Engineered EV-Mimetic Nanoparticles as Therapeutic Delivery Vehicles for High-Grade Serous Ovarian Cancer

High-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy among women. Several obstacles impede the early diagnosis and effective treatment options for ovarian cancer (OC) patients, which most importantly include the development of platinum-drug-resistant strains. Currently, extensive efforts are being put into the development of strategies capable of effectively circumventing the physical and biological barriers present in the peritoneal cavity of metastatic OC patients, representing a late stage of gastrointestinal and gynecological cancer with an extremely poor prognosis. Naturally occurring extracellular vesicles (EVs) have been shown to play a pivotal role in progression of OC and are now being harnessed as a delivery vehicle for cancer chemotherapeutics. However, there are limitations to their clinical application due to current challenges in their preparation techniques. Intriguingly, there is a recent drive towards the use of engineered synthetic EVs for the delivery of chemotherapeutics and RNA interference therapy (RNAi), as they show the promise of overcoming the obstacles in the treatment of OC patients. This review discusses the therapeutic application of EVs in OC and elucidates the potential use of engineered EV-mimetic nanoparticles as a delivery vehicle for RNAi therapy and other chemotherapeutics, which would potentially improve clinical outcomes of OC patients.

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Neoadjuvant Chemotherapy Modulates the Tumor Microenvironment in High-Grade Serous Ovarian Cancer

10.21203/rs.3.rs-421498/v1 ◽

2021 ◽

Author(s):

Zhongling Zhuo ◽

Min Tang ◽

Hexin Li ◽

Lili Zhang ◽

Bingqing Han ◽

...

Keyword(s):

Gene Expression ◽

Ovarian Cancer ◽

T Cells ◽

Survival Analysis ◽

Tumor Microenvironment ◽

Neoadjuvant Chemotherapy ◽

Mapk Pathway ◽

Treatment Options ◽

High Grade ◽

Serous Ovarian Cancer

Abstract Background While surgical reduction with adjuvant chemotherapy is the traditional treatment for high-grade serous ovarian cancer (HGSOC), neoadjuvant chemotherapy (NACT) has increasingly been applied. This work aims to investigate the expression profiles before and after NACT, explore changes in the tumor microenvironment, expand current treatments, and design a combination of treatment options for patients. Methods We downloaded 326 pre-NACT RNA sequencing data and 37 matched pre- and post-NACT samples from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Differentially expressed genes (DEGs) were determined with EdgeR, and Gene Ontology analysis was performed to identify the clusters responsible for the biological processes and pathways of HGSOC. Immune infiltration was analyzed using Single-sample Gene Set Enrichment Analysis (ssGSEA) and CIBERSORT. Kaplan-Meier (KM) survival analysis was performed to assess prognosis, and the potential correlations between modules and phenotypes were explored using weighted gene co-expression network analysis (WGCNA). Results After NACT, a total of 352 genes showed significant changes in RNA expression, among which 180 genes were up-regulated and 172 down-regulated. The most influential pathway was the positive regulation of mitogen-activated protein kinase (MAPK) cascade. Correlation analysis and KM survival analysis showed that overexpression of MAPK cascade genes correlated with shorter survival time in HGSOC patients. ssGSEA results showed that the expressions of anti-tumor cells (central memory CD4+ T cell and central memory CD8+ T cell) and pro-tumor cells (neutrophil and dendritic cells) were significantly increased after NACT. CIBERSORT showed that the abundances of memory B cells, NK cells, and monocytes were increased and the abundance of plasma cells was decreased after NACT. WGCNA and KM survival analysis showed that a lower abundance of Regulatory T cells (Tregs) was correlated with a better prognosis. Conclusions Gene expression of the MAPK pathway is up-regulated and the abundance of CD4+ T regulation cell decreases after NACT. Thus, the MAPK pathway may promote the differentiation of CD4+ T cells into Th17 cells while inhibiting Tregs development. The inhibited Tregs' development can lead to a better prognosis. Therefore, it is speculated that Tregs inhibitors combined with platinum-based NACT are potential treatment options for HGSOC.

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Characterization of Candidate Factors Associated With the Metastasis and Progression of High Grade Serous Ovarian Cancer

10.21203/rs.3.rs-497718/v1 ◽

2021 ◽

Author(s):

Huiping Liu ◽

Ling Zhou ◽

Hongyan Cheng ◽

Shang Wang ◽

Wenqing Luan ◽

...

Keyword(s):

Ovarian Cancer ◽

Primary Tumor ◽

Gynecological Cancer ◽

Wnt Signaling Pathway ◽

The Cancer Genome Atlas ◽

High Grade ◽

Serous Ovarian Cancer ◽

Hub Genes ◽

Bioinformatics Analyses ◽

Factors Associated

Abstract Background. High grade serous ovarian cancer (HGSOC) is the highest cause of gynecological cancer-related mortality due to the extremely metastatic nature of this disease. The goal of this study is to explore and evaluate the profiles and characteristics of candidate factors associated with metastasis and progression of HGSOC.Methods. Transcriptomic data of HGSOC patients’ samples collected from the primary tumor and matched omental metastatic tumor were obtained from three independent studies in the NCBI GEO database. Genes significantly up-regulated and down-regulated were selected to evaluate the effects to prognosis and progression of ovarian cancer using data of ovarian cancer patients from The Cancer Genome Atlas (TCGA) database. Enrichment analysis for biological processes and pathways was performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) analysis. Furthermore, the hub genes immune landscapes were estimated by Tumor Immune Estimation Resource (TIMER) database.Results. 14 candidate genes included ADIPOQ, ALPK2, BARX1, CD37, CNR2, COL5A3, FABP4, FAP, GPR68, ITGBL1, MOXD1, PODNL1, SFRP2 and TRAF3IP3 were selected as up-regulated genes in metastatic tumors in every database while CADPS, GATA4, STAR and TSPAN8 were down-regulated. These 14 genes were significantly enriched for negative regulation of Wnt signaling pathway, fat cell differentiation, extracellular matrix organization. Finally, ALPK2, FAP, SFRP2 and GATA4, STAR, TSPAN8 were selected as hub genes that were found to be significantly associated with the survival and recurrence. All hub genes were correlated with several types of tumor microenvironmental cells infiltration significantly, especially for cancer associated fibroblasts and NK cells.Conclusions. This study indicates that screening for differentially expressed genes and pathways in HGSOC primary tumor and matched metastasis tumor using integrated bioinformatics analyses. In sum, we identify six hub genes correlated with the progression of HGSOC in our study, which might provide effective targets to predict prognosis and provide novel insights into immune-based therapy strategies of HGSOC well.

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Considerations for Chemotherapy Treatment in Platinum Resistant High-Grade Serous Ovarian Cancer

Sciential - McMaster Undergraduate Science Journal ◽

10.15173/sciential.v1i3.2244 ◽

2019 ◽

pp. 14-18

Author(s):

Caitlin Marie Reintjes

Keyword(s):

Ovarian Cancer ◽

Gynecological Cancer ◽

Cancer Prognosis ◽

Alternative Methods ◽

Platinum Resistance ◽

Primary Concern ◽

High Grade ◽

Serous Ovarian Cancer ◽

Individual Scale ◽

Platinum Chemotherapy

Ovarian cancer is considered to be the most fatal type of any gynecological cancer. Prognosis for the disease is poor, with a median survival of only thirty-two months following diagnosis and a five-year survival rate of only 39%. Many of the most lethal ovarian cancer cases are classified as part of the high-grade serous ovarian cancer (HGSOC) subtype, which is the most aggressive form of the disease. The primary concern with regards to treatment is that nearly 30% of patients will develop a resistance to forms of platinum chemotherapy, which is the main method of treatment. This suggests that a one-size fits all approach cannot be taken to treat ovarian cancer, and that further research must be done to understand how to treat the patients who present with platinum resistance. This literature review examines the mutations within two susceptible loci, specifically, the p53 and BRCA1/2 genes, in order to understand how platinum resistance develops and why it is present in some patients. The objectives of this review are to characterize the underlying genetic mechanisms affecting platinum resistance, specify the biomarkers associated with those mechanisms, and describe alternative methods for approaching the treatment of ovarian cancer on an individual scale.

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