Kun Song

Spliceosomal GTPase EFTUD2 mediates DDX41 intron retention to promote the malignant progression of ovarian cancer

Dysregulation of alternative splicing (AS) has been identified as a promising target for cancer therapy. Nevertheless, the precise molecular mechanisms by which AS influences ovarian cancer (OC) progression have not yet been fully elucidated. A comprehensive bioinformatics analysis was conducted to identify and screen core splicing factors in OC. The splicing factor EFTUD2 was found to be significantly overexpressed in clinical OC samples. Subsequent in vitro and in vivo assays elucidated the oncogenic role of EFTUD2 in OC. RNA-seq and AS events analysis were employed to determine the key downstream target regulated by EFTUD2. ASOs targeting EFTUD2 were developed for efficacy validation. EFTUD2 was identified as a critical splicing factor in the pathogenesis of OC, and EFTUD2 knockdown impeded OC tumorigenesis and progression. The EFTUD2-ASO significantly inhibited tumor growth in vivo. Mechanistically, EFTUD2 was shown to promote the malignant biological behavior of OC by facilitating the efficient splicing of DDX41 and maintaining the oncogenic expression of its functional proteins. Knockdown of DDX41 partially mitigated the EFTUD2-induced malignant progression of OC cells. Our findings suggest that the EFTUD2/DDX41 axis is a viable target for OC. ASO-mediated silencing of EFTUD2 presents promising new therapeutic options for OC patients.

STING inhibitors sensitize platinum chemotherapy in ovarian cancer by inhibiting the CGAS-STING pathway in cancer-associated fibroblasts (CAFs)

Chemotherapy resistance in ovarian cancer hampers cure rates, with cancer-associated fibroblasts (CAFs) playing a pivotal role. Despite their known impact on cancer progression and chemotherapy resistance, the specific mechanism by which CAFs regulate the tumor inflammatory environment remains unclear. This study reveals that cisplatin facilitates DNA transfer from ovarian cancer cells to CAFs, activating the CGAS-STING-IFNB1 pathway in CAFs and promoting IFNB1 release. Consequently, this reinforces cancer cell resistance to platinum drugs. High STING expression in the tumor stroma was associated with a poor prognosis, while inhibiting STING expression enhanced ovarian cancer sensitivity. Understanding the relevance of the CGAS-STING pathway in CAFs for platinum resistance suggests targeting STING as a promising combination therapy for ovarian cancer, providing potential avenues for improved treatment outcomes.

The splicing factor WBP11 mediates MCM7 intron retention to promote the malignant progression of ovarian cancer

Accumulating studies suggest that splicing factors play important roles in many diseases including human cancers. Our study revealed that WBP11, a core splicing factor, is highly expressed in ovarian cancer (OC) tissues and associated with a poor prognosis. WBP11 inhibition significantly impaired the proliferation and mobility of ovarian cancer cells in vitro and in vivo. Furthermore, FOXM1 transcriptionally activated WBP11 expression by directly binding to its promoter in OC cells. Importantly, RNA-seq and alternative splicing event analysis revealed that WBP11 silencing decreased the expression of MCM7 by regulating intron 4 retention. MCM7 inhibition attenuated the increase in malignant behaviors of WBP11-overexpressing OC cells. Overall, WBP11 was identified as an oncogenic splicing factor that contributes to malignant progression by repressing intron 4 retention of MCM7 in OC cells. Thus, WBP11 is an oncogenic splicing factor with potential therapeutic and prognostic implications in OC.

Comprehensive multi-omics analysis reveals WEE1 as a synergistic lethal target with hyperthermia through CDK1 super-activation

AbstractHyperthermic intraperitoneal chemotherapy’s role in ovarian cancer remains controversial, hindered by limited understanding of hyperthermia-induced tumor cellular changes. This limits developing potent combinatory strategies anchored in hyperthermic intraperitoneal therapy (HIPET). Here, we perform a comprehensive multi-omics study on ovarian cancer cells under hyperthermia, unveiling a distinct molecular panorama, primarily characterized by rapid protein phosphorylation changes. Based on the phospho-signature, we pinpoint CDK1 kinase is hyperactivated during hyperthermia, influencing the global signaling landscape. We observe dynamic, reversible CDK1 activity, causing replication arrest and early mitotic entry post-hyperthermia. Subsequent drug screening shows WEE1 inhibition synergistically destroys cancer cells with hyperthermia. An in-house developed miniaturized device confirms hyperthermia and WEE1 inhibitor combination significantly reduces tumors in vivo. These findings offer additional insights into HIPET, detailing molecular mechanisms of hyperthermia and identifying precise drug combinations for targeted treatment. This research propels the concept of precise hyperthermic intraperitoneal therapy, highlighting its potential against ovarian cancer.

Fruquintinib plus sintilimab in patients with advanced endometrial cancer with mismatch-repair proficient status: a multicenter, single-arm, phase Ib/II trial

This report presents the primary analysis of the endometrial cancer (EMC) cohort of FRUSICA-1 (ClinicalTrials.gov identifier, NCT03903705), a multicenter, single-arm, phase Ib/II study evaluating fruquintinib plus sintilimab. The cohort included Chinese patients with inoperable or advanced mismatch-repair proficient (pMMR) EMC who had progressed on or could not tolerate up to two prior platinum-based therapies, and comprised exploratory and pivotal phases. Patients received fruquintinib (5 mg orally once daily on a 2 weeks on/1 week off schedule) plus sintilimab (200 mg intravenously once every 3 weeks). The primary endpoint was objective response rate (ORR) assessed by an independent review committee (IRC). Secondary endpoints included ORR as assessed by the investigator, disease control rate, time to response, duration of response, progression-free survival (PFS) and tumor shrinkage as assessed by both the IRC and investigator, overall survival, and safety. By May 15, 2024, 98 patients with pMMR EMC were enrolled and treated. IRC-assessed ORR was 32.7% (95% confidence interval [CI] 23.5-42.9) for the total pMMR population (n = 98) and 31.6% (95% CI 21.4-43.3) for the pivotal population (n = 76). Median PFS was 8.6 months (95% CI 5.5-16.6) for the total population and 7.1 months (95% CI 5.4-16.6) for the pivotal population. The most common grade ≥3 treatment-related adverse event was hypertension (17.3%). In conclusion, fruquintinib plus sintilimab showed promising efficacy and tolerable safety in previously treated, advanced pMMR EMC.

Inhibition of SF3B1 improves the immune microenvironment through pyroptosis and synergizes with αPDL1 in ovarian cancer

AbstractOvarian cancer is resistant to immune checkpoint blockade (ICB) treatment. Combination of targeted therapy and immunotherapy is a promising strategy for ovarian cancer treatment benefit from an improved immune microenvironment. In this study, Clinical Proteomic Tumor Analysis Consortium (CPTAC) and The Cancer Genome Atlas (TCGA) cohorts were used to screen prognosis and cytotoxic lymphocyte infiltration-associated genes in upregulated genes of ovarian cancer, tissue microarrays were built for further verification. In vitro experiments and mouse (C57/BL6) ovarian tumor (ID8) models were built to evaluate the synergistic effect of the combination of SF3B1 inhibitor and PD-L1 antibody in the treatment of ovarian cancer. The results show that SF3B1 is shown to be overexpressed and related to low cytotoxic immune cell infiltration in ovarian cancer. Inhibition of SF3B1 induces pyroptosis in ovarian cancer cells and releases mitochondrial DNA (mtDNA), which is englobed by macrophages and subsequently activates them (polarization to M1). Moreover, pladienolide B increases cytotoxic immune cell infiltration in the ID8 mouse model as a SF3B1 inhibitor and increases the expression of PD-L1 which can enhance the antitumor effect of αPDL1 in ovarian cancer. The data suggests that inhibition of SF3B1 improves the immune microenvironment of ovarian cancer and synergizes ICB immunotherapy, which provides preclinical evidence for the combination of SF3B1 inhibitor and ICB to ovarian cancer treatment.

Global landscape of cervical cancer incidence and mortality in 2022 and predictions to 2030: The urgent need to address inequalities in cervical cancer

AbstractCervical cancer remains a major public health challenge worldwide, despite being largely preventable through effective interventions. Timely evidence regarding the global landscape of cervical cancer is crucial for measuring the magnitude of inequalities and monitoring progress towards cervical cancer elimination. We aimed to provide an updated overview of the global burden of cervical cancer using the GLOBOCAN 2022 database. Age‐standardized rates of incidence and mortality were presented according to countries, 20 United Nations‐defined world regions, and four‐tier Human Development Index (HDI) levels. The predicted burden of cervical cancer for 2030 was calculated based on global demographic projections. Globally, an estimated 662,301 new cervical cancer cases and 348,874 deaths occurred in 2022. Substantial geographic disparities in cervical cancer burden existed across countries and world regions. Low HDI countries exhibited two times higher incidence rates and five times higher mortality rates, compared to very high HDI countries. For women aged 15–44 years, cervical cancer ranked among the top three most frequent cancers in 149 countries, and among the top three causes of cancer deaths in 154 countries. If 2022 rates remain unchanged, the global burden of cervical cancer was predicted to increase to 760,082 new cases (a 14.8% increase) and 411,035 deaths (a 17.8% increase) by 2030. Our findings highlight the persistent and widening geographic and socioeconomic inequalities in the burden of cervical cancer. There is an urgent need for tailored national strategies to address these inequalities and accelerate progress towards the goal of cervical cancer elimination.

A ribosomal gene panel predicting a novel synthetic lethality in non-BRCAness tumors

AbstractPoly (ADP-ribose) polymerase (PARP) inhibitors are one of the most exciting classes of targeted therapy agents for cancers with homologous recombination (HR) deficiency. However, many patients without apparent HR defects also respond well to PARP inhibitors/cisplatin. The biomarker responsible for this mechanism remains unclear. Here, we identified a set of ribosomal genes that predict response to PARP inhibitors/cisplatin in HR-proficient patients. PARP inhibitor/cisplatin selectively eliminates cells with high expression of the eight genes in the identified panel via DNA damage (ATM) signaling-induced pro-apoptotic ribosomal stress, which along with ATM signaling-induced pro-survival HR repair constitutes a new model to balance the cell fate in response to DNA damage. Therefore, the combined examination of the gene panel along with HR status would allow for more precise predictions of clinical response to PARP inhibitor/cisplatin. The gene panel as an independent biomarker was validated by multiple published clinical datasets, as well as by an ovarian cancer organoids library we established. More importantly, its predictive value was further verified in a cohort of PARP inhibitor-treated ovarian cancer patients with both RNA-seq and WGS data. Furthermore, we identified several marketed drugs capable of upregulating the expression of the genes in the panel without causing HR deficiency in PARP inhibitor/cisplatin-resistant cell lines. These drugs enhance PARP inhibitor/cisplatin sensitivity in both intrinsically resistant organoids and cell lines with acquired resistance. Together, our study identifies a marker gene panel for HR-proficient patients and reveals a broader application of PARP inhibitor/cisplatin in cancer therapy.

Fertility and prognosis assessment between bleomycin/etoposide/cisplatin and paclitaxel/carboplatin chemotherapy regimens in the conservative treatment of malignant ovarian germ cell tumors: a multicenter and retrospective study

To evaluate the impact of bleomycin/etoposide/cisplatin (BEP) and paclitaxel/carboplatin (PC) chemotherapy regimens on the fertility and prognostic outcomes in malignant ovarian germ cell tumor (MOGCT) patients who underwent fertility-sparing surgery (FSS). A propensity score matching algorithm was performed between the BEP and PC groups. The χ² test and the Kaplan-Meier method were used to compare the fertility outcome, disease-free survival (DFS) and overall survival (OS). The Cox proportional hazards regression analysis was used to identify risk factor of DFS. We included 213 patients, 185 (86.9%) underwent BEP chemotherapy, and 28 (13.1%) underwent PC chemotherapy. The median age was 22 years (range, 8-44 years), and the median follow-up period was 63 months (range, 2-191 months). Fifty-one (29.3%) patients had a pregnancy plan, and 35 (85.4%) delivered successfully. In the before and after propensity score matching cohorts, there were no significant differences in spontaneous abortion, selective termination of pregnancy, during-pregnancy status, and live birth between the BEP and PC groups (p>0.05). Fourteen (6.6%) patients experienced recurrence, including 11 (5.9%) in the BEP group and 3 (10.7%) in the PC group. Four (1.9%) patients in the BEP group died. Kaplan-Meier analysis revealed no significant differences in DFS (p=0.328) and OS (p=0.446) between the BEP and PC groups, and the same survival results were observed in the after matching cohort. The PC regimen is as safe as the BEP regimen for MOGCT patients with fertility preservation treatment, and no differences were observed in fertility and clinical prognosis.

Analysis of the Safety and Pregnancy Outcomes of Fertility-sparing Surgery in Ovarian Malignant Sex Cord-stromal Tumours: A Multicentre Retrospective Study

To assess the difference in survival between fertility-sparing surgery (FSS) and radical surgery and explore pregnancy outcomes after FSS in stage I malignant sex cord-stromal tumours (MSCSTs). We carried out a multicentre retrospective cohort study on patients who were diagnosed with MSCSTs and the tumour was confined to one ovary. The patients were divided into FSS and radical surgery groups. Inverse probability of treatment weighting (IPTW) was used to balance variables between the two groups. Kaplan-Meier analysis was used to compare the difference in disease-free survival (DFS). Univariate and multivariate Cox regression analysis was used to find risk factors of DFS. Univariate logistic regression analysis was used to assess risk factors of pregnancy. In total, 107 patients were included, of whom 54 (50.5%) women underwent FSS and 53 (49.5%) received radical surgery. After IPTW, a pseudo-population of 208 was determined and all of the covariates were well balanced. After a median follow-up time of 50 months (range 7-156 months), 10 patients experienced recurrence and two died. There was no significant difference in DFS between the two groups, both in unweighted (P = 0.969) or weighted cohorts (P = 0.792). In the weighted cohort, stage IC (P = 0.014), tumour diameter >8 cm (P = 0.003), incomplete staging surgery (P = 0.003) and no adjuvant chemotherapy (P < 0.001) were the four high-risk factors associated with a shorter DFS. Among 14 patients who had pregnancy desire, 11 (78.6%) women conceived successfully; the live birth rate was 76.9%. In univariate analysis, only adjuvant chemotherapy (P = 0.009) was associated with infertility. On the premise of complete staging surgery, FSS is safe and feasible in early stage MSCSTs with satisfactory reproductive outcomes.

Progress in the management of ovarian granulosa cell tumor: A review

AbstractOvarian granulosa cell tumor (GCT) is a rare, low‐grade malignant tumor that accounts for 70% of the sex cord‐stromal tumors. It has two histopathologic types with different clinical and biologic features: adult GCT and juvenile GCT. Most women diagnosed with the adult GCT have a favorable prognosis, with a 5‐year survival rate of 97%–98%, but adult GCT has a feature of late relapse; the recurrence time could be more than 20 years after diagnosis. Juvenile GCT has a survival rate of 97% in stage I and a 5‐year survival rate of 0%–22% in advanced stage with earlier recurrence than adult GCT. Consequently, the scenario emphasizes the need for early diagnosis, standardized treatment protocols, and long‐term follow up. However, there is a lack of consensus regarding accurate diagnosis of GCT and adjuvant treatment. Furthermore, GCT tends to occur in young women, which emphasizes the viability of fertility‐sparing surgery. The current review performed a systematic literature review of 60 articles to summarize the latest advances in GCT, with an emphasis on the molecular pathogenesis and survival after fertility‐sparing surgery. We found that young women with fertility‐sparing surgery had a desirable reproductive and survival outcome compared with those undergoing radical surgery.

Risk Stratification of Early-Stage Cervical Cancer with Intermediate-Risk Factors: Model Development and Validation Based on Machine Learning Algorithm

Abstract Background Adjuvant therapy for patients with cervical cancer (CC) with intermediate-risk factors remains controversial. The objectives of the present study are to assess the prognoses of patients with early-stage CC with pathological intermediate-risk factors and to provide a reference for adjuvant therapy choice. Materials and Methods This retrospective study included 481 patients with stage IB–IIA CC. Cox proportional hazards regression analysis, machine learning (ML) algorithms, Kaplan-Meier analysis, and the area under the receiver operating characteristic curve (AUC) were used to develop and validate prediction models for disease-free survival (DFS) and overall survival (OS). Results A total of 35 (7.3%) patients experienced recurrence, and 20 (4.2%) patients died. Two prediction models were built for DFS and OS using clinical information, including age, lymphovascular space invasion, stromal invasion, tumor size, and adjuvant treatment. Patients were divided into high-risk or low-risk groups according to the risk score cutoff value. The Kaplan-Meier analysis showed significant differences in DFS (p = .001) and OS (p = .011) between the two risk groups. In the traditional Sedlis criteria groups, there were no significant differences in DFS or OS (p &amp;gt; .05). In the ML-based validation, the best AUCs of DFS at 2 and 5 years were 0.69/0.69, and the best AUCs of OS at 2 and 5 years were 0.88/0.63. Conclusion Two prognostic assessment models were successfully established, and risk grouping stratified the prognostic risk of patients with CC with pathological intermediate-risk factors. Evaluation of long-term survival will be needed to corroborate these findings. Implications for Practice The Sedlis criteria are intermediate-risk factors used to guide postoperative adjuvant treatment in patients with cervical cancer. However, for patients meeting the Sedlis criteria, the choice of adjuvant therapy remains controversial. This study developed two prognostic models based on pathological intermediate-risk factors. According to the risk score obtained by the prediction model, patients can be further divided into groups with high or low risk of recurrence and death. The prognostic models developed in this study can be used in clinical practice to stratify prognostic risk and provide more individualized adjuvant therapy choices to patients with early-stage cervical cancer.

Radical partial vulvectomy combined with through vulva incision laparoendoscopic single-site inguinal lymphadenectomy for vulva cancer