Treatment Of Ovarian Cancer Patients Research Articles

Prediction of response to promising first-line chemotherapy in ovarian cancer patients with residual peritoneal tumors: practical biomarkers and robust multiplex models.

Platinum/taxane (TC) chemotherapy with debulking surgery stays the mainstay of the treatment in ovarian cancer patients with peritoneal metastasis, and recently its novel modality, intraperitoneal carboplatin with dose-dense paclitaxel (ddTCip), was shown to have greater therapeutic impact. Nevertheless, the response varies among patients and consequent recurrence, or relapse often occurs. Discovery of therapeutic response predictor to ddTCip and/or TC therapy is eagerly awaited to improve the treatment outcome. Using datasets in 76 participants in our ddTCip study and published databases on patients received TC therapy, we first validated a total of 75 previously suggested markers, sought out more active biomarkers through the association analyses of genome-wide transcriptome and genotyping data with progression-free survival (PFS) and adverse events, and then developed multiplex statistical prediction models for PFS and toxicity by mainly using multiple regression analysis and the classification and regression tree (CART) algorithm. The association analyses revealed that SPINK1 could be a possible biomarker of ddTCip efficacy, while ABCB1 rs1045642 and ERCC1 rs11615 would be a predictor of hematologic toxicity and peripheral neuropathy, respectively. Multiple regression analyses and CART algorithm finally provided a potent efficacy prediction model using 5 gene expression data and robust multiplex toxicity prediction models-CART models using a total of 4 genotype combinations and multiple regression models using 15 polymorphisms on 12 genes. Biomarkers and multiplex models composed here could work well in the response prediction of ddTCip and/or TC therapy, which might contribute to realize optimal selection of the key therapy.

Immune-related gene methylation prognostic instrument for stratification and targeted treatment of ovarian cancer patients toward advanced 3PM approach

Immune-related gene methylation prognostic instrument for stratification and targeted treatment of ovarian cancer patients toward advanced 3PM approach

Research progress in endometriosis-associated ovarian cancer.

Endometriosis-associated ovarian cancer (EAOC) is a unique subtype of ovarian malignant tumor originating from endometriosis (EMS) malignant transformation, which has gradually become one of the hot topics in clinical and basic research in recent years. According to clinicopathological and epidemiological findings, precancerous lesions of ovarian clear cell carcinoma (OCCC) and ovarian endometrioid carcinoma (OEC) are considered as EMS. Given the large number of patients with endometriosis and its long time window for malignant transformation, sufficient attention should be paid to EAOC. At present, the pathogenesis of EAOC has not been clarified, no reliable biomarkers have been found in the diagnosis, and there is still a lack of basis and targets for stratified management and precise treatment in the treatment. At the same time, due to the long medical history of patients, the fast growth rate of cancer cells, and the possibility of eliminating the earliest endometriosis-associated ovarian cancer, it is difficult to find the corresponding histological evidence. As a result, few patients are finally diagnosed with EAOC, which increases the difficulty of in-depth study of EAOC. This article reviews the epidemiology, pathogenesis, risk factors, clinical diagnosis, new treatment strategies and prognosis of endometriosis-associated ovarian cancer, and prospects the future direction of basic research and clinical transformation, in order to achieve stratified management and personalized treatment of ovarian cancer patients.

Ovarian cancer management in an ESGO ovarian cancer center of excellence: a systematic case study of the interprofessional and interdisciplinary interaction.

With growing knowledge about ovarian cancer over the last decades, diagnosis, evaluation and treatment of ovarian cancer patients have become highly specialized, and an individually adapted approach should be made in each woman by interdisciplinary cooperation. The present study aims to show the variety and extent of medical specialties involved at our institution according to the European Society of Gynecologic Oncology (ESGO) Quality indicators (QI). A woman, diagnosed with high-grade ovarian cancer, International Federation of Gynecology and Obstetrics (FIGO) class IVb was selected for a single case observational study. The observation period (total=22d) comprised preoperative diagnostic procedures, including imaging, the in-patient stay for cytoreductive surgery, and the postoperative course and case discussion at our interdisciplinary tumor board. Data were obtained by self-reporting and by patient file review. Patient tracking demonstrated an interdisciplinary cooperation of 12 medical specialties [62 physicians (63% male, 37% female)], 8 different types of nursing staff [n=59 (22% male, 78% female)], and 9 different types of perioperative/administrative staff (n=23; male 17,4%, female n=19, 82,6%). Contact with the patient was direct (n=199; 76%) or without face-to-face interaction (n=63; 24%). The present study demonstrates the high diversity of physicians and the affiliated medical staff, as well as interdisciplinary intersections within teams of a specialized hospital. Matching the ESGO QIs, this report underlines the requirement of an adequate infrastructure for the complex management of advanced ovarian cancer patients. Future prospective studies are warranted to evaluate the specific procedures and actions to optimize the interprofessional and interdisciplinary workflows.

Implementing MyChoice® CDx HRD testing for the Nordics: lessons from 2021 to 2023.

Assessment of homologous recombinant deficient (HRD) phenotypes is key for managing Poly (ADP-ribose) polymerase inhibitor (PARPi) treatment. To accommodate the need for a validated HRD platform and enhance targeted treatment of ovarian cancer patients, a Nordic core facility for the myChoice® CDx platform was established in Denmark. Comparative calculations and statistics are based on information from test requisitions and results (Genome Instability Score [GIS], BRCA status and combined HRD status) obtained from ovarian and breast cancer samples submitted for HRD-testing by myChoice® CDx through the Nordic core facility in the 2-year period. Copenhagen University Hospital received 1,948 requisitions during the 2-year period. Conclusive results were obtained in 89% of the tests, while 7% were inconclusive due to the lack of GIS and 4% were not able to be analysed. Comparing the conclusive HRD status results across countries, Sweden had the highest percentage of HRD positives (38%) compared to Denmark, Norway, and Finland (28-32%). The myChoice® CDx Nordic core facility has been well received among the Nordic countries and provides new insights on the influence of national guidelines on HRD testing. Overall, we experienced an efficient turnaround time and a high fraction of conclusive results. Interestingly, prior somatic BRCA testing is redundant when assessing HRD status through myChoice® CDx test since somatic BRCA screening is already a significant component of the myChoice® CDx test. Thus, it should be considered to omit prior somatic BRCA testing to ensure a rationalised HRD diagnostic flow optimised for clinical use.

Dual-inhibition of NAMPT and PAK4 induces anti-tumor effects in 3D-spheroids model of platinum-resistant ovarian cancer

Ovarian cancer follows a characteristic progression pattern, forming multiple tumor masses enriched with cancer stem cells (CSCs) within the abdomen. Most patients develop resistance to standard platinum-based drugs, necessitating better treatment approaches. Targeting CSCs by inhibiting NAD+ synthesis has been previously explored. Nicotinamide phosphoribosyltransferase (NAMPT), which is the rate limiting enzyme in the salvage pathway for NAD+ synthesis is an attractive drug target in this pathway. KPT-9274 is an innovative drug targeting both NAMPT and p21 activated kinase 4 (PAK4). However, its effectiveness against ovarian cancer has not been validated. Here, we show the efficacy and mechanisms of KPT-9274 in treating 3D-cultured spheroids that are resistant to platinum-based drugs. In these spheroids, KPT-9274 not only inhibited NAD+ production in NAMPT-dependent cell lines, but also suppressed NADPH and ATP production, indicating reduced mitochondrial function. It also downregulated of inflammation and DNA repair-related genes. Moreover, the compound reduced PAK4 activity by altering its mostly cytoplasmic localization, leading to NAD+-dependent decreases in phosphorylation of S6 Ribosomal protein, AKT, and β-Catenin in the cytoplasm. These findings suggest that KPT-9274 could be a promising treatment for ovarian cancer patients who are resistant to platinum drugs, emphasizing the need for precision medicine to identify the specific NAD+ producing pathway that a tumor relies upon before treatment.

Signatures of tumor-associated macrophages correlate with treatment response in ovarian cancer patients.

Ovarian cancer (OC) ranks as the second leading cause of death among gynecological cancers. Numerous studies have indicated a correlation between the tumor microenvironment (TME) and the clinical response to treatment in OC patients. Tumor-associated macrophages (TAMs), a crucial component of the TME, exert influence on invasion, metastasis, and recurrence in OC patients. To delve deeper into the role of TAMs in OC, this study conducted an extensive analysis of single-cell data from OC patients. The aim is to develop a new risk score (RS) to characterize the response to treatment in OC patients to inform clinical treatment. We first identified TAM-associated genes (TAMGs) in OC patients and examined the protein and mRNA expression levels of TAMGs by Western blot and PCR experiments. Additionally, a scoring system for TAMGs was constructed, successfully categorizing patients into high and low RS subgroups. Remarkably, significant disparities were observed in immune cell infiltration and immunotherapy response between the high and low RS subgroups. The findings revealed that patients in the high RS group had a poorer prognosis but displayed greater sensitivity to immunotherapy. Another important finding was that patients in the high RS subgroup had a higher IC50 for chemotherapeutic agents. Furthermore, further experimental investigations led to the discovery that THEMIS2 could serve as a potential target in OC patients and is associated with EMT (epithelial-mesenchymal transition). Overall, the TAMGs-based scoring system holds promise for screening patients who would benefit from therapy and provides valuable information for the clinical treatment of OC.

Effect of bevacizumab in combination with chemotherapy for ovarian cancer on wound healing in patients: Ameta-analysis.

In this meta-analysis, we reviewed the findings and definitive findings of a new study that assessed the impact of bevacizumab on wound healing following combined chemotherapy for ovarian cancer (OC). The results of a controlled study that assessed the efficacy of bevacizumab in the treatment of ovarian cancer were retrieved from 4 databases, such as the Web of Science and EMBASE. The results of the adverse event associated with wound healing were determined by comparison of the controlled studies of bevacizumab plus chemotherapy in the treatment of ovarian cancer. A meta-analysis was conducted with either a randomized or a fixed-effect model in order to establish an odds ratio for time to event variables and for a binary outcome. In the research literature, 830 trials have been identified and seven have been chosen to be included in a definitive analysis of the trial. Among the 4134 cases who received chemotherapy after operation, 2098 received standard chemotherapy and 2036 received the addition of bevacizumab. A total of 7 trials have shown that the use of bevacizumab in the treatment of ovarian cancer patients has reduced wound healing (OR, 0.55; 95% CI: 0.37, 0.80, p = 0.002). Four trials demonstrated that there was no change in the incidence of haemorrhage in patients with ovarian cancer when administered with or without bevacizumab (OR, 0.48; 95% CI, 0.10, 2.34, p = 0.37). The combined use of bevacizumab and chemotherapy may have a negative effect on the healing of wound.

Activation of PI3K/AKT/mTOR signaling axis by UBE2S inhibits autophagy leading to cisplatin resistance in ovarian cancer

BackgroundEpithelial ovarian cancer (OC) is the fourth leading cause of cancer-related deaths in women, with a 5-year survival rate of 30%-50%. Platinum resistance is the chief culprit for the high recurrence and mortality rates. Several studies confirm that the metabolic regulation of ubiquitinating enzymes plays a vital role in platinum resistance in OC.MethodsIn this study, we selected ubiquitin-conjugating enzyme E2S (UBE2S) as the candidate gene for validation. The levels of UBE2S expression were investigated using TCGA, GTEx, UALCAN, and HPA databases. In addition, the correlation between UBE2S and platinum resistance in OC was analyzed using data from TCGA. Cisplatin-resistant OC cell lines were generated and UBE2S was knocked down; the transfection efficiency was verified. Subsequently, the effects of knockdown of UBE2S on the proliferation and migration of cisplatin-resistant OC cells were examined through the CCK8, Ki-67 immunofluorescence, clone formation, wound healing, and transwell assays. In addition, the UBE2S gene was also validated in vivo by xenograft models in nude mice. Finally, the relationship between the UBE2S gene and autophagy and the possible underlying regulatory mechanism was preliminarily investigated through MDC and GFP-LC3-B autophagy detection and western blotting experiments. Most importantly, experimental validation of mTOR agonist reversion (the rescuse experiments) was also performed.ResultsUBE2S was highly expressed in OC at both nucleic acid and protein levels. The results of immunohistochemistry showed that the level of UBE2S expression in platinum-resistant samples was significantly higher relative to the platinum-sensitive samples. By cell transfection experiments, knocking down of the UBE2S gene was found to inhibit the proliferation and migration of cisplatin-resistant OC cells. Moreover, the UBE2S gene could inhibit autophagy by activating the PI3K/AKT/mTOR signaling pathway to induce cisplatin resistance in OC in vivo and in vitro.ConclusionIn conclusion, we discovered a novel oncogene, UBE2S, which was associated with platinum response in OC, and examined its key role through bioinformatics and preliminary experiments. The findings may open up a new avenue for the evaluation and treatment of OC patients at high risk of cisplatin resistance.

CAR-T cell immunotherapy for ovarian cancer: hushing the silent killer.

As the most lethal gynecologic oncological indication, carcinoma of the ovary has been ranked as the 5th cause of cancer-related mortality in women, with a high percentage of the patients being diagnosed at late stages of the disease and a five-year survival of ~ 30%. Ovarian cancer patients conventionally undergo surgery for tumor removal followed by platinum- or taxane-based chemotherapy; however, a high percentage of patients experience tumor relapse. Cancer immunotherapy has been regarded as a silver lining in the treatment of patients with various immunological or oncological indications; however, mirvetuximab soravtansine (a folate receptor α-specific mAb) and bevacizumab (a VEGF-A-specific mAb) are the only immunotherapeutics approved for the treatment of ovarian cancer patients. Chimeric antigen receptor T-cell (CAR-T) therapy has achieved tremendous clinical success in the treatment of patients with certain B-cell lymphomas and leukemias, as well as multiple myeloma. In the context of solid tumors, CAR-T therapies face serious obstacles that limit their therapeutic benefit. Such hindrances include the immunosuppressive nature of solid tumors, impaired tumor infiltration, lack of qualified tumor-associated antigens, and compromised stimulation and persistence of CAR-Ts following administration. Over the past years, researchers have made arduous attempts to apply CAR-T therapy to ovarian cancer. In this review, we outline the principles of CAR-T therapy and then highlight its limitations in the context of solid tumors. Ultimately, we focus on preclinical and clinical findings achieved in CAR-T-mediated targeting of different ovarian cancer-associated target antigens.

CT-based radiomics prediction of CXCL13 expression in ovarian cancer.

Ovarian cancer, the most common malignancy in the female reproductive system, and patients tend to be at middle and advanced clinical stages when diagnosed. Therefore, early detection and early diagnosis have important clinical significance for the treatment of ovarian cancer patients. CXCL13, a chemokine with the ligands CXCR3 and CXCR5, is involved in the tumor metastasis process. This study aimed to predict mRNA expression of CXCL13 in ovarian cancer tissues noninvasively. Medical imaging data and transcriptomic sequencing data of the 343 ovarian cancer patients were downloaded from the TCIA and TCGA databases, respectively. Seventy-six radiomics features were extracted from the CT data. Seven features were selected for model construction by using logistic regression. Accuracy, specificity, sensitivity, positive predictive value, and negative predictive value were used to evaluate the radiomics model. High CXCL13 expression was found to be a significant protective factor for OS [HR (95% CI)=0.755 (0.622-0.916), p=0.004]. There was a significant positive correlation between CXCL13 and the degree of eosinophil infiltration. A calibration curve and the Hosmer-Lemeshow goodness-of-fit test showed that the prediction probability of the radiomics prediction model for high expression of CXCL13 was consistent with the true value. The AUC value of the nomogram model's ability to predict OS (12 months) was 0.758. The calibration plot and DCA both showed high clinical applicability for the nomogram model. CXCL13 is a candidate predictive biomarker for OC and correlates with the degree of plasma cell and eosinophil infiltration.

Metastatic pattern of ovarian cancer delineated by tracing the evolution of mitochondrial DNA mutations

Ovarian cancer (OC) is the most lethal gynecologic tumor and is characterized by a high rate of metastasis. Challenges in accurately delineating the metastatic pattern have greatly restricted the improvement of treatment in OC patients. An increasing number of studies have leveraged mitochondrial DNA (mtDNA) mutations as efficient lineage-tracing markers of tumor clonality. We applied multiregional sampling and high-depth mtDNA sequencing to determine the metastatic patterns in advanced-stage OC patients. Somatic mtDNA mutations were profiled from a total of 195 primary and 200 metastatic tumor tissue samples from 35 OC patients. Our results revealed remarkable sample-level and patient-level heterogeneity. In addition, distinct mtDNA mutational patterns were observed between primary and metastatic OC tissues. Further analysis identified the different mutational spectra between shared and private mutations among primary and metastatic OC tissues. Analysis of the clonality index calculated based on mtDNA mutations supported a monoclonal tumor origin in 14 of 16 patients with bilateral ovarian cancers. Notably, mtDNA-based spatial phylogenetic analysis revealed distinct patterns of OC metastasis, in which a linear metastatic pattern exhibited a low degree of mtDNA mutation heterogeneity and a short evolutionary distance, whereas a parallel metastatic pattern showed the opposite trend. Moreover, a mtDNA-based tumor evolutionary score (MTEs) related to different metastatic patterns was defined. Our data showed that patients with different MTESs responded differently to combined debulking surgery and chemotherapy. Finally, we observed that tumor-derived mtDNA mutations were more likely to be detected in ascitic fluid than in plasma samples. Our study presents an explicit view of the OC metastatic pattern, which sheds light on efficient treatment for OC patients.

Prevalence of Homologous Recombination Deficiency in First-Line PARP Inhibitor Maintenance Clinical Trials and Further Implication of Personalized Treatment in Ovarian Cancer.

Among ovarian cancer patients with BRCA mutation or homologous recombination deficiency (HRD), the efficacy of Poly-ADP-ribose polymerase (PARP) inhibitors such as olaparib, niraparib, veliparib, and rucaparib has been proven in a number of clinical trials. BRCA mutation and HRD are currently indicated for PARP inhibitor maintenance treatment in ovarian cancer. HRD diagnostic tests examine various components, resulting in different HRD status definitions and, as a result, different treatment decisions. A number of HRD diagnostic tests exist, but test results provided by different companies may differ as they use different methods and different cutoffs. HRD prevalence difference was shown between PARP inhibitor maintenance trials. It is important to select an appropriate method that can present accurate HRD phenotypes to predict sensitivity to PARP inhibitors so that patients who are most likely to benefit from treatment are selected. Additionally, in the subset data of the PARP inhibitor maintenance trials, there was a difference in HRD prevalence by race as higher HRD prevalence in Japanese and Chinese ovarian cancer patients was shown. Further large-scale investigations on racial differences in HRD prevalence are needed and this may contribute to changes in determining the treatment plan and personalized treatment in ovarian cancer patients.

A biscarbene gold(I)-NHC-complex overcomes cisplatin-resistance in A2780 and W1 ovarian cancer cells highlighting pERK as regulator of apoptosis

PurposeCisplatin resistance is the major obstacle in the clinical treatment of ovarian cancer patients. Molecular mechanisms of cisplatin resistance are multifaceted. Gold(I)-compounds, i.e. N-heterocyclic carbene-gold(I)-complexes (NHC-Au(I)) has been regarded as promising cytotoxic drug candidates. However, their potential to overcome cisplatin resistance has hardly been addressed yet. Here we investigated the activity of the gold(I) drug auranofin and the NHC-Au(I)-compound MC3 in W1CR and A2780cis cisplatin-resistant ovarian cancer cells.MethodsCytotoxicity of auranofin and MC3 was detected by MTT assay, correlated with intracellular gold(I) content, analyzed by AAS, and with flow cytometric detection of the cell cycle. Insight into cellular redox balance was provided by fluorimetric ROS-formation assay and western blotting thioredoxin (Trx) and Nrf2. The role of ERK was elucidated by using the inhibitor SCH772984 and its impact on cytotoxicity upon co-treatment with cisplatin and Au(I)-compounds, respectively.ResultsMC3 overcomes cisplatin resistance in A2780cis and W1CR, and auranofin in W1CR cells completely, which is neither reflected by intracellular gold levels nor cell cycle changes. Upregulated redox balance appears as a basis for resistance. W1CR cells possess higher Trx levels, whereas A2780cis cells display strong Nrf2 expression as anti-oxidative protection. Nevertheless, overcoming redox balance appears not primary mode of activity comparing cisplatin and gold(I)-compounds. pERK emerges as a critical component and thus a promising target for overcoming resistance, regulating apoptosis differently in response to either gold(I) or cisplatin in A2780 cells.ConclusionThese data reflect the complexity of cisplatin resistance in cell models and emphasize NHC-Au(I)-complexes as prospective cytotoxic agents for further investigations in that respect.

High expression of RARG accelerates ovarian cancer progression by regulating cell proliferation.

To explore the relationship between retinoic acid receptor gamma (RARG) and ovarian cancer (OC) cell proliferation and the prognosis of patients. The transcriptome and clinical information of 379 OC and 88 normal ovarian samples were downloaded from the Cancer Genome Atlas (TCGA) database and the Genotype Tissue Expression (GTEx) database. We compared the mRNA level of RARG between ovrian normal and tumor tissues with the Wilcoxon rank sum test.The R package "limma" was used to analyze the differences in RARG expression between different clinical subgroups. Kaplan-Meier analysis was applied to evaluate the correlation between RARG and prognosis of patients. A nomogram was established to predict the effect of RARG on prognosis of OC patients. Immunohistochemistry and qRT-PCR experiments were conducted to determine the differential expression of RARG between ovarian normal and tumor tissues. Finally, we altered RARG expression using specific siRNA and lentiviral expression vectors to explore the function of RARG by CCK-8, cell cycle, colony formation, and xenograft assays in nude mice. RARG was highly expressed in ovarian tumors and was an independent predictor of poor overall survival outcomes. Subgroup analysis showed the high expression of RARG was related to FIGO stage III-IV (P=0.027), overall survival time <5 years (P=0.013) and dead status (P=0.041). The Kaplan-Meier curve indicated that patients with high RARG expression level had poor prognosis. The area under the curve (AUC) of RAGR expression for predicting patient survival rates at 1, 5 and 9 years were 0.659, 0.616 and 0.627, respectively. The GSEA enrichment analysis revealed that RARG was involved in ovarian cancer progression through multiple pathways. In cellular experiments in vitro, downregulation of RARG expression significantly suppressed the proliferation and colony formation capacity of OC cells. In cellular experiments in vivo, knockdown of RARG significantly reduced tumor growth in nude mice, decreased expression levels of Ki-67 and proliferation cell nuclear antigen (PCNA). High expression of RARG could promote OC cell proliferation and was an independent predictor of poor prognosis. RARG might work as a potential molecular target and biomarker for individualized diagnosis and treatment in OC patients.

190P Real-world applications of poly (ADP-ribose) polymerase inhibitors for ovarian cancer: A single-center study in China

Olaparib and niraparib have been approved for first/second-line maintenance treatment of ovarian cancer patients in China for more than 3 years. In this study, we analyzed the clinical application characteristics of PARPi in the maintenance therapy of ovarian cancer in real world to promote their rational application.

An Acid Response IR780-Based Targeted Nanoparticle for Intraoperative Near-Infrared Fluorescence Imaging of Ovarian Cancer

IntroductionComplete resection of all visible disease (R0 resection) is critical for the treatment of ovarian cancer patients, and accurate real-time guidance provided by intraoperative near-infrared (NIR) fluorescence images is beneficial for achieving complete resection of all visible disease.MethodsBased on the optical properties of IR780 and the characteristics of the acidic tumor microenvironment, we develop a new smart nanoparticle (eg, FA-IR780&PFOB-SNPs) by using the pH response nano framework (FA-PEG-PLGA-PEOz) and adjusting the amount of IR780. The FA-IR780&PFOB-SNPs was characterized for morphology, microstructure, particle size, pH-response, drug-loading efficiency and biological safety. The ultraclear fluorescence Navigation Endoscopy System was applied to evaluate the tumor recognition of FA-IR780&PFOB-SNPs in vivo.ResultsThe structure of FA-IR780&PFOB-SNPs was stable in a neutral environment, and the near-infrared (NIR) fluorescence was turned off, while the structure of FA-IR780&PFOB-SNPs was degraded in the acidic tumour microenvironment, and the NIR fluorescence was turned on. Through the ovarian subcutaneous xenograft tumour and ovarian intraperitoneal xenograft tumour models, it was confirmed that FA-IR780&PFOB-SNPs could clearly display the boundaries of abdominal micron-sized tumours through near-infrared fluorescence imaging, with a TBR greater than 5.ConclusionThe FA-IR780&PFOB-SNPs have the potential to provide to ovarian cancer intraoperative near infrared fluorescence navigation during precision tumour resection to achieve R0 and improve the prognosis of ovarian cancer patients.

Characteristics of homologous recombination repair pathway genes mutation in ovarian cancers

AbstractBackgroundFew studies have investigated the characteristics of non‐BRCA homologous recombination repair (HRR) pathway somatic mutations, and the impact of these mutations on efficacy of treatment in ovarian cancer patients is not clear. Therefore, we conducted this study to analyze the frequency and spectrum of somatic mutations in HRR pathway genes in patients with ovarian cancer and to examine the relationships between somatic mutations in HRR pathway genes and their effects on the efficacy of platinum‐based chemotherapy.MethodsWe performed targeted sequencing of 688 genes related to the occurrence, development, treatment, and prognosis of solid tumors. Somatic mutations were identified by paired analysis of tumor tissue and germline DNA in blood cells.ResultsA total of 38 patients with ovarian cancer were included in the study, and 35 (92.1%) patients were diagnosed with high‐grade serous carcinoma. All patients exhibited somatic mutations in the tumor tissue samples. The commonly mutated genes were TP53 (73.7%), BRCA2 (55.3%), NF1 (52.6%), BRCA1 (47.4%), and CDH1 (47.4%). Overall, 71.1% of the patients exhibited mutation in at least one HRR pathway gene. The most frequently altered HRR genes were BRCA2 (55.3%), followed by BRCA1 (47.4%), ATM (44.7%), BARD1 (42.1%), and CHEK1 (36.8%). The median progression‐free survival (PFS) in patients with HRR pathway mutation was 36.0 months compared with 13.6 months in patients with no HRR pathway mutation (hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.08–0.77; p = 0.016). Patients harboring BRCA1/2 and/or CDK12 mutations displayed a longer PFS (median, 36.0 months) compared with patients with no BRCA1/2 or CDK12 mutation (median, 13.6 months; HR, 0.21; 95% CI, 0.07–0.61; p = 0.004). In multivariate analysis Cox proportional hazards models, after adjustment for tumor stage at diagnosis and histology of initial diagnosis, patients with HRR pathway mutation had a longer PFS than patients with HRR wild‐type genes (p = 0.006).ConclusionsHRR pathway somatic mutations are common in Chinese patients with ovarian cancer. HRR pathway somatic mutations were associated with improved sensitivity to platinum‐based chemotherapy. Large‐scale prospective studies are needed to verify our findings.

Identification Of key prognostic genes in ovarian cancer using WGCNA and LASSO analysis

Ovarian cancer (OC) is the fifth leading cause of death in females. This study aims to identify new prognostic genes of OC through bioinformatics analysis. Based on two datasets from the NCBI GEO public database, we constructed two WGCNA networks. We then selected and intersected two key modules and 177 key genes were identified. The GO, KEGG and PPI network were determined based on the screened genes. According to the LASSO analysis and KM plotter, three hub genes were associated with the overall survival. GEPIA and IHC staining showed that CCDC80 expression level was lower while FBXO16 expression level was higher in OC tissues than in normal ovarian tissues. The relationship between hub genes and clinical characteristics was evaluated and the prognostic significance was validated in 60 clinical patients with OC. CIBERSORT shows that both CCDC80 and FBXO16 were significantly correlated with the immune cell content. Drug sensitivity analysis shows that CCDC80 affected the IC50 value of Gefitinib, and FBXO16 affected the IC50 value of Cisplatin and Docetaxel. CCDC80 and FBXO16 were identified as two robust prognostic factors in OC that could be explored further with respect to the diagnosis and treatment of OC patients.

Specificity of Binding and Antitumor Efficacy of a Covalent Microtubule Stabilizer

Microtubule stabilizers, including the taxanes paclitaxel and docetaxel, are a mainstay in the treatment of solid tumors, including breast and ovarian cancers. Although these agents are often effective as first‐line therapy, they are susceptible to common drug resistance mechanisms, including the upregulation of drug efflux pumps. Therefore, there is a critical need to develop novel classes of microtubule targeted agents that retain activity in taxane‐resistant settings. The C22,23‐epoxy taccalonolides are a class of plant‐derived microtubule stabilizers that covalently and irreversibly bind microtubules, allowing them to retain efficacy in a variety of taxane‐resistant cancer models. We employed cellular‐based binding studies to fully map the taccalonolide pharmacophore and confirm the target specificity of this covalent compound. The identification of β‐tubulin residues that are critical for taccalonolide binding in a cellular context has provided the opportunity to generate functional taccalonolide mimetics through a synthetically tractable approach.Herein, we demonstrate that taccalonolide AF is less susceptible to p‐glycoprotein‐mediated drug efflux than paclitaxel in two separate ovarian cancer models and that it has superior cellular persistence after drug washout, likely due to irreversible target engagement. While taccalonolide AF demonstrated potent and persistent in vivo antitumor efficacy against the taxane‐resistant NCI/ADR‐RES ovarian cancer model as a flank xenograft when administered systemically, it was associated with a narrow therapeutic window. Additional studies showing that intratumoral injection of the taccalonolides into flank tumors provided long‐term antitumor efficacy months after the final dose prompted a study of their utility in the targeted delivery to a disseminated orthotopic ovarian cancer model representing localized metastasis. Indeed, we found that taccalonolide‐treated animals showed a significant decrease in micrometastasis of taxane‐resistant ovarian cancer cells to the spleen, as detected by quantitative RT‐PCR, without any evidence of systemic toxicity. We propose that the irreversible mechanism of microtubule stabilization elicited by the taccalonolides has the unique potential for intraperitoneal treatment of locally disseminated taxane‐resistant disease, which represents a significant unmet clinical need in the treatment of ovarian cancer patients.