Evolutionary states and trajectories characterized by distinct pathways stratify patients with ovarian high grade serous carcinoma

Cancer Cell, Год журнала: 2023, Номер 41(6), С. 1103 - 1117.e12

Опубликована: Май 18, 2023

Ovarian high-grade serous carcinoma (HGSC) is typically diagnosed at an advanced stage, with multiple genetically heterogeneous clones existing in the tumors long before therapeutic intervention. Herein we integrate clonal composition and topology using whole-genome sequencing data from 510 samples of 148 patients HGSC prospective, longitudinal, multiregion DECIDER study. Our results reveal three evolutionary states, which have distinct features genomics, pathways, morphological phenotypes, significant association treatment response. Nested pathway analysis suggests two trajectories between states. Experiments five tumor organoids PI3K inhibitors support targeting enriched PI3K/AKT alpelisib. Heterogeneity anatomical sites shows that site-of-origin 70% more unique than metastatic or ascites. In conclusion, these visualization methods enable integrative evolution to identify patient subtypes cohorts.

Язык: Английский

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Paradigm Shift: A Comprehensive Review of Ovarian Cancer Management in an Era of Advancements

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(3), С. 1845 - 1845

Опубликована: Фев. 3, 2024

Ovarian cancer (OC) is the female genital malignancy with highest lethality. Patients present a poor prognosis mainly due to late clinical presentation allied common acquisition of chemoresistance and high rate tumour recurrence. Effective screening, accurate diagnosis, personalised multidisciplinary treatments are crucial for improving patients’ survival quality life. This comprehensive narrative review aims describe current knowledge on aetiology, prevention, treatment OC, highlighting latest significant advancements future directions. Traditionally, OC involves combination cytoreductive surgery platinum-based chemotherapy. Although more therapeutical approaches have been developed, lack established predictive biomarkers guide disease management has led only marginal improvements in progression-free (PFS) while patients face an increasing level toxicity. Fortunately, because better overall understanding ovarian tumourigenesis disease’s (epi)genetic molecular profiling, paradigm shift emerged identification new proposal targeted therapeutic postpone recurrence decrease side effects, survival. Despite this progress, several challenges management, including heterogeneity drug resistance, still need be overcome.

Язык: Английский

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Targeted therapy in high grade serous ovarian Cancer: A literature review

Gynecologic Oncology Reports, Год журнала: 2024, Номер 54, С. 101450 - 101450

Опубликована: Июль 6, 2024

Ovarian cancer continues to have a high mortality rate despite therapeutic advances. Traditionally, treatment has focused on surgery followed by systemic platinum- based chemotherapy. Unfortunately, most patients develop resistance platinum agents, highlighting the need for targeted therapies. PARP inhibitors and anti-angiogenic such as bevacizumab, more recently changed upfront therapy. other therapies including immunotherapy not seen same success. Emerging targets modalities small molecule tyrosine kinase inhibitors, lipid metabolism targeting gene therapy, ribosome drugs well several classes been are currently under investigation. In this review, we discuss in grade serous ovarian from preclinical studies phase III clinical trials.

Язык: Английский

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The “Road” to Malignant Transformation from Endometriosis to Endometriosis-Associated Ovarian Cancers (EAOCs): An mTOR-Centred Review

Cancers, Год журнала: 2024, Номер 16(11), С. 2160 - 2160

Опубликована: Июнь 6, 2024

Ovarian cancer is an umbrella term covering a number of distinct subtypes. Endometrioid and clear-cell ovarian carcinoma are endometriosis-associated cancers (EAOCs) frequently arising from ectopic endometrium in the ovary. The mechanistic target rapamycin (mTOR) crucial regulator cellular homeostasis dysregulated both endometriosis cancer, potentially favouring carcinogenesis across spectrum benign disease with cancer-like characteristics, through atypical phase, to frank malignancy. In this review, we focus on mTOR dysregulation EAOCs, investigating driver gene mutations their potential interaction pathway. Additionally, explore complex pathogenesis transformation, considering environmental, hormonal, epigenetic factors. We then discuss postmenopausal propensity for malignant transformation. Finally, summarize current advancements mTOR-targeted therapeutics EAOCs.

Язык: Английский

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Promising new drugs and therapeutic approaches for treatment of ovarian cancer—targeting the hallmarks of cancer

BMC Medicine, Год журнала: 2025, Номер 23(1)

Опубликована: Янв. 6, 2025

Abstract Ovarian cancer remains the most lethal gynecological malignancy. Despite approval of promising targeted therapy such as bevacizumab and PARP inhibitors, 5-year survival has not improved significantly. Thus, there is an urgent need for new therapeutics. New advancements in therapeutic strategies target pivotal hallmarks cancer. This review giving updated overview innovative upcoming therapies treatment ovarian that focuses specific on The constitute a broad concept to reenact complexity malignancies furthermore identify possible targets strategies. For this purpose, we analyzed approvals current clinical phase III studies (registered at ClinicalTrials.gov (National Library Medicine, National Institutes Health; U.S. Department Health Human Services, 2024)) drugs basis their mechanisms action identified approaches. A spectrum currently under investigation targeting mainly “self-sufficiency growth signals,” “genomic instability,” “angiogenesis.” benefit immune checkpoint inhibitors been demonstrated first time. Besides, tumor microenvironment growing interest. Replicative immortality, energy metabolism, promoting inflammation, microbiome are still barely by drugs. Nevertheless, precision medicine, which disease characteristics, becoming increasingly important treatment. Graphical

Язык: Английский

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Efficacy and Safety of Low-Dose Lenvatinib and Toripalimab in Patients With Recurrent Platinum-Resistant Ovarian Cancer: Study Protocol of a Multicenter, Open-Label, Single-Arm, Phase II Clinical Trial

International Journal of Women s Health, Год журнала: 2025, Номер Volume 17, С. 325 - 333

Опубликована: Фев. 1, 2025

Purpose: Therapeutic options for patients with platinum-resistant ovarian cancer (PROC) remain a major unmet need. PROC multiple recurrences are unable to continue highly toxic treatment after prior lines of systemic therapy. Chemotherapy-free option lenvatinib plus anti-programmed cell death protein-1 (PD-1) combination therapy has shown promising results in several malignancies including cancer, but the toxicity high starting dose is also notable and needs be improved. Our previous pilot study indicated that reduced may maintain comparable anti-tumor activity favorable safety heavily pre-treated cancer. This designed further validate efficacy low-dose PD-1 inhibitor toripalimab recurrent PROC. Study Design Methods: The as multicenter, open-label, single-arm, prospective phase II study. Patients epithelial who have disease progression either during or within 6 months completion platinum-based will included. A total 69 participants receive (8 mg 12 mg, daily, orally, based on patient's body weight) (240 every 21 days, intravenously). Treatment until development unacceptable progression. primary endpoint progression-free survival. secondary endpoints include objective response rate, duration response, control overall survival, patients' quality life. Exploratory objectives aim identify biomarkers molecular signatures predicting prognosis. Keywords: platinum-resistant, immune checkpoint inhibitor, lenvatinib, adjustment

Язык: Английский

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Cyclin E1 overexpression sensitizes ovarian cancer cells to WEE1 and PLK1 inhibition

Oncogene, Год журнала: 2025, Номер unknown

Опубликована: Фев. 24, 2025

Abstract Cyclin E1 (CCNE1) amplification is associated with poor prognosis of ovarian carcinomas across histological subtypes. Inhibitors targeting PLK1 or WEE1 are emerging as promising therapeutic agents for cancer treatment that disrupt the critical G2/M checkpoint, leading to cell death. However, biomarkers predict response these inhibitors not well defined. Here, we evaluated efficacy inhibitor, volasertib, and adavosertib, along biomarker potential cyclin in cells. Both suppressed proliferation E1-overexpressing cells a greater extent than exhibiting low expression. TP53 silencing did increase sensitivity inhibitors. In cells, inhibition reduced proportion G1 phase increased those sub-G1 phases. without clear peak S-G2/M growth tumors vivo. Taken together, overexpression, regardless status, may serve predictive inhibitors, offering personalized strategies cancer.

Язык: Английский

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Efficacy and Safety of Combination Therapy with PARP Inhibitors and Anti-Angiogenic Agents in Ovarian Cancer: A Systematic Review and Meta-Analysis

Journal of Clinical Medicine, Год журнала: 2025, Номер 14(5), С. 1776 - 1776

Опубликована: Март 6, 2025

Introduction: Ovarian cancer is a significant contributor to gynecological cancer-related mortality, necessitating innovative treatment strategies. This systematic review and meta-analysis aimed assess the efficacy safety of combining PARP inhibitors with anti-angiogenic agents (AAAs) in ovarian cancer. Methods: study adhered Preferred Reporting Items for Systematic Reviews Meta-Analysis (PRISMA) guidelines was registered on PROSPERO (CRD42022319461). A search three electronic databases, including MEDLINE (via PubMed), EMBASE, Cochrane Library conducted identify relevant randomized controlled trials (RCT) that evaluated combination therapy. Subgroup analyses were based BRCA mutation status. Meta-analysis estimate pooled hazard ratios (HR) risk (RR) progression-free survival (PFS) adverse events, respectively. The therapy compared alone chemotherapy. Heterogeneity assessed using Higgins Thompson's I2 statistic where applicable. Results: Seven RCTs involving 2397 patients included. Combination did not show statistically improvement PFS inhibitor monotherapy general population (HR 0.63, CI 0.37-1.06), or BRCA-mutated 0.70, 0.30-1.63) wild-type subgroups 0.39, 0.14-1.07). When chemotherapy, produced no benefit recurrent 0.83, 0.42-1.63) total population. Safety analysis revealed hypertension diarrhea significantly more frequent (RR 6.80, 2.87-16.06 RR 10.04, 2.25-44.75) chemotherapy 13.80, 3.43-55.57 6.57, 2.84-15.24). Conclusions: AAAs demonstrate While generally well tolerated, occurred significantly. These findings suggest may provide clear advantage setting. Further high-quality, biomarker-driven clinical are needed refine patient selection, optimize toxicity management, determine potential role treatment.

Язык: Английский

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Ovarian cancer: Advances in clinical research

Elsevier eBooks, Год журнала: 2025, Номер unknown, С. 221 - 250

Опубликована: Янв. 1, 2025

Язык: Английский

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Overexpression of ABCC1 and ABCG2 confers resistance to talazoparib, a poly (ADP-Ribose) polymerase inhibitor

Drug Resistance Updates, Год журнала: 2023, Номер 73, С. 101028 - 101028

Опубликована: Ноя. 29, 2023

Язык: Английский

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