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Objective: Advanced-stage high-grade serous ovarian cancer (HGSOC) remains a deadly gynecologic malignancy with high rates of disease recurrence and limited, effective therapeutic options for patients. There is a significant need to better stratify HGSOC patients into platinum refractory (PRF) vs. sensitive (PS) cohorts at baseline to improve therapeutic responses and survival outcomes for PRF HGSOC., Methods: We performed NanoString for GeoMx Digital Spatial Profile (G-DSP) multiplex protein analysis on PRF and PS tissue microarrays (TMAs) to study the bidirectional communication of cancer cells with immune cells in the tumor microenvironment (TME) of HGSOC. We demonstrate robust stratification of PRF and PS tumors at baseline using multiplex spatial proteomic biomarkers with implications for tailoring subsequent therapy., Results: PS patients had elevated apoptotic and anti-tumor immune profiles, while PRF patients had dual AKT1 and WNT signaling with immunosuppressive profiles. We found that dual activity of AKT1 and WNT signaling supported the exclusion of immune cells, specifically tumor infiltrating lymphocytes (TILs), from the TME in PRF tumors, and this was not observed in PS tumors. The exclusion of immune cells from the TME of PRF tumors corresponded to abnormal endothelial cell structure in tumors with dual AKT1 and WNT signaling activity., Conclusions: We believe our findings provide improved understanding of tumor-immune crosstalk in HGSOC TME highlighting the importance of the relationship between AKT and WNT pathways, immune cell function, and platinum response in HGSOC., Competing Interests: Declaration of competing interest Dr. Rebecca Arend has been on Advisory Boards for Leap Therapeutics, AstraZeneca, GSK, Merck, VBL Therapeutics, and Caris Life Sciences. The other authors declare no potential conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Among uterine malignancies, endometrial cancer (EC) is the most common cancer of the female reproductive tract. Traditionally, risk stratification in EC is determined by standard clinicopathological risk factors. Although circulating tumor DNA (ctDNA) has emerged as a prognostic biomarker in various malignancies, its clinical validity in EC remains to be established., Methods: In this analysis of real-world data, 267 plasma samples from 101 patients with stage I EC were analyzed using a tumor-informed ctDNA assay (Signatera™ bespoke mPCR-NGS). Patients were followed post-surgically and monitored with ctDNA testing for a median of 6.8 months (range: 0.37-19.1)., Results: Patients who tested ctDNA-positive at both their first time point and longitudinally experienced inferior recurrence-free survival (RFS) (HR = 6.2; p = 0.0006 and HR = 15.5; p < 0.0001, respectively), and showed a recurrence rate of 58% and 52%, vs. 6% and 0%, respectively for the ctDNA-negative patients. Most ctDNA-positive patients had high-risk histologies or sarcoma, versus low-risk and high-intermediate risk (H-IR) EC. Furthermore, patients with high-risk histologies who were ctDNA-positive showed shorter RFS compared to those who tested negative (HR = 9.5; p = 0.007), and those who tested positive in the low/H-IR cohort (HR = 0.25; p = 0.04). Post-surgically, detectable ctDNA was highly prognostic of clinical outcome and remained the only significant risk factor for recurrence when adjusted for clinicopathological risk factors, such as histologic risk group, mismatch repair (MMR), and p53 status., Conclusion: Incorporating ctDNA monitoring along with traditional known risk factors may aid in identifying patients with stage I EC who are at highest risk of recurrence, and possibly aid in treatment stratification., Competing Interests: Declaration of Competing Interest COIs for A.P: Stock ownership: Natera. COIs for R.H: Speaker's Bureau: Natera, Inc., Bard Davol, AstraZeneca, GSK, Merck, Eisai; Consultant: Genelux. C.B·S, E.K., S.RH., T.F., P.D., M.M., A.E., and M.C.L. are employees of Natera, Inc. and have stock/option to hold stock in the company. T.B. and B.N. are former employees of Natera, Inc. Additional COIs for M.C.L: Grants/Contracts: Funding to Institution (Mayo) from: Eisai, Exact Sciences, Genentech, Genomic Health, GRAIL, Menarini Silicon Biosystems, Merck, Novartis, Seattle Genetics, Tesaro; Travel Support Reimbursement from AstraZeneca, Genomic Health, Ionis; Ad hoc advisory board meetings. All funds to Mayo Clinic. No personal compensation from: AstraZeneca, Celgene, Roche/Genentech, Genomic Health, GRAIL, Ionis, Merck, Pfizer, Seattle Genetics, Syndax. All other authors have no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Several studies have demonstrated the prognostic value of circulating tumor DNA (ctDNA); however, the correlation of mean tumor molecules (MTM)/ml of plasma and mean variant allele frequency (mVAF; %) with clinical parameters is yet to be understood. In this study, we analyzed ctDNA data in a pan-cancer cohort of 23 543 patients who had ctDNA testing performed using a personalized, tumor-informed assay (Signatera™, mPCR-NGS assay). For ctDNA-positive patients, the correlation between MTM/ml and mVAF was examined. Two subanalyses were performed: (a) to establish the association of ctDNA with tumor volume and (b) to assess the correlation between ctDNA dynamics and patient outcomes. On a global cohort, a positive correlation between MTM/ml and mVAF was observed. Among 18 426 patients with longitudinal ctDNA measurements, 13.3% had discordant trajectories between MTM/ml and mVAF at subsequent time points. In metastatic patients receiving immunotherapy (N = 51), changes in ctDNA levels expressed both in MTM/ml and mVAF showed a statistically significant association with progression-free survival; however, the correlation with MTM/ml was numerically stronger., (© 2023 Natera, Inc. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: Sensitive and reliable biomarkers for early detection of recurrence are needed to improve post-definitive radiation risk stratification, disease management, and outcomes for patients with unresectable early-stage or locally advanced non-small cell lung cancer (NSCLC) who are treated with definitive radiation therapy (RT). This prospective, multistate single-center, cohort study investigated the association of circulating tumor DNA (ctDNA) status with recurrence in patients with unresectable stage I-III NSCLC who underwent definitive RT., Methods: A total of 70 serial plasma samples from 17 NSCLC patients were collected before, during, and after treatment. A personalized, tumor-informed ctDNA assay was used to track a set of up to 16 somatic, single nucleotide variants in the associated patient's plasma samples., Results: Pre-treatment ctDNA detection rate was 82% (14/17) and varied based on histology and stage. ctDNA was detected in 35% (6/17) of patients at the first post-RT timepoint (median of 1.66 months following the completion of RT), all of whom subsequently developed clinical progression. At this first post-RT time point, patients with ctDNA-positivity had significantly worse progression-free survival (PFS) [hazard ratio (HR): 24.2, p=0.004], and ctDNA-positivity was the only significant prognostic factor associated with PFS (HR: 13.4, p=0.02) in a multivariate analysis. All patients who developed clinical recurrence had detectable ctDNA with an average lead time over radiographic progression of 5.4 months, and post-RT ctDNA positivity was significantly associated with poor PFS (p<0.0001)., Conclusion: Personalized, longitudinal ctDNA monitoring can detect recurrence early in patients with unresectable NSCLC patients undergoing curative radiation and potentially risk-stratify patients who might benefit most from treatment intensification., Competing Interests: NS reports research funding from Novartis. DG reports research funding from Astra Zeneca and Varian and receives Honoraria from Johnson and Johnson, MedLearning Gropu, and GRAIL. YM-G reports travel, accommodation, and expenses from AstraZeneca and Loxo Oncology/Eli Lilly. She acknowledges honoraria from Virology Education and Projects in Knowledge for a CME program funded by an educational grant from Amgen. She acknowledges associated research funding to the institution from Mirati Therapeutics, Loxo Oncology at Eli Lilly, Elucida Oncology, Taiho Oncology, Hengrui USA, Ltd/Jiangsu Hengrui Pharmaceuticals, Luzsana Biotechnology, and Endeavor Biomedicines. She acknowledges royalties from Rutgers University Press and Wolters Kluwer. She acknowledges food/beverages from Endeavor Biomedicines. YM-G acknowledges receipt of training through an institutional K30 grant from the NIH CTSA UL1TR00457. She has received funding from a Kristina M. Day Young Investigator Award from Conquer Cancer, the ASCO Foundation, endowed by Dr. Charles M. Baum and Carol A. Baum. She is also funded by the Fiona and Stanley Druckenmiller Center for Lung Cancer Research, the Andrew Sabin Family Foundation, the Society for MSK, and a Paul Calabresi Career Development Award for Clinical Oncology NIH/NCI K12 CA184746. JJ has a patent licensed by MDSeq Inc. JC has served as a consultant for Astra Zeneca, Bristol-Myers Squib, Genentech, Merck, Flame Biosciences, Novartis, Regeneron-Sanofi, Guardant Health, and Janssen as well as received research funding to her institution from Astra Zeneca, Bristol-Myers Squib, Genentech, and Merck. MGK receives personal fees from Novartis, Sanofi-Genzyme, AstraZeneca, Pfizer, Janssen, and Daiichi-Sankyo. He has also received honoraria for participation in educational programs from WebMD, OncLive, Physicians Education Resources, Prime Oncology, Intellisphere, Creative Educational Concepts, Peerview, i3 Health, Paradigm Medical Communications, AXIS, Carvive Systems, and AstraZeneca. MGK has received travel support from AstraZeneca, Pfizer, and Genentech as well as editorial support from Hoffman La-Roche. EK, JF, CBS, SS, CCP, MMa, MK, HS, AA, and MCL reported employment and stock ownership or option at Natera, Inc outside the submitted work. MCL reported receiving grants funding to Mayo Clinic from Eisai, Exact Sciences, Genentech, Genomic Health, GRAIL, Menarini Silicon Biosystems, Merck, Novartis, Seattle Genetics and Tesaro, and travel support from AstraZeneca, Genomic Health and Ionis, outside the submitted work. AS has stock ownership in ArcellX and Doximity. AW reports research support from CivaTech Oncology, Inc, Honoraria from Nanovi A/S, serves on the Scientific Advisory Board of Simphotek, Inc, and has stock in Simphotek, Inc. CS reports Honoraria from Varian and Novocure and serves in a Leadership position for the Proton Collaborative Group, American Society for Radiation Oncology, NRG Oncology, American Radium Society, and Annals of Palliative Medicine. DG reports research funding to her institution from Merck. CR reports personal fees from AbbVie, Amgen, Ascentage, AstraZeneca, Bicycle, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Jansen, Jazz, Lilly/Loxo, Pfizer, PharmaMar, Syros, Vavotek, Bridge Medicines, and Harpoon Therapeutics, outside the submitted work. DG reports grants to his institutions from Varian, AstraZeneca, Merck, and Bristol Myers Squibb, personal fees from Varia, AstraZeneca, Merck, US Oncology, Bristol Myers Squibb, Relfexion, WebMD, Vindico, and Medscape; and has served on the advisory board for AstraZeneca; he has also received Honoraria from Johnson and Johnson, MedLearning Group, and GRAIL. PR received institutional grant/funding from Grail, Illumina, Novartis, Epic Sciences, ArcherDx and Consultation/Ad board/Honoraria from Novartis, Foundation Medicine, AstraZeneca, Epic Sciences, Inivata, Natera, and Tempus. JR-F is a paid consultant of Goldman Sachs, Paige.AI and REPARE Therapeutics, a member of the Scientific Advisory Board of Goldman Sachs, Paige.AI and Volition RX, and ad hoc member of the scientific advisory board of Roche, Genetech, Roche Tissue Diagnostics, Ventana, Novartis, InVicro and GRAIL. JR-F reports receiving personal/consultancy fees from Goldman Sachs, Bain Capital, REPARE Therapeutics, Saga Diagnostics and Paige.AI, membership of the scientific advisory boards of VolitionRx, REPARE Therapeutics and Paige.AI, membership of the Board of Directors of Grupo Oncoclinicas, and ad hoc membership of the scientific advisory boards of Astrazeneca, Merck, Daiichi Sankyo, Roche Tissue Diagnostics and Personalis, outside the scope of this study. JR-F is funded in part by the Breast Cancer Research Foundation, by a Susan G Komen Leadership grant, and by the NIH/NCI P50 CA247749 01 grant. JI reports equity in LumaCyte, LLC and has served as an uncompensated member of a steering committee for Genentech. BL has served as an uncompensated advisor and consultant to Amgen, Genentech, Boehringer Ingelheim, Lilly, AstraZeneca, Daiichi Sankyo. He has received research grants to his institution from Amgen, Genentech, AstraZeneca, Daiichi Sankyo, Lilly, Illumina, GRAIL, Guardant Health, Hengrui Therapeutics, MORE Health and Bolt Biotherapeutics. He has received academic travel support from MORE Health, and Jiangsu Hengrui Medicine. He is an inventor on two institutional patents at MSK US62/685,057, US62/514,661 and has intellectual property rights as a book author at Karger Publishers and Shanghai Jiao Tong University Press. AR reports research funding from Varian Medical Systems, Boehringer Ingelheim, Astra Zeneca, Merck, and Pfizer and serves in Leadership Positions for the International Thymic Malignancies Group and International Mesothelioma Interest group. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lebow, Shaverdian, Eichholz, Kratochvil, McCune, Murciano-Goroff, Jee, Eng, Chaft, Kris, Kalashnikova, Feeney, Scalise, Sudhaman, Palsuledesai, Malhotra, Krainock, Sethi, Aleshin, Liu, Shepherd, Wu, Simone, Gelblum, Johnson, Rudin, Gomez, Razavi, Reis-Filho, Isbell, Li and Rimner.)

The ascites ecosystem in ovarian cancer is inhabited by complex cell types and is bathed in an environment rich in cytokines, chemokines, and growth factors that directly and indirectly impact metabolism of cancer cells and tumor associated cells. This milieu of malignant ascites, provides a 'rich' environment for the disease to thrive, contributing to every aspect of advanced ovarian cancer, a devastating gynecological cancer with a significant gap in targeted therapeutics. In this perspective we focus our discussions on the 'acellular' constituents of this liquid malignant tumor microenvironment, and how they influence metabolic pathways. Growth factors, chemokines and cytokines are known modulators of metabolism and have been shown to impact nutrient uptake and metabolic flexibility of tumors, yet few studies have explored how their enrichment in malignant ascites of ovarian cancer patients contributes to the metabolic requirements of ascites-resident cells. We focus here on TGF-βs, VEGF and ILs, which are frequently elevated in ovarian cancer ascites and have all been described to have direct or indirect effects on metabolism, often through gene regulation of metabolic enzymes. We summarize what is known, describe gaps in knowledge, and provide examples from other tumor types to infer potential unexplored roles and mechanisms for ovarian cancer. The distribution and variation in acellular ascites components between patients poses both a challenge and opportunity to further understand how the ascites may contribute to disease heterogeneity. The review also highlights opportunities for studies on ascites-derived factors in regulating the ascites metabolic environment that could act as a unique signature in aiding clinical decisions in the future., Competing Interests: Declaration of competing interest Authors have no conflicts to declare., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: Our study used transcriptomic and metabolomic strategies to determine the molecular profiles of HGSOC patient samples derived from primary tumor and ascites cells. These data identified clinically relevant heterogeneity among and within patients and highlighted global and patient-specific cellular responses to neoadjuvant chemotherapy (NACT)., Experimental Design: Tissue from 61 treatment-naïve patients with HGSOC were collected. In addition, 11 benign, 32 ascites, and 18 post-NACT samples (matched to the individual patient's pre-NACT sample) were collected. RNA sequencing (RNA-seq) was performed on all samples collected. Two-dimensional spatial proteomic data was collected for two pairs of pre- and post-NACT. Untargeted metabolomics data using GCxGC-MS was generated for 30 treatment-naive tissues. Consensus clustering, analysis of differential expression, pathway enrichment, and survival analyses were performed., Results: Treatment-naïve HGSOC tissues had distinct transcriptomic and metabolomic profiles. The mesenchymal subtype harbored a metabolomic profile distinct from the other subtypes. Compared with primary tumor tissue, ascites showed significant changes in immune response and signaling pathways. NACT caused significant alterations in gene expression and WNT activity, and this corresponded to altered immune response. Overall, WNT signaling levels were inversely correlated with immune cell infiltration in HGSOC tissues and WNT signaling post-NACT was inversely correlated with progression-free survival., Conclusions: Our study concluded that HGSOC is a heterogenous disease at baseline and growing molecular differences can be observed between primary tumor and ascites cells or within tumors in response to treatment. Our data reveal potential exploratory biomarkers relevant for treatment selection and predicting patient outcomes that warrant further research., (©2022 American Association for Cancer Research.)

In the USA, endometrial cancer (EMCA) incidence is increasing as the risk factors of obesity, diabetes, and hypertension become more prevalent. Although most EMCA is detected at an early stage and surgical intervention is curative, a subset of patients termed 'high-intermediate risk' (H-IR) experience an increased rate of recurrence. Unfortunately, adjuvant therapies in patients with H-IR EMCA have yet to increase overall survival. Historically, stratification of these patients from their low-risk counterparts incorporated clinical and pathologic findings. However, due to developments in molecular testing and genomic sequencing, tumor biomarkers are now being incorporated into the risk-assessment criteria in the hope of finding molecular profile(s) that could highlight treatment regimens that will increase patient survival. Since modern research aims to accurately identify patients with a higher risk of recurrence and develop effective interventions to improve patient survival, these molecular-based analyses could allow for an enhanced understanding of a patient's true risk of recurrence to facilitate the rise of personalized medicine. This review summarizes key clinical trials and recent advances in molecular and genomic profiles that have influenced current treatment regimens for patients with H-IR EMCA and laid the foundation for subsequent research., (© 2022. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: Progress in immunotherapy use for gynecologic malignancies is hampered by poor tumor antigenicity and weak T cell infiltration of the tumor microenvironment (TME). Wnt/β-catenin pathway modulation demonstrated patient benefit in clinical trials as well as enhanced immune cell recruitment in preclinical studies. The purpose of this study was to characterize the pathways by which Wnt/β-catenin modulation facilitates a more immunotherapy-favorable TME., Methods: Human tumor samples and in vivo patient-derived xenograft and syngeneic murine models were administered Wnt/β-catenin modulating agents DKN-01 and CGX-1321 individually or in sequence. Analytical methods included immunohistochemistry, flow cytometry, multiplex cytokine/chemokine array, and RNA sequencing., Results: DKK1 blockade via DKN-01 increased HLA/MHC expression in human and murine tissues, correlating with heightened expression of known MHC I regulators: NFkB, IL-1, LPS, and IFNy. PORCN inhibition via CGX-1321 increased production of T cell chemoattractant CXCL10, providing a mechanism for observed increases in intra-tumoral T cells. Diverse leukocyte recruitment was noted with elevations in B cells and macrophages, with increased tumor expression of population-specific chemokines. Sequential DKK1 blockade and PORCN inhibition decreased tumor burden as evidenced by reduced omental weights., Conclusions: Wnt/β-catenin pathway modulation increases MHC I expression and promotes tumor leukocytic infiltration, facilitating a pro-immune TME associated with decreased tumor burden. This intervention overcomes common tumor immune-evasion mechanisms and may render ovarian tumors susceptible to immunotherapy., (Published by Elsevier Inc.)

Among gynecologic malignancies, ovarian cancer (OC) has the poorest survival rate, and its clinical management remains challenging due to the high rate of recurrence and chemoresistance. Improving survival for these patients is critical, although this requires the ability to translate preclinical studies to actual patient care: bench to bedside and back. Our objective was to develop a preclinical model that accurately represents tumor biology and its microenvironment. We utilized SKOV-3, OVCAR-8, and CS-99 cell lines to show that this model was suitable for in vitro assessment of cell proliferation. We tested OC cells independently and in co-culture with cancer associated fibroblasts (CAFs) or immune cells. Additionally, we used patient-derived ovarian carcinoma and carcinosarcoma samples to show that the system maintains the histologic morphology of the primary tissue after 7 days. Moreover, we tested the response to chemotherapy using both cell lines and patient-derived tumor specimens and confirmed that cell death was significantly higher in the treated group compared to the vehicle group. Finally, we immune profiled the 3-D model containing patient tissue after several days in the bioreactor system and revealed that the immune populations are still present. Our data suggest that this model is a suitable preclinical model to aid in research that will ultimately impact the treatment of patients with gynecologic cancer., Competing Interests: Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: R.C.A. has participated in Advisory Boards for Leap Therapeutics, AstraZeneca, GSK, Merck, VBL Therapeutics, and Caris Life Sciences. M.J.B. serves as an advisory board member for AstraZeneca, Clovis, and GSK. The remaining authors declare no conflict of interest., (© The Author(s) 2021.)

Background: Patients with high-intermediate risk endometrial cancer (H-IR EMCA) have an elevated risk of recurrence compared to low-risk counterparts. Many H-IR EMCA patients are treated with radiation or chemotherapy, but their overall survival is not significantly impacted by treatment. The objective of this study was to compare molecular profiles of H-IR EMCA patients with disease recurrence to those without to identify characteristics that could better predict patient outcomes., Methods: Tissue was acquired from H-IR EMCA patients with disease recurrence (n=15) and without disease recurrence (n=15) who had not received adjuvant therapy and performed DNA and RNA analyses., Results: In recurrent population, 5 patients had matchingrecurrent and initial tumor tissues. Of note, 5/7 (71%) African Americanpatients had disease recurrence compared to 10/23 (43%) White patients. Inaddition, several new mutations were found in individual patient's recurrentcompared to initial tumors., Conclusions: Currently the treatment ofendometrial cancer is rapidly changing with molecular profiling becoming partof the standard of care. Additionally, it and is being incorporated intoclinical trials in this group of patients. The specific gene mutations and RNAexpression signatures that were observed in our small cohort need to bevalidated in larger cohorts to determine their impact., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Ovarian cancer is the second most common gynecologic malignancy in the United States and the most common cause of gynecologic cancer-related death. The majority of ovarian cancers ultimately recur despite excellent response rates to upfront platinum- and taxane-based chemotherapy. Maintenance therapy after frontline treatment has emerged in recent years as an effective tool for extending the platinum-free interval of these patients. Maintenance therapy with PARP inhibitors (PARPis), in particular, has become part of standard of care in the upfront setting and in patients with platinum-sensitive disease. Homologous recombination deficient (HRD) tumors have a nonfunctioning homologous recombination repair (HRR) pathway and respond well to PARPis, which takes advantage of synthetic lethality by concomitantly impairing DNA repair mechanisms. Conversely, patients with a functioning HRR pathway, that is, HR-proficient tumors, can still elicit benefit from PARPi, but the efficacy is not as remarkable as what is seen in HRD tumors. PARPis are ineffective in some patients due to HR proficiency, which is either inherent to the tumor or potentially acquired as a method of therapeutic resistance. This review seeks to outline current strategies employed by clinicians and scientists to overcome PARPi resistance-either acquired or inherent to the tumor., (©2021 American Association for Cancer Research.)

Objective: Mechanical forces including tension, compression, and shear stress are increasingly implicated in tumor progression and metastasis. Understanding the mechanisms behind epithelial ovarian cancer (EOC) progression and metastasis is critical, and this study aimed to elucidate the effect of oscillatory and constant tension on EOC., Methods: SKOV-3 and OVCAR-8 EOC cell lines were placed under oscillatory tension for 3 days and compared to cells placed under no tension. Cell proliferation, migration, and invasion were analyzed while RNAseq and Western Blots helped investigate the biological mechanisms underlying the increasingly aggressive state of the experimental cells. Finally, in vivo experiments using SCID mice assisted in confirming the in vitro results., Results: Oscillatory tension (OT) and constant tension (CT) significantly increased SKOV-3 proliferation, while OT caused a significant increase in proliferative genes, migration, and invasion in this cell line. CT did not cause significant increases in these areas. Neither OT nor CT increased proliferation or invasion in OVCAR-8 cells, while both tension types significantly increased cellular migration. Two proteins involved in metastasis, E-cadherin and Snail, were both significantly affected by OT in both cell lines, with E-cadherin levels decreasing and Snail levels increasing. In vivo, tumor growth and weight for both cell types were significantly increased, and ascites development was significantly higher in the experimental OVCAR-8 group than in the control group., Conclusions: This study found that mechanical forces are influential in EOC progression and metastasis. Further analysis of downstream mechanisms involved in EOC metastasis will be critical for improvements in EOC treatment., Competing Interests: Declaration of Competing Interest R.C.A. has participated in Advisory Boards for Leap Therapeutics, AstraZeneca, GSK, Merck, VBL Therapeutics, and Caris Life Sciences. M.J.B. serves as an advisory board member for AstraZeneca, Clovis, and GSK. The remaining authors declare no conflict of interest., (Copyright © 2021. Published by Elsevier Inc.)

Objective: Immune checkpoint blockade (ICB) therapy shows limited efficacy in ovarian cancers due to the "cold" immune phenotype surrounding these tumors. Previous studies have shown that in ovarian cancer Wnt/β-catenin pathway activation contributes to this immune phenotype. Here, we evaluated the anti-tumor and immune-enhancing properties of the Wnt inhibitor, CGX-1321, used alone or in combination with either DKN-01 or anti-PD-1 therapy, in pre-clinical ovarian cancer models., Methods: The parental ID8 murine ovarian cancer model harboring a knock-out of p53 (ID8p53 -/- ) and MISIIR-Tag spontaneous ovarian cancer models were used to test the effects of CGX-1321 alone or in combination therapies on tumor burden and immune cell landscape in the tumor microenvironment (TME). Flow cytometry and NanoString analyses were used to characterize the changes in tumor-intrinsic signaling and immune-related profiles in the TME of ovarian cancer in response to treatments., Results: CGX-1321 significantly reduced tumor burden and constrained tumor progression in the ID8p53 -/- and MISIIR-Tag models. Furthermore, CGX-1321 increased infiltrating CD8+ T cells in the TME. Combining CGX-1321 with either DKN-01 or anti-PD-1 therapy also decreased tumor burden and increased CD8+ T cell infiltration in the omentum TME but did not do so to a greater extent that CGX-1321 monotherapy., Conclusions: CGX-1321 significantly reduced tumor burden and enhanced CD8+ T cell levels in ovarian cancer, nevertheless the addition of DKN-01 or anti-PD-1 therapies did not enhance these effects of CGX-1321. Further investigation is needed to determine if CGX-1321 + DKN-01 combination treatment sensitizes pre-clinical ovarian cancer to ICB therapy., Competing Interests: Declaration of Competing Interest RCA has participated in Advisory Boards for Leap Therapeutics, AstraZeneca, GSK, Merck, VBL Therapeutics, and Caris Life Sciences., (Copyright © 2020. Published by Elsevier Inc.)