Jun Yao

Comparing treatment strategies for placental site trophoblastic tumour (PSTT): study protocol for a systematic review and network meta-analysis

Introduction Placental site trophoblastic tumour (PSTT) is a rare type of gestational trophoblastic malignancy. Despite different guidelines recommending surgery, chemotherapy or immunotherapy, there has been no optimal first-line treatment owing to its rarity. Direct comparisons of efficacy and safety across interventions remain limited. We aim to perform a systematic review and network meta-analysis (NMA) to explore each PSTT treatment and to help develop individualised, evidence-based clinical decisions. Methods and analysis This systematic review, registered on PROSPERO and adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-P 2015 guidelines, will evaluate all available treatments for PSTT. Databases (PubMed, Scopus, Embase, Web of Science) will be searched from inception to 31 May 2025 using Medical Subject Headings terms and keywords related to PSTT. The inclusion criteria will be studies reporting confirmed PSTT patients and treatment outcomes; the exclusion criteria will be non-human studies, abstracts and reviews. Two researchers will independently screen studies, resolving discrepancies via discussion or a third reviewer. Manual reference checks will complement searches. Data on study characteristics, interventions (chemotherapy, surgery or other treatments) and outcomes (overall survival (OS), progression-free survival, adverse events, fertility) will be extracted. The primary outcome will be the OS. Quality will be assessed using the Newcastle-Ottawa Scale (NOS) for observational studies and V.2 Cochrane Risk of Bias Assessment Tool (RoB 2) for randomised controlled trials. Statistical analyses will be conducted via Review Manager 5.4.1 and Stata 16.0. The ORs, along with 95% CIs will be calculated with random-effects or fixed-effects models depending on the heterogeneity between studies. The sensitivity analyses and publication bias (funnel plots, Begg’s/Egger’s tests) will be assessed if indicated. Ethics and dissemination As this study analyses previously published data, no additional ethical approval is required, nor will patient safety be compromised. The collected results will be submitted for publication in a peer-reviewed journal following PRISMA-NMA guidelines. No datasets will be generated or analysed during the current study. PROSPERO registration number CRD420251013082.

Targeting polyploid giant cancer cells potentiates a therapeutic response and overcomes resistance to PARP inhibitors in ovarian cancer

To understand the mechanism of acquired resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) olaparib, we induced the formation of polyploid giant cancer cells (PGCCs) in ovarian and breast cancer cell lines, high-grade serous cancer (HGSC)–derived organoids, and patient-derived xenografts (PDXs). Time-lapse tracking of ovarian cancer cells revealed that PGCCs primarily developed from endoreplication after exposure to sublethal concentrations of olaparib. PGCCs exhibited features of senescent cells but, after olaparib withdrawal, can escape senescence via restitutional multipolar endomitosis and other noncanonical modes of cell division to generate mitotically competent resistant daughter cells. The contraceptive drug mifepristone blocked PGCC formation and daughter cell formation. Mifepristone/olaparib combination therapy substantially reduced tumor growth in PDX models without previous olaparib exposure, while mifepristone alone decreased tumor growth in PDX models with acquired olaparib resistance. Thus, targeting PGCCs may represent a promising approach to potentiate the therapeutic response to PARPi and overcome PARPi-induced resistance.

Combination Therapy with Copanlisib and Niraparib in Patients with Recurrent Endometrial and Ovarian Cancer (COPANIRA): Efficacy, Toxicity, and Translational Insights

Abstract Purpose: Patients with recurrent endometrial or ovarian cancer have poor survival outcomes. We evaluated the clinical efficacy and toxicity of copanlisib [a phosphatidylinositol 3-kinase (PI3K) inhibitor] and niraparib [a poly (ADP-ribose) polymerase inhibitor (PARPi)] in this patient population with translational insights. Patients and Methods: This was a phase Ib trial. Copanlisib was administered intravenously on days 1, 8, and 15 of a 28-day cycle, and niraparib was given orally once daily. Four dose levels were explored over a dose-limiting toxicity (DLT) window of 28 days. The primary objective was to determine the recommended phase II dose (RP2D) of this combination. Secondary objectives included safety, objective response rate (ORR), and pharmacokinetics. Tumor biopsies were analyzed using reverse phase protein array (RPPA) to identify molecular correlates of response. Results: Thirty patients were enrolled. An RP2D was not established due to DLTs, most commonly a grade 3 maculopapular rash attributed to copanlisib. The ORR was 12.5% (95% confidence interval, 2.8%–33.6%). RPPA was performed on tumors from eight patients. PI3K pathway activity did not correlate with PI3K mutational status. Nineteen proteins were differentially expressed between patients with stable disease and those with progressive disease; many were substrates of Akt (protein kinase B), implicating downstream PI3K signaling in response. Conclusions: The combination of copanlisib and niraparib demonstrated limited tolerability, and the ORR was modest. However, functional proteomic analyses identified candidate biomarkers—particularly Akt pathway substrates—which may inform future strategies to optimize PI3K and PARPi combinations.