Transcriptome Profiling and Characterization of Peritoneal Metastasis Ovarian Cancer Xenografts in Humanized Mice DOI
Sung Wan Kang, Ji‐Young Lee, Ok-Ju Kang

et al.

Published: Oct. 28, 2023

ABSTRACT Background Although immunotherapy has not yet been as successful in ovarian cancer (OC), it remains a potential therapeutic strategy. Preclinical models of OC are necessary to evaluate the efficacy immuno-oncology (IO) drugs targeting human and immune components but have underutilized. Developing mouse with humanized (Hu) system can help understand response IO drugs, including checkpoint inhibitors (ICIs), which demonstrated limited effectiveness patients. Methods We established xenograft Hu-mouse by intraperitoneally injecting luciferase-expressing SKOV-3 Luc OVCAR-3 cells into CD34 + Hu-mice. Tumor growth was monitored through bioluminescence imaging (BLI). assessed PD-1 blockade pembrolizumab model. The profiles tumors were characterized using colorimetric immunostaining flow cytometry. Additionally, we analyzed RNA-seq data investigate gene expression signature refractory tumors. Results confirmed tumor development both cell lines within In these models, lymphocyte myeloid subsets present tumors, draining lymph nodes, blood, spleens. tumor-bearing Hu-mice did respond monotherapy. These exhibited high presence tumor-infiltrating macrophages. Tumors unresponsive showed lower abundance CD8 T-cells, memory B cells, plasma higher proportion naïve M0 macrophages mast compared PBS control. Furthermore, identified 43 significantly enriched sets differentially expressed genes (DEGs) predominantly HDAC class I, RB1, KLF1/3, TCF21, MYD88, SMARCE1 target genes, associated epithelial-mesenchymal transition (EMT) fibroblasts. Conclusion Our model provides valuable tool for investigating drugs. insights gained from this offer avenues explore mechanisms resistance PD-1/PD-L1 OC.

Language: Английский

Immunotherapy and the ovarian cancer microenvironment: Exploring potential strategies for enhanced treatment efficacy DOI Creative Commons
Zhibin Wang, Xiu Zhang, Chao Fang

et al.

Immunology, Journal Year: 2024, Volume and Issue: 173(1), P. 14 - 32

Published: April 15, 2024

Despite progress in cancer immunotherapy, ovarian (OC) prognosis continues to be disappointing. Recent studies have shed light on how not just tumour cells, but also the complex microenvironment, contribute this unfavourable outcome of OC immunotherapy. The complexities immune microenvironment categorize as a 'cold tumour'. Nonetheless, understanding precise mechanisms through which influences effectiveness immunotherapy remains an ongoing scientific endeavour. This review primarily aims dissect inherent characteristics and behaviours diverse cells within along with exploration into its reprogramming metabolic changes. It is expected that these insights will elucidate operational dynamics lay theoretical groundwork for improving efficacy management.

Language: Английский

Citations

5
Extracellular Vesicles in Ovarian Cancer: From Chemoresistance Mediators to Therapeutic Vectors DOI Creative Commons
Muttiah Barathan,

Nur Dina Muhammad Fuad,

Faizul Jaafar

et al.

Biomedicines, Journal Year: 2024, Volume and Issue: 12(8), P. 1806 - 1806

Published: Aug. 9, 2024

Ovarian cancer (OC) remains the deadliest gynecological malignancy, with alarming projections indicating a 42% increase in new cases and 51% rise mortality by 2040. This review explores challenges OC treatment, focusing on chemoresistance mechanisms potential of extracellular vesicles (EVs) as drug delivery agents. Despite advancements treatment strategies, including cytoreductive surgery, platinum-based chemotherapy, targeted therapies, high recurrence rate underscores need for innovative approaches. Key resistance include efflux, apoptosis disruption, enhanced DNA repair, stem cells, immune evasion, complex tumor microenvironment. Cancer-associated fibroblasts play crucial roles modulating microenvironment facilitating chemoresistance. EVs, naturally occurring nanovesicles, emerge promising carriers due to their low toxicity, biocompatibility, inherent targeting capabilities. They have shown delivering chemotherapeutics like doxorubicin, cisplatin, paclitaxel, well natural compounds such curcumin berry anthocyanidins, enhancing therapeutic efficacy while reducing systemic toxicity models. However, production yields, heterogeneity, rapid clearance, inefficient loading methods be addressed clinical application. Ongoing research aims optimize EV production, efficiency, targeting, paving way novel more effective strategies treatment. Overcoming these obstacles is unlocking full EV-based therapies improving outcomes patients.

Language: Английский

Citations

4
Overcoming Immune Checkpoint Inhibitor Resistance via Potent and Selective Dual αvβ6/8 Inhibitors Based on Engineered Lasso Peptides DOI Creative Commons
Anna Lechner, Peter A. Jordan, Gabriella Costa Machado da Cruz

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Abstract Integrins αvβ6 and αvβ8 in the tumor microenvironment (TME) have been shown to activate immunosuppressive TGF-β, which serves as an important mechanism for immune checkpoint inhibitor resistance a range of tumors. In this study, we demonstrate utility lasso peptides versatile scaffolds designing new therapeutics. A series highly potent selective dual αvβ6/8 inhibitors were engineered through combination epitope scanning, computational design, directed evolution. Several analogs, such lassotides 36 47 , fully characterized physicochemical, vitro pharmacological, vivo data are reported. Lassotide half-life extended derivative was strongly sensitize anti-mPD-1-resistant tumors mice when dosed with inhibitor. The /anti-mPD-1 halt growth regress mouse models triple negative breast ovarian cancers. Dual inhibition integrins expressed TME thus represents promising tumor-specific strategy overcome TGF-β-driven enhance anti-tumor efficacy inhibitors.

Language: Английский

Citations

0
Myeloid targeting antibodies PY159 and PY314 for platinum-resistant ovarian cancer DOI Creative Commons
Oladapo O. Yeku, Minal Barve, Winston Tan

et al.

Journal for ImmunoTherapy of Cancer, Journal Year: 2025, Volume and Issue: 13(3), P. e010959 - e010959

Published: March 1, 2025

Background Novel treatment options are required in patients with platinum-resistant ovarian cancer (PROC). Myeloid-derived suppressor cells promote a hostile tumor microenvironment and associated worse clinical outcomes PROC. We evaluated the safety preliminary efficacy of PY159, an agonist antibody to Triggering receptor expressed on myeloid cells-1 (TREM1) that reprograms immunosuppressive intratumoral cells, PY314, antagonist cells-2 (TREM2) depletes tumor-associated macrophages, as single agents combination pembrolizumab subjects Methods PY159 PY314 were individually Patients treated monotherapy (PY159 3 mg/kg or 10 mg/kg), based recommended dose for expansion derived from phase 1a studies. At time first progression, could continue study drug crossover therapy (200 mg) every weeks at discretion investigator. Disease assessment by Response Evaluation Criteria Solid Tumor version 1.1 was performed 6 weeks. Results 17 enrolled (median age 67, range 22–77; median prior therapies 6, 2–18) 16 65.5, 49–81; 4, 2–10). 7 8 crossed over therapy. Safety events included following: treatment-related adverse occurred 15 (88.2%) 9 (56.3%) PY314. Infusion-related reactions (35.3%) (18.8%) Immune-related 13 (76.5%) (arthralgias) 1 patient (6.3%) (diarrhea). Serious (36.3%) (1 related) 12 (75%) (all unrelated). The best radiographic response stable disease 8/16 (50%; weeks, 9–33), it 6–36). Median PFS 2.76 months 2.69 respectively. There no responses arm. Conclusions Both well tolerated, acceptable profile, both pembrolizumab. warrant further investigation heavily pretreated

Language: Английский

Citations

0
The discovery of acyl thiourea derivatives as potent hydrophobic tagging degraders targeting SIRT2 for the treatment of ovarian cancer DOI
Dandan Wang, Xiaoyu Ma,

Yijin Zhao

et al.

Chinese Chemical Letters, Journal Year: 2025, Volume and Issue: unknown, P. 111143 - 111143

Published: March 1, 2025

Language: Английский

Citations

0
Genetic Links between Endometriosis and Endometriosis-Associated Ovarian Cancer—A Narrative Review (Endometriosis-Associated Cancer) DOI Creative Commons
Tanja Pejović, Ann M. Cathcart,

Rofieda Alwaqfi

et al.

Life, Journal Year: 2024, Volume and Issue: 14(6), P. 704 - 704

Published: May 30, 2024

Endometriosis is a frequent, estrogen-dependent, chronic disease, characterized by the presence of endometrial glands and stroma outside uterine cavity. Although it not considered precursor cancer, endometriosis associated with ovarian cancer. In this review, we summarized evidence that clear-cell endometrioid carcinomas (endometriosis-associated carcinoma-EAOC) may arise in endometriosis. The most frequent genomic alterations these are mutations AT-rich interaction domain containing protein 1A (ARID1A) gene, subunit SWI/SNF chromatin remodeling complex, phosphatidylinositol 3-kinase (PI3K) which frequently coexist. Recent studies have also suggested simultaneous role

Language: Английский

Citations

3
Efficacy and safety of PD-1/PD-L1 immune checkpoint inhibitors in the treatment of recurrent ovarian cancer: A systematic review and meta-analysis DOI Creative Commons
Ya‐Fang Chen, Xiaomei Liu, Ying Hu

et al.

Medicine, Journal Year: 2024, Volume and Issue: 103(18), P. e38019 - e38019

Published: May 3, 2024

Background: Recurrent ovarian cancer (OC) presents a significant therapeutic challenge with limited treatment success. Programmed cell death protein 1 (PD-1/PD-L1) immune checkpoint inhibitors have emerged as potential avenue, necessitating systematic review and meta-analysis to evaluate their efficacy safety. Methods: Adhering preferred reporting items for reviews meta-analyses guidelines, we conducted comprehensive literature search across PubMed, Embase, Web of Science, Cochrane Library, culminating in the inclusion studies focusing on recurrent OC PD-1/PD-L1 inhibitors. Studies were evaluated using Newcastle-Ottawa Scale analyzed fixed or random effects models depending heterogeneity levels. Results: Our yielded 1215 articles, 6 meeting criteria final analysis. varied size reported median age, overall survival (OS), progression-free (PFS), adverse events. The showed improved Objective Response Rates (ORR), Disease Control Rate (DCR), PFS patients treated event rate was 17.9%, indicating need careful patient selection monitoring. No publication bias detected, enhancing reliability our findings. Conclusions: offer promising option OC, improving ORR, DCR, PFS. However, higher incidence events necessitates cautious approach use. Future research should focus long-term outcomes, biomarker identification, optimal combination therapies.

Language: Английский

Citations

2
Antibody-Drug Conjugates: The New Treatment Approaches for Ovarian Cancer DOI Open Access
Sho Sato, Tadahiro Shoji,

Ami Jo

et al.

Cancers, Journal Year: 2024, Volume and Issue: 16(14), P. 2545 - 2545

Published: July 15, 2024

Ovarian cancer (OC), accounting for approximately 200,000 deaths worldwide annually, is a heterogeneous disease showing major differences in terms of its incidence, tumor behavior, and outcomes across histological subtypes. In OC, primary chemotherapy, paclitaxel carboplatin, bevacizumab, PARP inhibitors have shown prolonged progression-free survival favorable overall response rate compared to conventional treatments. However, treatment options platinum-resistant recurrence cases are limited, with no effective therapies that significantly prolong the prognosis. Recently, mirvetuximab soravtansine, an alpha-folate receptor (FRα)-targeted antibody-drug conjugate (ADC), was approved by US Food Drug Administration patients FRα-positive recurrent epithelial OC (EOC). This approval based on Phase II study, which demonstrated efficacy such patients. ADCs comprise antibody, linker, payload, representing new concept agents without precedence. Advanced clinical studies developing targeting solid tumors as gynecologic cancer. Ongoing trials evaluating FRα human epidermal growth factor 2, trophoblast cell surface antigen-2, sodium-dependent phosphate transport protein 2B, cadherin-6 II/III studies. this review, we summarize existing evidence supporting use discuss ongoing preclinical studies, explore potential these innovative address challenges treatment.

Language: Английский

Citations

2
Unlocking the potential of immunotherapy in platinum-resistant ovarian cancer: rationale, challenges, and novel strategies DOI Open Access
Joanna Kefas,

Michael Flynn

Cancer Drug Resistance, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 15, 2024

Ovarian cancer is a significant global health challenge, with cytoreductive surgery and platinum-based chemotherapy serving as established primary treatments. Unfortunately, most patients relapse ultimately become platinum-resistant, at which point there are limited effective treatment options. Given the success of immunotherapy in inducing durable responses several other cancers, its potential platinum-resistant ovarian (PROC) currently being investigated. However, unselected advanced populations, researchers have reported low response rates to immune checkpoint inhibition, thus far, no validated biomarkers predictive response. Understanding intricate interplay between platinum resistance, recognition, tumour microenvironment (TME) crucial. In this review, we examine research challenges encountered biological rationale for immunotherapy, underlying mechanisms new strategies overcome resistance.

Language: Английский

Citations

2
TIGIT: A potential immunotherapy target for gynecological cancers DOI

Siyue Jiang,

Wen-Hua Wang,

Yongxiu Yang

et al.

Pathology - Research and Practice, Journal Year: 2024, Volume and Issue: 255, P. 155202 - 155202

Published: Feb. 7, 2024

Language: Английский

Citations

1