Ning Li

Fuzuloparib with or without apatinib as maintenance therapy in newly diagnosed, advanced ovarian cancer (FZOCUS‐1): A multicenter, randomized, double‐blind, placebo‐controlled phase 3 trial

Abstract Although poly(adenosine diphosphate‐ribose) polymerase inhibitors (PARPis) and bevacizumab were approved as first‐line maintenance for advanced ovarian cancer (OC), evidence comparing this combination with PARPi monotherapy, especially in BRCA ‐mutated/homologous recombination‐deficient (HRD) patients, is lacking. This study compared combined fuzuloparib (a PARPi) plus apatinib (a vascular endothelial growth factor receptor‐2 inhibitor) with either fuzuloparib or placebo as first‐line maintenance in patients with advanced OC. Patients who had newly diagnosed, advanced OC and responded to first‐line, platinum‐based chemotherapy were randomized 2:2:1 to receive combined fuzuloparib (100 mg twice daily) plus apatinib (375 mg daily), fuzuloparib (150 mg twice daily) plus placebo, or double‐placebo treatment. The primary end point was blinded independent review committee (BIRC)‐assessed progression‐free survival (PFS). Six hundred seventy‐four patients were randomized to receive fuzuloparib plus apatinib ( n  = 269), fuzuloparib ( n  = 269), or placebo ( n  = 136). At the final analysis (November 1, 2024; 385 BIRC‐assessed PFS events; median follow‐up, 40 months), the median BIRC‐assessed PFS was 26.9 months with the combination versus placebo (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.44–0.75; one‐sided p  < .0001) and 29.9 months with fuzuloparib monotherapy versus placebo (HR, 0.58; 95% CI, 0.44–0.75; one‐sided p  < .0001) compared with 11.1 months with placebo. A PFS benefit was observed regardless of germline BRCA1/2 mutation status. In homologous recombination‐deficient patients (including those with BRCA1/2 mutations), combined fuzuloparib and apatinib produced a PFS similar to that of fuzuloparib (34.1 vs. 35.8 months, respectively); in homologous recombination‐proficient patients, PFS had a trend favoring the combination (16.6 vs. 11.0 months; HR, 0.73; 95% CI, 0.45–1.19). Both treatments were well tolerated. Overall survival was immature. Both fuzuloparib and combination therapy improved PFS compared with placebo as maintenance therapy for patients who had newly diagnosed, advanced OC. Adding apatinib to fuzuloparib did not prolong PFS among homologous recombination‐deficient patients. There was a PFS benefit trend among homologous recombination‐proficient patients who received combination therapy compared with those who received monotherapy.

PARPis response and outcome of ovarian cancer patients with BRCA1/2 germline mutation and a history of breast cancer

The aim of this study was to determine the poly (ADP-ribose) polymerase inhibitors (PARPis) response and outcome of ovarian cancer (OC) patients with BRCA1/2 germline mutation and a history of breast cancer (BC). Thirty-nine OC patients with BRCA1/2 germline mutation and a history of BC were included. The clinicopathological characteristics, PARPis response and prognosis were analyzed. The median interval from BC to OC diagnosis was 115.3 months (range=6.4-310.1). A total of 38 patients (38/39, 97.4%) received platinum-based chemotherapy after surgical removal. The majority of these patients were reported to be platinum sensitive (92.1%, 35/38). 21 patients (53.8%) received PARPis treatment with 16 patients (76.2%) for maintenance treatment and 5 patients (5/21, 23.8%) for salvage treatment. The median duration for PARPis maintenance and salvage treatment was 14.9 months (range=2.0-56.9) and 8.2 months (range=5.2-20.7), respectively. In the entire cohort, 5-year progression-free survival (PFS) and overall survival (OS) rate was 33.1% and 78.9%, respectively. Patients with BRCA1 mutation had a non-significantly worse 5-year PFS (28.6% vs. 45.8%, p=0.346) and 5-year OS (76.9% vs. 83.3%, p=0.426) than those with BRCA2 mutation. In patients with stage III-IV (n=31), first line PARPis maintenance treatment associated with a non-significantly better PFS (median PFS: NR vs. 22.4 months; 5-year PFS: 64.3% vs. 21.9%, p=0.096). The current study shows that these patients may have a good response to platinum-based chemotherapy and a favorable survival. And these patients can benefit from PARPis treatment and will likely be suitable candidates for PARPis.

The Downregulation of MMP23B Facilitates the Suppression of Vitality and Induction of Apoptosis in Endometrial Cancer Cells

AbstractEndometrial cancer is a malignant tumor that commonly occurs in the female reproductive system and its incidence is still increasing. The mechanism of the development of endometrial cancer has not yet been fully clarified, so we need to continuously study the relevant mechanisms of endometrial cancer and continue to explore its biomarkers in order to discover more precise and effective treatment methods for endometrial cancer. RT-qPCR (Real-Time quantitative Polymerase Chain Reaction) experiments were used to detect the expression level of MMP23B (Matrix Metalloproteinase 23B) in endometrial cancer cells; the clinical data of the TCGA (The Cancer Genome Atlas) database were downloaded, and gene expression profiles were analyzed to investigate the correlation between MMP23B (Matrix Metalloproteinase 23B) and the survival prognosis of endometrial cancer, and functional enrichment analysis was performed on MMP23B (Matrix Metalloproteinase 23B) related genes. After silencing MMP23B (Matrix Metalloproteinase 23B), CCK8 (Cell Counting Kit-8), RT-qPCR (Real-Time quantitative Polymerase Chain Reaction), scratch assay, and transwell assay were used to detect cell viability, levels of apoptotic factors, migration rate, and invasion number of endometrial cancer, respectively. MMP23B (Matrix Metalloproteinase 23B) was highly expressed in endometrial cancer, which is closely related to a poor survival prognosis for endometrial cancer, and may act on endometrial cancer through apoptosis-related functions. The downregulation of MMP23B (Matrix Metalloproteinase 23B) reduced the cell viability of endometrial cancer cells, upregulated the expression levels of CASP3 (Caspase-3), CASP8 (Caspase-8) and CASP9 (Caspase-9) in cells, and inhibited cell migration and invasion.

Iron promotes ovarian cancer malignancy and advances platinum resistance by enhancing DNA repair via FTH1/FTL/POLQ/RAD51 axis

AbstractIron is crucial for cell DNA synthesis and repair, but an excess of free iron can lead to oxidative stress and subsequent cell death. Although several studies suggest that cancer cells display characteristics of ‘Iron addiction’, an ongoing debate surrounds the question of whether iron can influence the malignant properties of ovarian cancer. In the current study, we initially found iron levels increase during spheroid formation. Furthermore, iron supplementation can promote cancer cell survival, cancer spheroid growth, and migration; vice versa, iron chelators inhibit this process. Notably, iron reduces the sensitivity of ovarian cancer cells to platinum as well. Mechanistically, iron downregulates DNA homologous recombination (HR) inhibitor polymerase theta (POLQ) and relieves its antagonism against the HR repair enzyme RAD51, thereby promoting DNA damage repair to resist chemotherapy-induced damage. Additionally, iron tightly regulated by ferritin (FTH1/FTL) which is indispensable for iron-triggered DNA repair. Finally, we discovered that iron chelators combined with platinum exhibit a synergistic inhibitory effect on ovarian cancer in vitro and in vivo. Our findings affirm the pro-cancer role of iron in ovarian cancer and reveal that iron advances platinum resistance by promoting DNA damage repair through FTH1/FTL/POLQ/RAD51 pathway. Our findings highlight the significance of iron depletion therapy, revealing a promising avenue for advancing ovarian cancer treatment.

Overview of fuzuloparib in the treatment of ovarian cancer: background and future perspective

Over the last decade, clinical trials using various poly ADP ribose polymerase (PARP) inhibitors on patients with ovarian cancer have shown promising results. The introduction of PARP inhibitors has changed the treatment landscape and improved outcomes for patients with ovarian cancer. Fuzuloparib, developed by Jiangsu Hengrui Pharmaceuticals Co., Ltd., is a novel orally available small molecule PARP inhibitor. By introducing the trifluoromethyl group into chemical structure, fuzuloparib exhibits higher stability and lower inter-individual variability than other PARP inhibitors. Several clinical trials (FZOCUS series and others) have been carried out to assess the efficacy and safety of fuzuloparib through different lines of treatments for advanced or recurrent ovarian cancer in both treatment and maintenance. Here, we present the most recent data from these studies, discuss current progress and potential future directions.

An Open-label, Multicenter, Single-arm, Phase II Study of Fluzoparib in Patients with Germline BRCA1/2 Mutation and Platinum-sensitive Recurrent Ovarian Cancer

Abstract Purpose: Fluzoparib (PARP inhibitor) showed promising antitumor activity for advanced ovarian cancer in a phase I study. This study aimed to assess the efficacy and safety of fluzoparib in patients with germline BRCA1/2-mutated recurrent ovarian cancer. Patients and Methods: This open-label, multicenter, single-arm, phase II study enrolled patients with platinum-sensitive recurrent ovarian cancer and germline BRCA1/2 mutation who had previously received two to four lines of platinum-based chemotherapy. Fluzoparib 150 mg was administered orally twice daily. The primary endpoint was independent review committee (IRC)-assessed objective response rate per RECIST v1.1. Results: A total of 113 patients were enrolled and received at least one dose of fluzoparib. As of data cutoff on March 21, 2020, the median follow-up period was 15.9 months (interquartile range, 13.5–18.5). The IRC- and investigator-assessed objective response rates were 69.9% [95% confidence interval (CI), 60.6–78.2] and 70.8% (95% CI, 61.5–79.0), respectively. The objective response rates were similar across all prespecified subgroups. The median IRC- and investigator-assessed progression-free survival was 12.0 months (95% CI, 9.3–13.9) and 10.3 months (95% CI, 9.2–12.0), respectively. The 12-month survival rate was 93.7% (95% CI, 87.2–96.9). Grade ≥3 adverse events occurred in 63.7% (72/113) of the patients, with the most common one being anemia/decreased hemoglobin. Adverse events that led to treatment interruption, dose reduction, and discontinuation occurred in 39.8%, 34.5%, and 0.9% of patients, respectively. One treatment-related death occurred. Conclusions: Fluzoparib demonstrated promising antitumor activity and acceptable safety profile in germline BRCA1/2-mutated, platinum-sensitive relapsed ovarian cancer. Thus, fluzoparib might be a novel treatment option for this population.

The anticancer effect of extract of medicinal mushroom Sanghuangprous vaninii against human cervical cancer cell via endoplasmic reticulum stress-mitochondrial apoptotic pathway

Sanghuangprous vaninii (Ljub.) L.W. Zhou & Y.C. Dai, known as "Sanghuang" in China, is mainly distributed in the northeast of China. As a traditional medicinal mushroom, "Sanghuang" is medicinally used for resolving the symptoms of gynecological tumors including vaginal bleeding, leucorrhea, abdominal pain and abdominal mass. This mushroom is potential for gynecological cancers therapy. However, there is a lack of scientific evidence on its anti-tumor activity against human cervical cancer, the most common gynecological cancer. To identify the anti-tumor potential of the extract of Sanghuangprous vaninii (ESV) on human cervical cancer SiHa cells, and explore detailed mechanisms of ESV inducing cancer cell death. The anti-proliferation effects were evaluated by Cell Counting Kit-8 (CCK8) assay. Transmission electron microscope was applied to determined the cellular ultrastructure changes. The cell cycle distribution, quantification of apoptotic cells, mitochondrial transmembrane potential, reactive oxygen species (ROS) level, and cytosolic calcium level were determined by flow cytometer. Western blot analysis was used to explore the alterations in the expression levels of endoplasmic reticulum stress-marked and apoptosis-related proteins. The in-vivo anti-tumor effect was identified by mouse xenograft model. ESV significantly inhibited the proliferation of SiHa cells in vivo and vitro. Blocking cell cycle and causing cell apoptosis contributed to cell death induced by ESV. Mechanistically, ESV induced endoplasmic reticulum stress evidenced by the elevated expressions of GRP78 and CHOP, which accompanied by the release of calcium (Ca Our results revealed that Sanghuangprous vaninii was effective against human cervical cancer SiHa cells in vitro and vivo. There is a promising potential that Sanghuangprous vaninii might be a candidate for cervical cancer therapy.

Pan-Asia adapted ESMO Clinical Practice Guideline for the management of patients with newly diagnosed and relapsed epithelial ovarian cancer

The European Society for Medical Oncology (ESMO) Clinical Practice Guideline for the diagnosis, treatment and follow-up of patients with newly diagnosed and relapsed epithelial ovarian cancer (EOC), published in 2023, was adapted in July 2024, according to established standard methodology, to produce the Pan-Asian adapted ESMO consensus guideline for the management of Asian patients with EOC. The adapted guideline presented in this manuscript represents the consensus opinions reached by a panel of Asian experts in the treatment of patients with EOC representing the oncological societies of China, Indonesia, India, Japan, Korea, Malaysia, the Philippines, Singapore, Taiwan and Thailand, coordinated by ESMO and the Indian Society of Medical and Pediatric Oncology. Voting was based on scientific evidence and was independent of current treatment practices, drug access restrictions and reimbursement decisions in the represented countries. Drug access and reimbursement across Asia are discussed separately in the manuscript. The Pan-Asian consensus aims to guide the optimisation and harmonisation of management of patients with EOC in Asia, drawing on the evidence provided by both Western and Asian trials. Attention is drawn to the disparity in the drug approvals and reimbursement strategies between countries.