compiled in REDCap, and analyzed using R. Results: Between February 2021 and November 2022, a total of 498 patients completed the questionnaire (72.7% White, 10.2% Black, 7.0% Asian/Pacific Islander, 9.8% Other, and 0.2% not stated). The median age was 50 years (range: 40-86). Nearly half (47.2%) reported at least one symptom. The most common isolated single symptom was urinary urgency or frequency (22.9%); 12.3% of these patients had a urinary tract infection. The least common single symptom was early satiety (8.8%). 12 patients (2.4%) reported all four symptoms, and most had explanatory existing diagnoses such as endometriosis, adenomyosis or chronic pelvic pain. No cancers have been diagnosed to date. Conclusions: Ovarian cancer symptom-based screening using electronic medical records is feasible, but alone may not be clinically beneficial. Patients reporting three or more symptoms were 6.6% of the respondents and may represent an ideal group for focused ovarian cancer screening efforts and selective enrolment to novel imaging/tumor marker and proximate fluid analyses.

Citation Format: Kian Behbakht, Cam Nguyen, Stephen Rotholz, Saketh Guntupalli, Barbara Goff, Benjamin Bitler. Feasibility of an electronic medical records based ovarian cancer symptom screening patient questionnaire [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 B042.
Abstract B043: Feasibility of a traceback approach to facilitate genetic testing in the Genetic Risk Analysis in Ovarian Cancer (GRACE) study
Authors: White Larissa L. , Prado Yolanda K. , Reyes Ana A. , Zepp Jamilyn M. , Sawyer Jennifer , Maiyani Mahesh , Zucker Rachel , Vertrees Sarah , Rope Alan F. , Weinmann Sheila , Caruncho Mika , Lee Sandra Soo-Jin , Henrikson Nora B. , Feigelson Heather Spencer , Hunter Jessica Ezzell
Published: March 2024

Current guidelines state that genetic testing is clinically indicated for all individuals diagnosed with ovarian cancer (OC). Individuals with a prior diagnosis of OC who have not received genetic testing represent missed opportunities to identify individuals and their families with inherited variants that put them at a higher risk for cancer. The Genetic Risk Analysis in Ovarian Cancer (GRACE) study aims to address this significant healthcare gap using a “traceback testing” approach to identify individuals with a prior diagnosis of OC and to offer genetic risk information to them and their family members. Tumor registry data at two integrated health care systems (Kaiser Permanente Northwest and Colorado) identified cases of OC diagnosed 1998-2020 with no prior genetic testing or testing limited to BRCA1/2. The study aimed to provide genetic risk information to OC survivors as well as family members of patients who were deceased by leveraging stored pathology specimens for germline testing. Comprehensive genetic testing using a panel of 60 cancer risk genes was offered; genetic testing of the familial variant was offered to first- and second-degree relatives if a pathogenic or likely pathogenic variant was detected. A total of 317 eligible OC survivors were identified from tumor registry and medical record review; 79 (25%) consented for testing. Sixteen (21%) were found to carry a pathogenic or likely pathogenic variant in a cancer risk gene. Genes with pathogenic variants included BRCA1/2, BARD1, PMS2, DICER1, MUTYH, APC, and SDHB. Of 73 relatives eligible for cascade testing, 24 consented (≈ 33% uptake) and 9 were found to carry the familial variant. The uptake of testing by OC survivors and their relatives reflects a strong interest in genetic risk information. However, practical barriers must be addressed to provide genetic risk information to relatives of individuals who are deceased. The GRACE study can inform broad implementation of future traceback programs, providing information to prevent and mitigate the burden of ovarian and other hereditary cancers.

Citation Format: Larissa L. White, Yolanda K. Prado, Ana A. Reyes, Jamilyn M. Zepp, Jennifer Sawyer, Mahesh Maiyani, Rachel Zucker, Sarah Vertrees, Alan F. Rope, Sheila Weinmann, Mika Caruncho, Sandra Soo-Jin Lee, Nora B. Henrikson, Heather Spencer Feigelson, Jessica Ezzell Hunter. Feasibility of a traceback approach to facilitate genetic testing in the Genetic Risk Analysis in Ovarian Cancer (GRACE) study [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 B043.
Abstract B056: The unconfounded effect of bevacizumab on advanced ovarian clear cell carcinoma: a systematic review, traditional meta-analysis, and network meta-analysis
Authors: Huang Fisher Kuan-Ju
Published: March 2024

Background Ovarian clear cell carcinoma (OCCC) accounts for 5-20% of all epithelail ovarian cancers, and is associated high recurrence rate and chemoresistance. There are some new therapies available in recent years, including bevacizumab, an anti-VEGF monoclonal antibody, and the poly ADP-ribose polymerase (PARP) inhibitors. Previous research and current support the use of both medication in OCCC. However, most of the studies reported results for all subtypes collectively in which OCCC only accounted for a small proportion of the study cohort. Besides, dislike the high-grade serous subtype, only around 10% of OCCC respond to poly ADP-ribose polymerase (PARP) inhibitor. In the subgroup analysis from ICON7, Bevacizumab had limited role in OCCC patients, in which OCCC of any stage were included. On the other hand, another 2 multi-center studies evaluated Bevacizumab as the front-line or salvage therapy revealed positive results. However, the results could be biased due to unadjusted confounders. Objective: To find the real effect of Bevacizumab on advanced stage OCCC. Materials and Methods: A systematic review via searching the Pubmed with "ovarian clear cell carcinoma" and "bevacizumab" was performed. Any comparative study met the inclusion criteria. The data were extracted, evaluated and classified by their combination of potential confounders. Primary data from National Taiwan University Hospital (NTUH) Database were collected and incorporated into the traditional meta-analysis, and the network meta-analysis. The potential confounders for analysis include "residual tumor", "FIGO stage", and "functional status". Results: There were 3 retrospective studies, including one single-center study from Japan (N=28), one multi-center study from Japan (N=145), and one multi-center study from Korea (N=138). There were 64 patients identified from NTUH database between 2011 and 2020. By traditional meta-analysis, it revealed Bevacizumab is associated with improved progression-free survival (HR 0.62, 95% C.I. 0.44 - 0.87, common effect model, I2= 50%). After adjusted for confonders and analyzed by network meta-analysis, however, only "no residual tumor" is associated with improved progression-free survival (HR 0.37, 95% C.I. 0.14 - 0.97). The role of Bevacizumab on OCCC is limited (HR 1.20, 95% C.I. 0.51 - 2.83). Conclusion: By adjusting for possible confounders in published studies, it reveals that Bevacizumab may not improve progression-free survival in advanced-stage OCCC from a network meta-analysis.

Citation Format: Fisher Kuan-Ju Huang. The unconfounded effect of bevacizumab on advanced ovarian clear cell carcinoma: a systematic review, traditional meta-analysis, and network meta-analysis [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 B056.
Abstract B089: Intratumoral expression analysis of mast cells in high grade serous ovarian cancer
Authors: McAdams Julia , Ebott Jasmine , De La Cruz Payton , James Nicole E.
Published: March 2024

Objective: The goal of this study is to examine intratumoral expression and phenotypic changes in mast cells following neoadjuvant chemotherapy (NACT) exposure in high grade serous ovarian cancer (HGSOC). Methods: 37 HGSOC matched pre-and post-NACT patient tumors were stained with a commercially available mast cell hemotoxic-based kit and both intratumoral and stromal mast cells were quantified. Immunohistochemistry was employed to stain for histamine in 19 matched HGSOC patient tumors and mean intensity and integrated optical density was quantified using Image J. Kaplan Meier curve analysis was employed to determine the relationship between mast cells levels and progression-free survival (PFS). Immortalized human mast cells, LUVA were treated with carboplatin and paclitaxel and specific genomic changes were measured by quantitative PCR (qPCR). Results. Mast cells were more prominently expressed in intraepithelial regions compared to stromal cells, however both populations were significantly (p<0.05) increased following NACT. Total mast cells stratified by upper and lower quartile demonstrated that higher levels were significantly (p<0.05) associated with improved PFS. Furthermore, histamine, a marker of mast cell degranulation was significantly (p<0.05) increased in HGSOC tumors post-NACT and significantly correlated (r=0.553, p=0.013) with the change in total mast cells. Following chemotherapy treatment LUVA cells demonstrated an over 7-fold increase in amphiregulin (AREG) expression (p<0.01), a key marker of mast cell activation. Interestingly, angiogenic and pro-tumorigenic factors IL-10, IL-8, and VEGFA exhibited no significant differences in expression following chemotherapy exposure. Conclusions: Overall, our findings suggest a correlation in NACT exposure and intratumoral mast cell recruitment, degranulation, and activation. Further studies include investigating differences in specific tumorigenic genes and cell signaling pathways in mast cells pre- and post- NACT, as well as determining if mast cells can impact HGSOC chemotherapy response.

Citation Format: Julia McAdams, Jasmine Ebott, Payton De La Cruz, Nicole E. James. Intratumoral expression analysis of mast cells in high grade serous 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 B089.
Abstract B097: Image analysis-guided spatial transcriptomics improves recognition of biological features important for outcome in high grade serous carcinoma
Authors: Laury Anna R. , Zheng Shuyu , Aho Niina , Fallegger Robin , Hänninen Satu M. , Rodriguez Julio Saez , Tanevski Jovan , Youssef Omar , Tang Jing , Carpén Olli
Published: March 2024

High-grade serous ovarian carcinoma (HGSC) is characterized by late presentation, frequent recurrence, and treatment resistance. Our understanding of this disease is limited, partly due to considerable tumor heterogeneity, which is reflected in the variable tumor morphology. Beyond the diagnosis itself, no particular histologic features have proven sensitive or specific enough for use in clinical practice. Image analysis based deep learning models are now able to extract new information from standard H&E pathology slides, though biological interpretation of the regions detected by artificial intelligence (AI) remains a challenge. In this work, we interrogate the molecular features of tissue regions identified as being highly associated with patient outcome by a deep-learning based AI classification model. We determined the spatial transcriptomic profiles of these regions in 16 patients and compared them to the profiles of background tumor regions not selected by the AI model. We used multiple methods to characterize the regions types, including: differential gene expression, UMAP distances, machine learning-based outcome prediction, pathway enrichment, and spatial organization analyses. We find that regions identified by the AI-based model are significantly different from background tumor regions, and that their transcriptomic profiles are more predictive of patient outcome. We determine the differential signaling pathways and validate a representative transcript using RNA in-situ hybridization. We show that AI-detected regions in poor prognosis tumors have upregulated JUN expression, and are characterized by tumor cell subpopulations with a stress-associated transcriptomic signature. In contrast, spatial pattern analyses show that AI-detected regions in tumors with better outcome are typified by macrophage and plasma cell depleted DNA repair-signature tumor cell subpopulations. The synergy of spatial transcriptomic and image analysis data in our study offers a promising strategy to enhance clinical translation by establishing a more interpretable AI model.

Citation Format: Anna R. Laury, Shuyu Zheng, Niina Aho, Robin Fallegger, Satu M. Hänninen, Julio Saez Rodriguez, Jovan Tanevski, Omar Youssef, Jing Tang, Olli Carpén. Image analysis-guided spatial transcriptomics improves recognition of biological features important for outcome in high grade serous 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 B097.
Abstract B107: Elucidating the influence of long-chain fatty acids on ovarian cancer progression
Authors: Ogura Jumpei , Yamanoi Koji , Taki Mana , Murakami Ryusuke , Yamaguchi Ken , Hamanishi Junzo , Mandai Masaki
Published: March 2024

Objective: High-fat diets have been associated with cancer progression. Yet, studies indicate that the effects can differ based on the type of fat involved, such as saturated versus unsaturated fatty acids. Uncovering the role of fatty acids may help guide nutrition and provide dietary therapy for cancer patients. In this study, we investigated the effect of common long-chain fatty acids, stearic acid (SA) and oleic acid (OA), on ovarian cancer (OC). Methods: We evaluated the cytotoxicity of SA and the effects of OA using IC50, a 72-hour proliferation assay, flow cytometry, and western blot. The concentration of fatty acids within the tumor was measured using liquid chromatography-mass spectrometry (LC/MS). CAY10566 was used to inhibit SCD1, the enzyme that converts SA to OA. In vivo, tumor growth was analyzed in human OC cell lines and patient-derived xenografts (PDX) using a mouse model fed with a normal diet (ND), an SA-rich diet, or an OA-rich diet combined with CAY10566. The SA-rich diet, which we specially created, had a stearic acid concentration of 33%. Results: SA displayed prominent cytotoxicity compared to other fatty acids. SA dose-dependently increased unfolded protein response (UPR) marker expression. Adding 1μM CAY10566 increased intracellular SA, decreased OA, and reduced IC50 to 20μM (p<0.05). CAY10566 significantly enhanced the cytotoxicity of SA, but the addition of exogenous OA canceled the increase in cell toxicity and UPR marker expression induced by SA (p<0.05). In vivo, tumor growth of OC cell lines and PDXs was significantly suppressed in the SA-rich with CAY10566 group compared to the ND group (p<0.05), while this suppression was nullified in the OA-rich with CAY10566 group. As confirmed by LC/MS, the stearic acid concentration significantly increased in the SA-rich group. Immunohistochemistry demonstrated that CHOP, gH2AX, and caspase-3 expression significantly increased in the SA-rich with CAY10566 group and dramatically decreased in the OA-rich with CAY10566 group (p<0.01). Conclusion: An ectopic supply of SA inhibits OC growth via UPR, while OA counteracts this effect. Creating a Stearate-rich/Oleate-limited environment through diet might affect tumor growth in vivo. Dietary content may greatly contribute to altering function in cancer.

Citation Format: Jumpei Ogura, Koji Yamanoi, Mana Taki, Ryusuke Murakami, Ken Yamaguchi, Junzo Hamanishi, Masaki Mandai. Elucidating the influence of long-chain fatty acids on ovarian cancer progression [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 B107.
Abstract IA010: Latest developments in targeting the DNA damage response in the clinic
Authors: Yap Timothy A.
Published: March 2024

Genomic instability is a key hallmark of cancer that arises owing to defects in the DNA damage response (DDR) and/or increased replication stress. These alterations promote the clonal evolution of cancer cells via the accumulation of driver aberrations, including gene copy-number changes, rearrangements, and mutations; however, these same defects also create vulnerabilities that are relatively specific to cancer cells, which could potentially be exploited to increase the therapeutic index of anticancer treatments and thereby improve patient outcomes. The discovery that BRCA-mutant cancer cells are exquisitely sensitive to inhibition of poly(ADP-ribose) polymerase has ushered in a new era of research on biomarker-driven synthetic lethal treatment strategies for different cancers. The therapeutic landscape of antitumor agents targeting the DDR has rapidly expanded to include inhibitors of other key mediators of DNA repair and replication, such as ATM, ATR, CHK1 and CHK2, DNA-PK, POLQ, USP1 and WEE1. Efforts to optimize these therapies are ongoing across a range of cancers, involving the development of predictive biomarker assays of responsiveness (beyond BRCA mutations), assessment of the mechanisms underlying intrinsic and acquired resistance, and evaluation of rational, tolerable combinations with standard-of-care treatments (such as chemotherapeutics and radiation), novel molecularly targeted agents and immune-checkpoint inhibitors.

Citation Format: Timothy A. Yap. Latest developments in targeting the DNA damage response in the clinic [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 IA010.
Abstract IA015: Is salpingectomy as effective as bilateral salpingo-oophorectomy in preventing ovarian, fallopian tube, and peritoneal cancer? Let’s prove it!
Authors: Pennington Kathryn P.
Published: March 2024

Since ovarian cancer screening does not reduce ovarian cancer mortality, the main focus to reduce ovarian cancer mortality is prevention. For individuals at increased risk of ovarian carcinoma, risk-reducing bilateral salpingo-oophorectomy (RRSO) is highly effective, but uptake at the recommended age is suboptimal, likely due to concerns about premature menopause. Mounting evidence suggests that many “ovarian” cancers originate in the fallopian tube, making bilateral salpingectomy with delayed oophorectomy an attractive, but as of yet, unproven option for risk-reduction in those who decline RRSO. This talk will review the scientific evidence supporting a tubal origin of ovarian cancer, preliminary data supporting the safety and possible efficacy of salpingectomy and will discuss two prospective clinical trials powered to test the hypothesis that bilateral salpingectomy with delayed oophorectomy is non-inferior to RRSO to reduce the incidence of ovarian, fallopian tube, and peritoneal cancer among mutation carriers at high risk of ovarian cancer.

Citation Format: Kathryn P. Pennington. Is salpingectomy as effective as bilateral salpingo-oophorectomy in preventing ovarian, fallopian tube, and peritoneal cancer? Let’s prove it! [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 IA015.
Abstract PR-008: Follicular fluid aids in cell adhesion, spreading and shows an age-dependent effect on DNA damage in fallopian tube epithelial cells
Authors: Salvi Amrita , Li Wenping , Cologna Stephanie M. , Pavone Mary Ellen , Duncan Francesca E. , Burdette Joanna E.
Published: March 2024

Ovarian cancer is the 5th leading cause of cancer related death in women with a low 5-year survival rate. Ovarian cancer is rarely detected early, and likely arises from the fimbriated end of the fallopian tube epithelium (FTE). There is a correlation between ovarian cancer and ovulation whereby ovulation suppression through use of oral contraception or pregnancy reduces the risk of ovarian cancer. Despite the association of ovarian cancer with ovulation, due to the lack of early detection methods, the disease typically presents as late stage, metastatic cancer in post-menopausal women who are no longer ovulating. The goal of this study was to understand how ovulation and the process of aging interact to provide a permissive environment for ovarian cancer initiation and progression in the FTE. The process of ovulation releases follicular fluid and induces the DNA damage response pathway in the FTE, but the role of aging on FTE exposure to follicular fluid has not been tested. De-identified follicular fluid samples were collected from 14 women (7 reproductively young (29-35 years) and 7 reproductively aged (40-44 years)) undergoing ART (Assisted Reproductive Technology) through the Northwestern University Reproductive Tissue Library (NU-RTL). We found that follicular fluid caused DNA damage and lipid oxidation in an age-dependent manner and cell proliferation in a dose-dependent manner in FTE cells. Interestingly, follicular fluid disrupted FTE spheroid formation and instead stimulated attachment and growth on ultra-low attachment plates. Follicular fluid when coated on the surface of the ultra-low plates enhanced FTE cell adhesion, spreading and proliferation. Proteomics analysis of the follicular fluid identified vitronectin, a glycoprotein as the factor responsible for FTE cell attachment and spreading. Overall, this study demonstrated that aging contributed to lipid oxidation and DNA damage of FTE cells and identified vitronectin in the follicular fluid as a protein factor that facilitates FTE cells to detach from 3D spheroids and spread on low attachment surfaces.

Citation Format: Amrita Salvi, Wenping Li, Stephanie M. Cologna, Mary Ellen Pavone, Francesca E. Duncan, Joanna E. Burdette. Follicular fluid aids in cell adhesion, spreading and shows an age-dependent effect on DNA damage in fallopian tube epithelial 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 PR-008.
Table S1 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 S1: Sample categorization and frequency for the marker selection study for novel multi-target stool DNA panel.
Figure S1 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 S1: Sample processing flowchart for marker selection and verification studies; ELISA, enzyme-linked immunosorbent assay; LQAS, long-probe quantitative amplified signal; MDM, methylated DNA marker; QuARTS, Quantitative Allele-specific Real-time Target and Signal
Figure S3 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 S3. Kinetics of neutralizing antibodies after preexposure.
Figure S15 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 S15. Reo preexposure induces Reo-specific NAbs and CD8+ T cells.
Supplementary Table 3 from An NFAT1-C3a-C3aR Positive Feedback Loop in Tumor-Associated Macrophages Promotes a Glioma Stem Cell Malignant Phenotype
Authors: Zhang Yaochuan , Song Yifu , Wang Xiaoliang , Shi Mengwu , Lin Yibin , Tao Dongxia , Han Sheng
Published: March 2024

Clinical information of the primary glioma stem-like cells
Supplementary Figure 6 from An NFAT1-C3a-C3aR Positive Feedback Loop in Tumor-Associated Macrophages Promotes a Glioma Stem Cell Malignant Phenotype
Authors: Zhang Yaochuan , Song Yifu , Wang Xiaoliang , Shi Mengwu , Lin Yibin , Tao Dongxia , Han Sheng
Published: March 2024

The association of C5/C5aR and NFAT1 in glioma.
Supplementary Figure 4 from An NFAT1-C3a-C3aR Positive Feedback Loop in Tumor-Associated Macrophages Promotes a Glioma Stem Cell Malignant Phenotype
Authors: Zhang Yaochuan , Song Yifu , Wang Xiaoliang , Shi Mengwu , Lin Yibin , Tao Dongxia , Han Sheng
Published: March 2024

NFAT1 regulated the expression of C3aR in tumor-associated macrophages.