High-grade Serous Ovarian Cancer Research Articles

Abstract A011: Assessing pro-tumorigenicity of the aging microenvironment in a murine ovarian cancer model

Abstract Over 70% of high-grade serous ovarian cancer (HGSOC) patients are diagnosed after age 55 and the average patient who succumbs to HGSOC is 70 years old. Despite this, the majority of ovarian cancer studies, and cancer studies generally, utilize young mice that are more representative of human children. This approach overlooks age as a variable, despite its status as a top risk factor for cancer. Our preliminary studies reveal tumor burden and disease severity is significantly higher in aged mice compared to young animals. We have developed an epithelial cell line derived from C57BL/6 oviducts and used CRISPR-Cas9 genome editing to establish tumorigenic lines for syngeneic studies. One line harbors Trp53, Pten, and Brca2 deletions, is tumorigenic, and can be serially passaged in vitro. When injected intraperitoneally (IP) into 8-week and 56-week-old mice, equating to approximately 10- and 45-year-old humans respectively, a stark increase in tumor mass was evident in aged mice. Furthermore, the aged mice succumbed to disease at a faster rate after inoculation than the young group, where all mice succumbed to disease within 1-month of IP injection compared to some young mice surviving up to 3 months after injection. These findings, combined with epidemiologic data, suggest a metastatic driver in the aged microenvironment that facilitates worsened ovarian cancer progression. We are investigating two factors that change with age, (1) a suppressed immune system and (2) age-related changes to adipose tissue, as possible mechanisms driving this difference. Histologic analysis of tumors from each cohort showed decreased cleaved caspase-3 in aged tumors, indicating a reduction in tumor cell killing in older animals. Characterization of the pre-cancerous, tumor-naive microenvironment via flow cytometry and cytokine array have revealed that aged mice microenvironment is highly inflamed and features changes in immune populations and inflammatory states. Meanwhile, total RNA-sequencing of tumors harvested from aged and young mice showed minimal changes, but DEGs point to possible roles of fat transport and metabolism in these aged tumors, indicated by upregulated CD36 and lipoprotein lipase. Follow-up ex vivo experiments had demonstrated increased adhesion and proliferation of the previously described murine cancer cells to fat pads when cultured in vitro. When assessing tumor-naive fat depots, aged adipose tissue is comprised of significantly larger adipocytes and the omentum, a common secondary site of ovarian cancer and fatty organ, was found to have increased phospholipid content in older animals. Both findings point to a change in metabolic function in aged mice. Our preliminary findings indicate an important role of the aged microenvironment in driving enhanced diseases progression in older individuals and identifying the mechanisms behind this phenotype are critical; an improved understanding of how age affects HGSOC progression could enable the development of treatment strategies to prevent cancer cells from establishing in the peritoneum. Citation Format: Katherine A. Cummins, Ronny Drapkin. Assessing pro-tumorigenicity of the aging microenvironment in a murine ovarian cancer model [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A011.

Germline BRCA1/2 status and chemotherapy response score in high-grade serous ovarian cancer.

High-grade serous ovarian cancer (HGSOC) can be treated with platinum-based neoadjuvant chemotherapy (NACT) and delayed primary surgery (DPS). Histopathological response to NACT can be assessed using Böhm's chemotherapy response score (CRS). We investigated whether germline BRCA1/2 (gBRCA1/2) genotype associated with omental CRS phenotype. A retrospective study of patients with newly diagnosed FIGO stage IIIC/IV HGSOC prescribed NACT and tested for gBRCA1/2 pathogenic variants (PVs) between September 2017 and December 2022 at The Christie Hospital. The Cox proportional hazards model evaluated the association between survival and key clinical factors. The chi-square test assessed the association between CRS3 (no/minimal residual tumour) and gBRCA1/2 status. Of 586 eligible patients, 393 underwent DPS and had a CRSreported. Independent prognostic factors by multivariable analysis were gBRCA1/2 status (PV versus wild type [WT]), CRS (3 versus 1 + 2), surgical outcome (complete versus optimal/suboptimal) and first-line poly (ADP-ribose) polymerase-1/2 inhibitor maintenance therapy (yes versus no) (all P < 0.05). There was a non-significant trend for tumours with a gBRCA2 PV having CRS3 versus WT (odds ratio [OR] = 2.13, 95% confidence intervals [CI] 0.95-4.91; P = 0.0647). By contrast, tumours with a gBRCA1 PV were significantly less likely to have CRS3 than WT (OR = 0.35, 95%CI 0.14-0.91; P = 0.0291). Germline BRCA1/2 genotype was not clearly associated with superior omental CRS. Further research is required to understand how HGSOC biology defines CRS.

Endothelin-1 receptor blockade impairs invasion patterns in engineered 3D high-grade serous ovarian cancer tumouroids.

High-grade serous ovarian cancer (HG-SOC), accounting for 70-80% of ovarian cancer deaths, is characterized by a widespread and rapid metastatic nature, influenced by diverse cell types, cell-cell interactions, and acellular components of the tumour microenvironment (TME). Within this tumour type, autocrine and paracrine activation of the endothelin-1 receptors (ET-1R), expressed in tumour cells and stromal elements, drives metastatic progression. The lack of three-dimensional models that faithfully recapitulate the unique HG-SOC TME has been the bottleneck in performing drug screening for personalized medicine. Herein, we developed HG-SOC tumouroids by engineering a dense central artificial cancer mass (ACM) containing HG-SOC cells, nested within a compressed hydrogel recapitulating the stromal compartment comprising type I collagen, laminin, fibronectin, and stromal cells (fibroblasts and endothelial cells). ET-1-stimulated HG-SOC cells in the tumouroids showed an altered migration pattern and formed cellular aggregates, mimicking micrometastases that invaded the stroma. Compared with control cells, ET-1-stimulated tumouroids showed a higher number of invasive bodies, which were reduced by treatment with the dual ET-1 receptor (ET-1R) antagonist macitentan. In addition, ET-1 increased the size of the invading aggregates compared with control cells. This study establishes an experimental 3D multicellular model eligible for mechanical research, investigating the impact of matrix stiffness and TME interactions, which will aid drug screening to guide therapeutic decisions in HG-SOC patients.

Abstract A025: RNA-Based Therapeutics to target the p53 pathway in high-grade serous ovarian cancer: TAp63-Regulated Oncogenic LncRNAs (TROLLs) as novel therapeutic targets in cancer

Abstract High-grade serous ovarian cancer (HGSOC) is the most common and malignant type of ovarian cancer with a high frequency of p53 mutation and hyperactivation of the AKT pathway. Even though roughly 85% of patients achieve remission after initial surgical debulking and chemotherapy, four out of five HGSOC patients will experience disease recurrence, resulting in a 5-year survival rate of 43%. We have identified and characterized two TAp63 Regulated Oncogenic Long non-coding RNAs (TROLL-2 and TROLL-3) whose transcription is induced by mutant p53 and high expression level correlate with a more aggressive ovarian cancer grade and phosphorylation of AKT. In-depth analysis demonstrated that TROLL-2 and TROLL-3 directly activate AKT in tumor cells, thus linking p53 alterations to AKT activity. The use of AKT inhibitors in the clinic is limited because of frequent adverse effects, likely due to the constitutive expression of AKT in all cells. TROLL-2 and TROLL-3 expression is limited to tumor cells and provides a more specific target for decreasing AKT activation, potentially minimizing off-target effects. We have optimized reduction of TROLL-2 and TROLL-3 expression using antisense oligonucleotides (ASOs) in an ex vivo perfusion platform for 3D culture of microtumors from primary patient derived tumors. Samples show maximum reduction of proliferation (EdU) and phosphorylation of AKT when TROLL-2 and TROLL-3 ASOs are used concurrently. We also performed phospho-proteomics and single cell RNAseq to compare individual ASO-mediated knockdown of each lncRNA to combined targeted ASO treatments. We have developed primary patient derived xenograft models using ovarian tumors orthotopically implanted into NSG mice generating a relevant preclinical model to determine the efficacy of ASO treatment. To reduce the rapid degradation and clearance of ASOs in circulation, ASOs were encapsulated into lipid nanoparticles and metal-organic frameworks (MOFs) and we are currently testing these in vivo. Since AKT activation is associated with increased staging and resistance to platinum and targeted therapies in ovarian cancer patients, our data provides preclinical rationale for the implementation of ASOs and the use of new delivery methods as a relevant translational therapy and novel method to exploit the specificity of TROLL-2 and TROLL-3 expression in HGSOC. Citation Format: Ashley Lui, Marco Napoli, Jaden R Baldwin, Christina L Carr, Angie Rivera, Duy Nguyen, W. Gregory Sawyer, Michael R Dunne, Erin George, Omar K Farha, Michelle Teplensky, Elsa R Flores. RNA-Based Therapeutics to target the p53 pathway in high-grade serous ovarian cancer: TAp63-Regulated Oncogenic LncRNAs (TROLLs) as novel therapeutic targets in cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr A025.

Integrated analysis of single-cell and bulk transcriptome reveals hypoxia-induced immunosuppressive microenvironment to predict immunotherapy response in high-grade serous ovarian cancer

BackgroundHypoxia is significantly associated with cancer progression and treatment outcomes. Nevertheless, the precise molecular mechanisms underlying the hypoxia-induced immunosuppressive microenvironment in high-grade serous ovarian cancer (HGSOC) are still not fully understood.MethodsBy analyzing five independent transcriptomic datasets, we investigated the effect of hypoxia on prognosis and tumor microenvironment (TME) in HGSOC. The hypoxia levels and the intercellular communication signaling pathways were studied by using single-cell analysis. Furthermore, the Hypoxia-TME classifier was developed and then validated in the multiple HGSOC datasets. In addition, we also investigated the prognostic significance, genetic variations, signaling pathways, and the potential for immunotherapy benefits in different Hypoxia-TME subgroups.ResultsHypoxia was identified as a crucial risk factor in HGSOC, and strongly correlated with an immunosuppressive microenvironment characterized by alterations in the composition and distribution of immune cells. Single-cell analysis elucidated the heterogeneity inherent within the TME in HGSOC, and demonstrated an association between the hypoxic TME and fibroblasts as well as macrophages. CellChat analysis identified SPP1-CD44 and CXCL12-CXCR4 as the principal signaling axes through which macrophages and fibroblasts interact with T cells, respectively. Moreover, a personalized Hypoxia-TME classifier was constructed and validated through the integration of the hypoxia (18 genes) and TME (7 immune cells) scores. It was observed that patients in the Hypoxialow/TMEhigh subgroup displayed a significantly better prognosis than other subgroups. Different subgroups exhibited unique genomic alterations and variations in signaling pathway differences, including TGF-β and Wnt/β-catenin pathways, which are closely associated with various biological functions. Finally, our results indicated that patients in the Hypoxialow/TMEhigh subgroup exhibit a better response to immunotherapy, suggesting the potential utility of the Hypoxia-TME classifier as a new biomarker in HGSOC.ConclusionOur study revealed hypoxia-induced immunosuppressive microenvironment, and developed Hypoxia-TME classifier to distinguish the prognosis, immune characteristics, and potential benefits of immunotherapy in HGSOC.

Hyperthermic intraperitoneal chemotherapy for recurrent ovarian cancer (CHIPOR): a randomised, open-label, phase 3 trial.

Hyperthermic intraperitoneal chemotherapy (HIPEC) at interval cytoreductive surgery for ovarian cancer improves overall survival but its role in recurrent disease is uncertain. We aimed to compare outcomes in patients treated with or without HIPEC during surgery for recurrent ovarian cancer. The multicentre, open-label, randomised, phase 3 CHIPOR trial was conducted at 31 sites in France, Belgium, Spain, and Canada, and enrolled patients with first relapse of epithelial ovarian cancer at least 6 months after completing platinum-based chemotherapy. Eligible patients were aged 18 years or older with WHO performance status of less than 2. After six cycles of platinum-based chemotherapy (and optional bevacizumab), patients amenable to complete cytoreductive surgery were randomly assigned centrally in a 1:1 ratio, using a web-based system and a minimisation procedure, during surgery to receive HIPEC (cisplatin 75 mg/m2 in 2 L/m2 of serum at 41±1°C for 60 min) or not, stratified by centre, completeness of cytoreduction score, platinum-free interval, and latterly, planned poly(ADP-ribose) polymerase inhibitor use. The primary endpoint was overall survival, analysed on an intention-to-treat basis in all randomly assigned patients. This ongoing trial is registered with ClinicalTrials.gov, NCT01376752. Between May 11, 2011, and May 14, 2021, 415 female patients were randomly assigned (207 HIPEC, 208 no HIPEC). At the primary analysis (median follow-up 6·2 years, IQR 4·1-8·1), 268 (65%) patients had died (126 [61%] of 207 in the HIPEC group; 142 [68%] of 208 in the no-HIPEC group). Overall survival was significantly improved with HIPEC (stratified hazard ratio 0·73, 95% CI 0·56-0·96; p=0·024). Median overall survival was 54·3 months (95% CI 41·9-61·7) with HIPEC versus 45·8 months (38·9-54·2) without. Grade 3 or worse adverse events within 60 days after surgery occurred in 102 (49%) of 207 patients receiving HIPEC versus 56 (27%) of 208 receiving no HIPEC, the most common being anaemia (47 [23%] vs 30 [14%]), hepatotoxicity (23 [11%] vs 18 [9%]), electrolyte disturbance (28 [14%] vs two [1%]), and renal failure (20 [10%] vs three [1%]). There were three deaths within 60 days of surgery, all in the no-HIPEC group. Adding HIPEC to cytoreductive surgery after response to platinum-based chemotherapy at first epithelial ovarian cancer recurrence significantly improved overall survival. When treating patients with late first relapse of high-grade serous or high-grade endometrioid ovarian cancer amenable to complete cytoreductive surgery at specialist centres, platinum-based HIPEC should be considered to extend overall survival. French National Cancer Institute and French League Against Cancer.

Dynamic Contrast-Enhanced and Diffusion-Weighted Imaging in Magnetic Resonance in the Assessment of Peritoneal Recurrence of Ovarian Cancer in Patients with or Without BRCA Mutation

Background: The aim of this study was to determine the differences in diffusion-weighted imaging (DWI) and dynamic contrast enhancement (DCE) parameters between patients with peritoneal high-grade serous ovarian cancer (HGSOC) recurrence with BRCA mutations (BRCAmut) or BRCA wild type (BRCAwt). Materials and Methods: We retrospectively analyzed the abdominal and pelvic magnetic resonance (MR) images of 43 patients suspected of having recurrent HGSOC, of whom 18 had BRCA1/2 gene mutations. Patients underwent MRI examination via a 1.5 T MRI scanner, and the analyzed parameters were as follows: apparent diffusion coefficient (ADC), time to peak (TTP) and perfusion maximum enhancement (Perf. Max. En.). Results: The mean ADC in patients with BRCAwt was lower than that in patients with BRCAmut: 788.7 (SD: 139.5) vs. 977.3 (SD: 103), p-value = 0.00002. The average TTP value for patients with BRCAwt was greater than that for patients with mutations: 256.3 (SD: 50) vs. 160.6 (SD: 35.5), p-value &lt; 0.01. The Perf. Max. En. value was lower in the BRCAwt group: 148.6 (SD: 12.3) vs. 233.6 (SD: 29.2), p-value &lt; 0.01. Conclusion: Our study revealed a statistically significant correlation between DWI and DCE parameters in examinations of peritoneal metastasis in patients with BRCA1/2 mutations. Adding DCE perfusion to the MRI protocol for ovarian cancer recurrence in patients with BRCAmut may be a valuable tool.

YAP signaling orchestrates the endothelin-1-guided invadopodia formation in high-grade serous ovarian cancer.

The high-grade serous ovarian cancer (HG-SOC) is a notoriously challenging disease, characterized by a rapid peritoneal dissemination. HG-SOC cells leverage actin-rich membrane protrusions, known as invadopodia, to degrade the surrounding extracellular matrix (ECM) and invade, initiating the metastatic cascade. In HG-SOC, the endothelin-1 (ET-1)/endothelin A receptor (ETAR)-driven signaling coordinates invadopodia activity, however how this axis integrates pro-oncogenic signaling routes, as YAP-driven one, impacting on the invadopodia-mediated ECM degradation and metastatic progression, deserves a deeper investigation. Herein, we observed that downstream of the ET-1/ET-1R axis, the RhoC and Rac1 GTPases, acting as signaling intermediaries, promote the de-phosphorylation and nuclear accumulation of YAP. Conversely, the treatment with the dual ETA/ETB receptor antagonist, macitentan, inhibits the ET-1-driven YAP activity. Similarly, RhoC silencing, or cell transfection with a dominant inactive form of Rac1, restore the YAP phosphorylated and inhibited state. Mechanistically, the ET-1R/YAP signal alliance coordinates invadopodia maturation into ECM-degrading structures, indicating how such ET-1R-guided protein network represents a route able to enhance the HG-SOC invasive potential. At functional level, we found that the interconnection between the ET-1R/RhoC and YAP signals is required for MMP-2 and MMP-9 proteolytic functions, cell invasion, and cytoskeleton architecture changes, supporting the HG-SOC metastatic strength. In HG-SOC patient-derived xenografts (PDX) macitentan, turning-off the invadopodia regulators RhoC/YAP, halt the metastatic colonization. ET-1R targeting, hindering the YAP activity, weakens the invadopodia machinery, embodying a promising therapeutic avenue to prevent peritoneal dissemination in HG-SOC.

Potential Transcriptomic Biomarkers for Predicting Platinum-based Chemotherapy Resistance in Patients With High-grade Serous Ovarian Cancer.

Due to the absence of screening protocols, high-grade serous ovarian cancer (HGSOC) patients are frequently diagnosed at an advanced stage, which significantly reduces the survival rate. Moreover, relapse occurs in approximately 70% of HGSOC patients after primary treatment. Predicting resistance to primary chemotherapy remains a challenge. In the research setting, transcriptomic analyses have emerged as powerful tools for predicting which HGSOC patients are likely to benefit from primary treatment. The aim of this review was to investigate the literature demonstrating the potential of transcriptomic signatures as biomarkers for assessing the risk of resistance to platinum-based chemotherapy. We conducted a three-step search process on PubMed to systematically review English-language articles published between 2020 and 2024. From the 123 articles retrieved, we included 11 articles that investigated transcriptomic signatures by RNA sequencing in tissues from chemo-sensitive and -resistant HGSOC patients. We report the clinicopathological data of 727 patients in the experimental cohorts, transcriptomic signatures, and technical aspects. Finally, the review lists 15 publicly available datasets used in the included studies. Furthermore, we investigated the overlap of 167 differentially expressed genes retrieved across the various articles. We believe this review might offer valuable insights for further studies focusing on predicting platinum resistance and personalized treatments. In addition to discussing the latest findings and potential candidates, we highlight the challenges of validating biomarkers across studies and publicly available datasets. Transcriptomic signatures represent a potential tool for patient stratification, prognosis, and the potential adoption of long-term therapies, such as poly (ADP-ribose) polymerase inhibitors (PARPis).

3D organoid models for predicting drug response in platinum-sensitive, high-grade serous ovarian cancer

3D organoid models for predicting drug response in platinum-sensitive, high-grade serous ovarian cancer

Homologous recombination status in BRCA wild-type patients as a predictor of disease volume and surgical outcome in patients with high-grade serous ovarian cancer

Homologous recombination status in BRCA wild-type patients as a predictor of disease volume and surgical outcome in patients with high-grade serous ovarian cancer

Microenvironment cell populations are associated with clinical outcomes in high-grade serous ovarian cancer

Microenvironment cell populations are associated with clinical outcomes in high-grade serous ovarian cancer

Use of DNA methyltransferase inhibitor and poly(adenosine diphosphate ribose) polymerase inhibitor (PARPi) in the treatment of PARPi-resistant, high-grade serous ovarian cancer

Use of DNA methyltransferase inhibitor and poly(adenosine diphosphate ribose) polymerase inhibitor (PARPi) in the treatment of PARPi-resistant, high-grade serous ovarian cancer

Supervised machine learning with a novel set of 20 genes predicts the likelihood of early or late recurrence of high-grade serous ovarian cancer

Supervised machine learning with a novel set of 20 genes predicts the likelihood of early or late recurrence of high-grade serous ovarian cancer

Efficacy and safety of alpelisib plus olaparib versus chemotherapy among patients with platinum-resistant or refractory high-grade serous ovarian cancer without BRCA mutation: Primary analysis of the EPIK-O trial

Efficacy and safety of alpelisib plus olaparib versus chemotherapy among patients with platinum-resistant or refractory high-grade serous ovarian cancer without BRCA mutation: Primary analysis of the EPIK-O trial

Does cancer appearance reflect genetic status? The relationship between the gross appearance of high-grade serous ovarian cancer and BRCA mutation status

Does cancer appearance reflect genetic status? The relationship between the gross appearance of high-grade serous ovarian cancer and BRCA mutation status

Association of high-grade serous ovarian cancer sample clonality with clinical outcomes

Association of high-grade serous ovarian cancer sample clonality with clinical outcomes

Impact of the tumor microenvironment in splenic metastasis in high-grade serous ovarian cancer revealed by quantitative proteomics

Impact of the tumor microenvironment in splenic metastasis in high-grade serous ovarian cancer revealed by quantitative proteomics

Focal adhesion kinase inhibitors as maintenance therapy in a homologous recombination repair proficient high-grade serous ovarian cancer murine model

Focal adhesion kinase inhibitors as maintenance therapy in a homologous recombination repair proficient high-grade serous ovarian cancer murine model

P53 functional status is associated with survival among high-grade serous ovarian cancer patients with copy number signature one

p53 functional status is associated with survival among high-grade serous ovarian cancer patients with copy number signature one