RARE DISEASE
Small cell carcinoma of the ovary
Small cell carcinoma of the ovary
Small cell carcinoma of the ovary
Synonyms: SCCO, Small cell ovarian carcinoma
Synonyms: SCCO, Small cell ovarian carcinoma
Synonyms: SCCO, Small cell ovarian carcinoma
Drug discovery
2
drugs
With orphan designations
Overview
Small cell carcinoma of the ovary (SCCO) is an ultra-rare, highly aggressive malignancy comprising 0.1% of ovarian cancers [1][6][10]. Primarily affecting young women (median age 23), it presents as SCCO hypercalcemic type (SCCOHT, 66% of cases) or pulmonary/neuroendocrine subtypes [1][10][18]. Two-thirds display paraneoplastic hypercalcemia, while non-hypercalcemic variants often occur post-menopause [1][5][18]. Despite maximal cytoreduction and platinum-based chemotherapy, prognosis remains poor with median survival <2 years [1][8][15].
Therapies
Radical surgery (hysterectomy/oophorectomy) + BEP chemotherapy (bleomycin/etoposide/cisplatin) [1][5][12]
Investigational approaches: High-dose chemo with stem cell rescue, pembrolizumab trials, pelvic radiotherapy [8][12][13]
Fertility-sparing surgery considered in stage IA disease without germline mutations [8][12]
Categories: rare gynecological and obstetric diseases, rare neoplastic diseases
Research Papers
1,891 drug discovery papers about Small cell carcinoma of the ovary, with 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,891 drug discovery papers about Small cell carcinoma of the ovary, with 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-29 | Case Report: Primary ovarian pulmonary-type small cell neuroendocrine carcinoma mimicking benign adnexal torsion: a diagnostic challenge.
Small cell carcinoma of the ovary, pulmonary type (SCCOPT), is a rare and aggressive ovarian neuroendocrine carcinoma. Because its clinical and radiological features overlap with benign adnexal conditions and metastatic neuroendocrine tumors, preoperative diagnosis remains challenging. Here, we report a rare case of SCCOPT presenting as acute abdomen associated with adnexal torsion, tumor rupture, and hemoperitoneum, which complicated recognition of the underlying malignancy. A woman in her early 60s presented with acute lower abdominal pain, abdominal distension, and syncope. Pelvic magnetic resonance imaging revealed a complex cystic-solid adnexal mass. Emergency laparoscopy demonstrated left adnexal torsion, tumor rupture, active bleeding, and approximately 550 mL of hemoperitoneum. Histopathological examination revealed a high-grade small cell neuroendocrine carcinoma. Immunohistochemical analysis supported the diagnosis of SCCOPT, showing positivity for synaptophysin, chromogranin A, and CD56, with negative TTF-1 expression, loss of Rb expression, and retained SMARCA4 expression. Postoperative evaluation, including PET-CT, gastroscopy, and colonoscopy, showed no evidence of an extra-ovarian primary tumor. Tumor-blood sequencing identified an HRD-negative/BRCA-wild-type profile and a somatic TP53 mutation, further supporting the high-grade neuroendocrine phenotype. The patient underwent surgical staging followed by six cycles of carboplatin plus etoposide chemotherapy and remained without clinically evident recurrence at the latest follow-up. SCCOPT may initially present as an acute gynecological emergency and mimic benign adnexal torsion, potentially delaying recognition of malignancy. Accurate diagnosis requires integration of clinical presentation, imaging findings, histopathology, immunophenotyping, molecular alterations, and exclusion of extra-ovarian primary sites. This case emphasizes the importance of considering ovarian malignancy, including SCCOPT, in postmenopausal women presenting with acute adnexal events.
2026-09-25 | Converting lysosomes into photothermal organelles enables nanoparticle-free tumor ablation via intracellular vapor bubbles.
Photothermal nanomaterials enable precise tumor ablation but face limitations in biodistribution, tissue penetration, toxicity, and biodegradability. Here, we present a unique concept for nanoparticle-free photothermal therapy based on the lysosomal entrapment of cationic amphiphilic small molecular dyes for spatially controlled vapor bubble (VB)-mediated tumor cell ablation. This strategy, which exploits a universal biological and physical effect, uses intracellular pH gradients for extensive local dye enrichment in acidified organelles, transforming them into transient endogenous nanosized photothermal reactors for subsequent light activation. Using sunitinib, a clinically approved lysosomotropic anticancer drug, and the commercially available dye LysoTracker Deep Red, lacking intrinsic anticancer activity, we demonstrate pulsed laser-induced VB formation from dye-enriched lysosomal compartments, leading to selective photomechanical disruption of various ex vivo cancer cell models across two-dimensional (2D) cultures, 3D spheroids, patient-derived neuroblastoma tumoroids, and tumor fragments from a patient with ovarian carcinoma. This approach allows precise, low-fluence, and wavelength-tunable cancer tissue ablation without the need for synthetic photoresponsive nanoparticles.
2026-09-01 | Identification of New Putative Autotaxin Inhibitors via Structure-Based Virtual Screening and Evaluation of Their Antiproliferative Properties Against Ovarian and Breast Cancer Cells.
Autotaxin (ATX), a lysophospholipase D playing an important role in several inflammatory diseases, as well as in tumor invasion, progression, and metastasis, is an attractive therapeutic target. Herein, we report a virtual screening study of an in-house molecular database. In silico simulations highlighted five putative ATX inhibitors. The enzyme assay showed that compound 3 achieves inhibition potency in the submicromolar range (IC50 = 0.534 µM), whereas all the other test compounds proved to be moderate (2) or weak (1, 4, and 5) inhibitors of ATX at 10 µM concentration. These compounds, evaluated for the in vitro antiproliferative activity in four ATX-expressing cancer cell lines, namely the ovarian cancer cell lines A2780 and SK-OV-3, the breast cancer cells MCF-7, and immortalized mouse embryonic fibroblast cell line NIH/3T3, demonstrated preliminary phenotypic effects, inhibiting cell proliferation with IC50 values mostly in the low micromolar range. Compound 4 (IC50 = 11.5 µM against SK-OV-3) significantly reduced the motility of SK-OV-3 ovarian carcinoma cells in the wound-healing assay, suggesting that it may represent a hit structure for the development of potential antimetastatic agents.
2026-08-19 | Case Report: Personalized therapy in gynecological neuroendocrine neoplasm: a case of BRCA2-mutated ovarian neuroendocrine carcinoma treated with PARP-inhibitor.
Neuroendocrine neoplasms (NENs) of the female genital tract are rare and typically aggressive malignancies, accounting for only 1-2% of gynecologic tumors. The majority (54%) are located in the cervix. Ovarian neuroendocrine carcinomas (O-NECs) represent less than 1% of all ovarian cancers and 16% of all gynecologic NENS; these tumors are associated with poor prognosis, with an overall survival (OS) ranging from 11 to 20 months and progression-free survival (PFS) between 12-14.71 months. To date, approximately 923 cases have been reported in the literature and owing to their rarity no standardized treatment protocols have been established. We retrospectively reviewed all cases of NENs of female genital tract treated at the Gynecologic Oncology Unit of Fondazione IRCCS Istituto Nazionale Tumori of Milan, Italy. Moreover, we describe an interesting case of a 66-year-old woman with O-NEC and harboring a BRCA2 mutation. Patient achieved a pathological complete response following platinum-based chemotherapy and subsequently received a maintenance therapy with PARP-inhibitor. From 2005 to June 2025, a total of 42 women with NENs of the female genital tract were treated at the Gynecologic Oncology Unit of Fondazione IRCCS Istituto Nazionale Tumori of Milan (Italy): 59% originated from cervix, 29% from endometrium and 12% from ovaries. Median OS and PFS of patients with O-NEC were consistent with literature data (15 and 11 months, respectively); all patients underwent surgery followed by platinum-etoposide chemotherapy and then follow up. In May 2024, a 66-year-old woman underwent exploratory laparoscopy for a large pelvic mass (121×83×137 mm) associated with hemoperitoneum, bilateral grade 3 hydronephrosis and rectum infiltration. Final histopathological diagnosis was of small cell ovarian neuroendocrine carcinoma (SCNEC), FIGO stage IV, due to the presence of the hepatic metastasis. Next-generation sequencing (NGS) performed on tumor tissue revealed a pathogenetic BRCA2 mutation. Following multidisciplinary tumor board discussion, patient received 4 cycles of carboplatin-etoposide chemotherapy with an excellent radiological response and significant tumor marker reduction (CA125: 477→9.4 U/ml; NSE: 629→8.9 ng/mL; CEA: 560→16.9 ng/mL). The histopathology report, performed after interval debulking surgery, confirmed a complete pathological response. She completed systemic treatment with two additional cycles of chemotherapy and then, she started compassionate-use maintenance therapy with PARP inhibitor based on the presence of the BRCA2 mutation. Today, after 12 months to the end of chemotherapy, patient has not evidence of recurrence disease, she is in good clinical condition and maintenance treatment with PARP inhibitor is still ongoing. To the best of our knowledge, only 1 prior case of BRCA2-mutated O-NEC patient treated with PARP-inhibitor has been reported in literature, with a PFS of 2 months, suggesting limited efficacy of PARP inhibitors in this setting. However, our case may indicate a potential benefit in selected patients. O-NECs are rare and poorly characterized malignancies, lacking standardized diagnostic and therapeutic protocols. Therefore, comprehensive characterization of individual cases is crucial to improve knowledge and patient outcomes. This case highlights the pivotal role of molecular profiling in identifying candidates for personalized therapeutic approaches. Further experiences are needed to expand current knowledge and evaluate the potential benefit of PARP inhibitors in BRCA-mutated O-NEC patients.
2026-07-24 | Atranorin suppresses the LUCAT1/STAT3 axis to induce ferroptotic cell death in ovarian cancer.
Ovarian cancer remains the most lethal gynecological malignancy and represents a major cause of cancer-related mortality among women worldwide. Despite advances in therapeutic strategies, treatment efficacy is frequently limited by systemic toxicity, chemoresistance, and disease recurrence, highlighting the urgent need for novel, mechanism-based targeted therapies with improved safety profiles. In the present study, we investigated the anti-cancer activity of atranorin (ATR), a naturally derived small-molecule compound, with a particular focus on its ability to induce ferroptosis by modulation of the LUCAT1/STAT3 signaling axis. Human ovarian cancer cell lines (OVCAR-3 and SKOV-3) and normal ovarian surface epithelial (OSE) cells were employed to evaluate cytotoxic selectivity and mechanistic effects. ATR selectively inhibited proliferation of ovarian cancer cells while exerting minimal cytotoxicity toward normal OSE cells. Mechanistic analyses demonstrated that ATR significantly suppressed LUCAT1 and STAT3 expression at both mRNA and protein levels, as confirmed by qRT-PCR and Western blotting. Concomitantly, ATR upregulated ferroptosis-related genes and proteins. Biochemical assessments revealed increased intracellular reactive oxygen species (ROS), elevated malondialdehyde (MDA) and iron accumulation, and depletion of glutathione (GSH), collectively indicating activation of ferroptotic cell death. Furthermore, ATR significantly impaired migratory and invasive capacities of ovarian cancer cells. Collectively, our findings identify ATR as a compound capable of inducing biochemical features consistent with ferroptosis in ovarian cancer through suppression of the LUCAT1/STAT3 axis. These results uncover a previously uncharacterized mechanistic pathway underlying ATR-mediated anti-tumor effect and support its potential development as a targeted therapeutic candidate for ovarian cancer management.
proteins
2026-09-07 | Integrating Tumor Targeting and Half-Life Extension into a Dual-Surfaced Single-Domain ADAPT Protein.
Folate receptor alpha (FRα) is frequently overexpressed in ovarian cancer while showing limited expression in healthy tissues. Targeting of FRα has been extensively investigated using antibody-based therapies but less so with small scaffold proteins. Small scaffold proteins represent an alternative approach with potential advantages such as site-specific conjugation and deep tumor penetration but are limited by a short half-life. Here, we describe the development of a dual-surfaced ADAPT scaffold protein (6 kDa) with simultaneous bispecificity for FRα and albumin. Using combinatorial libraries and phage display, we identified a candidate, termed ADAPT22, with high isoform selectivity and subnanomolar affinity for FRα (KD = 0.8 nM), paired with a low nanomolar affinity for albumin (KD = 2.4 nM). Importantly, ADAPT22 is able to interact with both targets simultaneously, truly combining extended retention in blood via albumin association and tumor targeting via FRα within a single-domain protein. The simultaneous nature was verified in vitro to soluble proteins and to FRα-positive cells and in vivo using a mouse xenograft model. In mice, ADAPT22 demonstrated markedly extended blood retention, reduced renal uptake, and specific accumulation in FRα-positive tumors, confirming simultaneous dual-surface binding. To the best of our knowledge, this is the smallest half-life extended affinity protein designed for therapeutic targeting of FRα.
2026-03-06 | Micropeptide YG-6 encoded by exosomal LINC01123 derived from highly migratory ovarian cancer cells promotes tumor progression.
BACKGROUND: Intercellular crosstalk plays a pivotal role in tumor progression and metastasis. Exosomes can package long non-coding RNAs (lncRNAs) to mediate extracellular communication. Although exosome research in various cancers has made remarkable progress, it remains unclear in ovarian cancer (OC) whether the cellular communication between OC cells with different metastatic potentials influences progression via exosomal-lncRNA. Besides, lncRNA can encode functional micropeptides, yet the association between OC and micropeptides encoded by exosomal-derived lncRNA has not been reported. METHODS: OC cell-derived exosomes were characterized using transmission electron microscopy, nanoparticle tracking analysis, and WB. Exosomal lncRNA sequencing results of highly migratory OC cells (HMOs) and low migratory OC cells (LMOs) were analyzed, and LINC01123 was selected for further study. The effect of exosome LINC01123 on the function of LMOs was detected by the co-culture experiment. Bioinformatics prediction, mass spectrometry (MS), WB, and a series of functional experiments showed that LINC01123 encodes a small 59 aa peptide, named YG-6 (LINC01123 Yield peptide Gaining metastasis function: ORF no.6). Immunofluorescence, qPCR, WB, immunohistochemistry, and MS analysis were used to detect the endogenous expression of YG-6 in OC cells and tissues. The function of YG-6 in OC was investigated by detecting cell migration ability and observing tumor metastasis in nude mice. Mechanistically, the relationship between the YG-6 and ACTC1 in OC was verified by Co-Immunoprecipitation, WB, MS, immunofluorescence, and functional experiment. RESULTS: LINC01123 was significantly up-regulated in exosomes derived from HMOs and was readily internalized by LMOs, promoting their malignant behavior. Interestingly, LINC01123 encodes a small peptide composed of 59 amino acids, named YG-6, which exhibits endogenous high expression in OC cells and tissues. Functional experiments demonstrated that LINC01123 promotes tumor progression by encoding the peptide YG-6, rather than via an RNA-dependent mechanism. Furthermore, we identified ACTC1 as a binding protein of YG-6, which can synergistically activate the focal adhesion signaling pathway together with YG-6, thereby promoting the migration and adhesion of LMOs. CONCLUSIONS: Our findings not only demonstrate the YG-6 peptide encoded by LINC01123 as a potential prognostic biomarker for OC but also uncover a new mechanism of OC progression driven by YG-6 peptides.
2025-12-09 | Pan-cancer profiling links C1orf50 to DNA repair and immune modulation in ovarian cancer.
C1orf50 encodes a small, evolutionarily conserved protein, the function of which remains unclear. Its significance across various human cancers, particularly its specific role in ovarian cancer within an immunogenomic context, is not yet fully understood. Utilizing The Cancer Genome Atlas and single-cell RNA sequencing (scRNA-seq) public datasets, we conducted a comprehensive profiling of C1orf50 across multiple cancer types, with a particular focus on ovarian cancer, to investigate its associations with copy-number status, genomic instability, tumor programs, and the immune microenvironment. Across cancer types, copy-number gain or amplification of C1orf50 was most frequent in ovarian cancer and closely tracked with higher messenger RNA levels. Higher C1orf50 expression was associated with a greater tumor mutational burden and homologous recombination deficiency, as indicated by gene-set patterns that suggested heightened cell-cycle and cellular stress responses accompanied by reduced oxidative phosphorylation, enrichment of regulatory T cells, and depletion of resting memory CD4 T cells. In ovarian cancer, focal events at chromosome 1p34.2 were accompanied by stepwise increases in C1orf50 expression by clinical stage and were linked to higher tumor mutational burden, homologous recombination deficiency, and greater loss of heterozygosity, together with more frequent gene alterations in BRCA1 or BRCA2. Immune composition clustered into profiles consistent with an immunosuppressive context in tumors with higher C1orf50 expression. The scRNA-seq data further revealed that cancer cells enhanced immune-suppressive interactions with various immune cell populations and diminished antigen-presentation signals. Analyses of genomic instability in ovarian cancer suggested mutational processes compatible with base-substitution patterns associated with cytidine deaminase activity and with insertion-deletion patterns characteristic of homologous recombination failure, while transcript-level patterns pointed to a broad downshift of canonical DNA repair activity with apparent compensatory adjustments in related pathways rather than a uniform change in any single pathway. The overexpression of C1orf50 characterizes an aggressive immunogenomic phenotype in ovarian cancer, distinguished by genomic instability, impaired DNA repair mechanisms, and extensive immunosuppression. These findings indicate that C1orf50 warrants consideration as a potential biomarker and a prospective target for therapeutic investigation. Furthermore, they advocate for the progression to prospective validation and functional studies to ascertain its clinical significance.
2025-11-08 | Tβ4-17 peptide enhances the chemo-sensitivity of ovarian cancer cells to DDP by affecting NF-κB signaling pathway.
Ovarian cancer is a gynecologic malignancy with high mortality and poor prognosis. Chemoresistance is a key cause of ovarian cancer recurrence and metastasis. It has been found that some bioactive peptides can inhibit the growth and metastasis of cancer cells and promote cell apoptosis, thus exerting anti-cancer effects. Tβ4-17 is a small polypeptide that we selected using ITRAQ technology, and its precursor protein is thymosin β4. This study mainly investigated its effect in combination with cisplatin (DDP) on the proliferation, migration and apoptosis of ovarian cancer resistant cells and related molecular mechanisms. Our results showed that Tβ4-17 peptide combined with DDP significantly inhibited the proliferation and migration of drug resistance cells in ovarian cancer, promoted apoptosis, and increased the chemo-sensitivity of ovarian cancer cells to DDP. In addition, qRT-PCR and Western blot showed that NF-κB was significantly highly expressed in DDP-resistant cells of ovarian cancer. After application of NF-κB inhibitors and activators, Western blot, CCK8, EDU fluorescence proliferation assay, and cell scratch assay showed that Tβ4-17 peptide down-regulated NF-κB p65 protein expression and inhibited cell proliferation and migration. In conclusion, our study demonstrates that Tβ4-17 peptide enhances the sensitivity of ovarian cancer cells to DDP by down-regulating NF-κB expression.
2025-07-13 | MYC Regulates a DNA Repair Gene Expression Program in Small Cell Carcinoma of the Ovary, Hypercalcemic Type.
SCCOHT is an aggressive and often fatal cancer that belongs to the ~20% of cancers defined by mutations to subunits of the SWI/SNF chromatin remodeling complex. In SCCOHT, mutations to the SMARCA4 gene, which encodes the SWI/SNF ATPase BRG1, are sufficient to impair SWI/SNF function. This single genetic lesion leads to a cascade of events that promote tumorigenesis, some of which may involve the intersection of SWI/SNF with oncogenic pathways such as those regulated by the MYC oncogene. In SCCOHT tumors and other cancers marked by SWI/SNF subunit mutation, MYC target genes are recurrently activated, pointing to a relationship between SWI/SNF and MYC that has yet to be fully explored. In this study, we investigate the contribution of MYC to SCCOHT biology by performing a combination of chromatin binding and transcriptome assays in genetically engineered SCCOHT cell lines, with subsequent validation using patient tumor expression data. We find that MYC binds to thousands of active promoters in the BIN-67 SCCOHT cell line and that the depletion of MYC results in a broad range of gene expression changes with a notable effect on the expression of genes related to DNA repair. We uncover an MYC-regulated DNA repair gene expression program in BIN-67 cells that is antagonized by BRG1 reintroduction. Finally, we identify a DNA repair gene signature that is upregulated in SCCOHT tumors and in tumors defined by loss of the SWI/SNF subunit SNF5. Collectively, these data implicate MYC as a robust regulator of DNA repair gene expression in SCCOHT and lay a foundation for future studies focused on interrogating the relationship between BRG1 and MYC.
oligonucleotides
2026-06-17 | Developing a pan cancer therapy based on DISE-inducing short RNAs.
RNA interference (RNAi) regulates gene expression through small RNAs that act via Argonaute-containing RNA-induced silencing complexes (RISCs). We previously found that short RNAs with G-rich 6mer seeds (e.g., GGGGGC and G5C) can kill cells by targeting C-rich 3' UTR seed matches in essential survival genes (SGs), a mechanism termed death induced by survival gene elimination (DISE). To assess therapeutic potential, we systemically delivered two DISE-inducing sRNAs, sG5C and sCAG (based on CAG trinucleotide repeats), using lipopolyplexes (LPPs) composed of low-molecular-weight polyethyleneimines and lipids. In mouse ovarian and prostate cancer models and a rat hepatocellular carcinoma model, LPP-delivered small RNAs (sRNAs) markedly reduced or eliminated tumors without harming normal tissues. Predicted SG targets were engaged in tumors. Transcriptomic analyses across 10 major human cancers showed that many sG5C-targeted SGs are consistently upregulated in tumors and increase with stage, revealing a therapeutic window. These results support LPP-delivered DISE-inducing sRNAs as a promising pan-cancer therapy.
2026-05-10 | Disruption of the SNRPF-DDX24-E2F4 Feedback Loop Uncouples Splicing and Transcriptional Regulation to Suppress Ovarian Cancer Progression.
Ovarian cancer (OC) remains a major cause of gynecologic cancer mortality, with progress in targeted therapy limited by an incomplete understanding of post-transcriptional oncogenic drivers. Dysregulated RNA splicing-particularly intron retention (IR)-is increasingly recognized as a key driver of tumor progression. Here, integrated transcriptomic and proteomic analyses identify SNRPF, a core spliceosomal component, as a potent oncogenic driver in OC. SNRPF is highly expressed in tumor specimens, and its overexpression predicts poor patient survival. Silencing SNRPF suppresses proliferation, invasion, and xenograft growth. IR-focused analysis reveals that SNRPF depletion induces intron 6 retention in DDX24, disrupting the Helicase_C domain and generating premature termination codons that activate nonsense-mediated decay (NMD), thereby reducing DDX24 protein abundance and markedly impairing its oncogenic function. DDX24 depletion similarly promotes intron 2 retention in E2F4, causing NMD-mediated downregulation. Notably, E2F4 directly binds the SNRPF promoter, forming a self-sustaining "SNRPF-DDX24-E2F4" axis linking splicing and transcriptional regulation. Antisense oligonucleotide-mediated inhibition of SNRPF disrupts this feedback loop, downregulates DDX24 and E2F4 via IR, and significantly impairs tumor growth in vitro, in vivo, and in patient-derived xenografts. These findings define a splicing-transcription coupling mechanism in OC and position SNRPF as a promising therapeutic target.
2026-04-04 | Single-cell transcriptomics reveals FXR1 as an actionable target for siRNA therapy in ovarian cancer.
Ovarian cancer is one of the leading causes of cancer-related mortality among women and remains exceptionally difficult to manage and treat effectively in the clinic. Fragile X-related protein 1 (FXR1) is highly amplified and overexpressed in ovarian and several other cancers. FXR1 is a key regulator of the translation of multiple oncogenes and therefore represents a vulnerable target for cancer therapy. RNA interference (RNAi) of FXR1 using a locked nucleic acid (LNA) form of siRNA (siFXR1-LNA) inhibits tumor growth, ascites formation, and metastasis of ovarian cancer more efficiently than the native form of FXR1 siRNA in vivo. LNA modification of siRNA improves resistance to RNase mediated degradation and enhances tumor tissue uptake of siRNA with robust inhibition of target mRNA in tumor tissues. Single-cell RNA sequencing (scRNA-seq) analysis of ascites composed of tumor, stromal, and immune cells analysis reveals that FXR1 silencing suppresses tumor cell proliferation and reduces tumor-promoting M2-like macrophages. FXR1 silencing also increases cytotoxic T cells, NK cells, and dendritic cells with anti-tumor characteristics in vivo. Collectively, our data establishes FXR1 as an important regulator of oncogenic processes in cancer tissues and serves as a therapeutic liability. Therefore, FXR1 silencing in tumor tissues provides an effective strategy to treat tumors expressing high levels of FXR1.
2025-12-09 | Synergistic effect study on the co-delivery of paclitaxel and SiRNA targeting STMN1 based on MPDA nanoparticles in the therapy of ovarian cancer.
Ovarian cancer is one of the most prevalent gynecologic malignancies and ranks as a leading cause of death in female cancers. Chemotherapy remains the primary treatment modality, however, the development of chemoresistance poses a significant obstacle in ovarian cancer therapy, contributing to its high mortality rate. In this paper, we report a multifunctional nanoparticle that enables laser-controlled release of co-loaded paclitaxel (PTX) and STMN1 siRNA for synergistic combination therapy. This nanoparticle can improve the microtubule stability by interfering the expression of STMN1, thereby increasing the sensitivity to PTX, blocking cells in the G2/M phase, and ultimately leading to cancer cell death. Additionally, it exhibits enhanced bioavailability, reduced systemic toxicity, and photothermal properties suitable for in vivo imaging. Our nanoparticle offers an innovative strategy for the concurrent therapy and monitoring of ovarian cancer, enhancing therapeutic efficacy and diagnostic precision.
2025-11-27 | Engineered NK92 cell-derived exosomes inhibit ovarian cancer progression by degrading GPRC5A.
Natural killer (NK) 92 (NK92) cells are critical immune-effectors with established roles in treating metastatic and hematological malignancies. Owing to the substantial adverse effects, including cytokine release syndrome, associated with NK92 cell therapy, research interest has pivoted toward the safer and potentially more efficient exosome-based approaches. However, the composition, properties, and functions of NK92 cell-derived exosomes remain largely unknown. In this study, NK92 cell-derived exosomes were isolated via ultracentrifugation. Small RNA sequencing and proteomic sequencing were performed on both the cells and their exosomes. To enhance exosome targeting to tumor cells, the tLyP-1 targeting peptide was displayed on NK92 cell surfaces through genetic engineering. The mechanism underlying tumor therapy mediated by NK92 cell-derived exosomes was investigated through in vitro and in vivo experiments. Additionally, we designed a cholesterol-modified ABCB1 siRNA that adsorbs onto exosome surfaces and enters recipient cells to silence target genes. First, small RNA sequencing and proteomic analysis of NK92 cells and NK92 cell-derived exosomes revealed that the exosomes retained the anti-tumor activity of parental NK cells, inhibiting tumor progression by modulating apoptosis, proliferation, and metastasis. Second, tLyP-1-modified exosomes exhibited enhanced tumor-targeting specificity and exerted anti-tumor effects via the miR-31-5p-GPRC5A axis. Furthermore, NK92 cell-derived exosomes effectively delivered ABCB1 siRNA into recipient cells, mediating efficient gene silencing to sensitize chemoresistant ovarian cancer cells to therapeutic agents. Overall, this study provides a novel strategy to treat ovarian cancer through the preparation of genetically modified NK92 cell-derived exosomes loaded with RNA interference.
antibodies
2026-05-22 | Assessment of delta-like ligand 3 (DLL3) immunostaining in neuroendocrine tumors of the gynecological tract and comparing expression with other high-grade gynecological malignancies.
Neuroendocrine tumors (NETs) of the gynecologic tract are diagnostically challenging because of their heterogeneity. Delta-like ligand 3 (DLL3), an inhibitory Notch receptor ligand, is frequently overexpressed in NETs and has emerged as a potential diagnostic and therapeutic target. This study evaluated DLL3 expression in 76 paraffin-embedded tissue samples from 74 patients, including cervical and ovarian small cell carcinomas/NETs, cervical large cell carcinoma/NET, metastatic NETs, dedifferentiated/undifferentiated carcinomas, carcinosarcomas, and high-grade serous carcinomas. DLL3 positivity was defined by cytoplasmic staining and assessed by staining intensity (0-3+) and percentage of positive tumor cells. DLL3 expression was detected in 83% of cervical small cell carcinomas/NETs, 67% of ovarian small cell carcinomas/NETs, and 100% of cervical large-cell carcinoma/NETs, all showing strong (3+) staining and seen in 5% to 100% of the tumor cells. Metastatic NETs demonstrated lower expression (14%, 3+), which was seen in 90% of the tumor cells. Among dedifferentiated/undifferentiated carcinomas, 60% showed DLL3 positivity in scattered undifferentiated foci with staining intensities ranging from 1+ to 3+. DLL3 expression was also identified in 62% of carcinosarcomas within scattered foci of sarcomatous areas, with 2+ to 3+ intensity. In contrast, high-grade serous carcinomas lacked DLL3 expression. These findings demonstrate frequent DLL3 expression in gynecologic NETs and selected dedifferentiated malignancies, supporting DLL3 as a promising diagnostic marker and potential therapeutic target in gynecologic cancers.
2026-05-10 | The case for tumour-agnostic reimbursement of dual immunotherapy.
Barjesteh van Waalwijk van Doorn-Khosrovani and colleagues raise important questions about this recommendation for tumour-agnostic reimbursement of nivolumab and ipilimumab in Australia. We respectfully offer a counterpoint and endorse the broad coverage. In 2025, Pharmaceutical Benefits Advisory Committee (PBAC) proposed that prescribing nivolumab and ipilimumab be guided by clinical judgement informed by the best available evidence for undefined "immunotherapy-sensitive" advanced or metastatic cancers, and, in January 2026 made a similar recommendation for pembrolizumab. Patients with rare and ultra-rare cancers, including but not limited to angiosarcoma, alveolar soft part sarcoma, gestational trophoblastic disease, small cell carcinoma of the ovary (hypercalcemic type), and adrenocortical carcinoma, face profound unmet need. Within many of these diseases, a subset of patients derives substantial benefit from immunotherapy. For example, the SWOG DART (Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors) trial, the largest prospective evaluation of nivolumab plus ipilimumab in rare/ultra-rare cancers, demonstrated clinically meaningful activity across multiple histologies, without biomarker selection. Notably, some patients with metastatic disease remain disease-free years after treatment, outcomes rarely achieved with chemotherapy or supportive care in refractory settings. Therefore, concerns that biomarker-agnostic approval signals an evidentiary retreat overlook both our incomplete understanding immune sensitivity and the global access limits to comprehensive genomic testing. Importantly, clinical judgement is not arbitrary; it reflects training, experience, ethical reasoning, and patient-centred decision making. The question is whether demanding perfect evidence should prevent access to potentially transformative treatment. Grounded in evidence and expertise, PBAC's decision prioritises meaningful access to effective therapy for patients with few alternatives.
2026-04-21 | ZW191, an FRα-Targeted Topoisomerase 1 Inhibitor ADC with a Differentiated Antitumor Efficacy and Tolerability Profile.
Multiple antibody-drug conjugates (ADC) are approved for the treatment of human cancers, yet there remains significant potential for design improvements through iterative learnings from nonclinical and clinical experience. ZW191 is a clinical-stage ADC bearing a novel topoisomerase I inhibitor payload and targeted to the clinically validated tumor antigen folate receptor α (FRα). The nonclinical activity and tolerability profiles of ZW191 were assessed in vitro and in vivo, focusing on properties of its antibody and payload components. ZW191 has a highly differentiated efficacy and tolerability profile, markedly improving on the FDA-approved FRα-targeted ADC mirvetuximab soravtansine in its activity in tumors with both high and low levels of FRα in multiple patient-derived xenograft models of ovarian cancer, endometrial cancer, non-small cell lung cancer, and triple-negative breast cancer. ZW191's novel FRα-targeting antibody demonstrates unique binding properties and is superior to multiple other clinical-stage ADC antibodies in its internalization, payload delivery, and penetration through 3D tumor spheroids. ZW191's novel payload drives strong antitumor activity in vitro, including bystander activity. Furthermore, ZW191 is effective in vivo in combination with clinically relevant standard-of-care drugs carboplatin, bevacizumab, and paclitaxel. ZW191's best-in-class tolerability profile in Good Laboratory Practice nonhuman primate toxicity studies is owing to its payload's moderate potency-an ADC feature that we show from a clinical landscape analysis allows for higher dosing in humans. ZW191 demonstrates favorable preclinical efficacy and tolerability. This differentiated profile is supported by initial clinical data, potentially positioning ZW191 to meaningfully improve responses and substantially widen the targetable patient population over standard-of-care treatment.
2026-04-18 | NKG2A inhibition promotes NK cell-CD8+ T cell interactions to improve anticancer immunity in ovarian carcinoma.
Natural killer (NK) cells contribute to tumor immunosurveillance, yet their heterogeneity across cancer types remains incompletely understood. Transcriptomic, spatial, and functional assays reveal that non-small cell lung carcinoma (NSCLC) is enriched in NK cells that mediate clinically relevant effector functions, whereas high-grade serous ovarian carcinoma (HGSOC) contains dysfunctional NK cells that express co-inhibitory receptors including NKG2A. Analysis of HGSOC patient samples and syngeneic mouse models indicates a crosstalk between NK cells and CD8⁺ T cells critical for effective antitumor immunity. Depletion of either population leads to phenotypic impairment of the reciprocal one. Blocking NKG2A restores NK cell cytotoxicity and promotes CD8⁺ T cell responses, significantly improving the efficacy of PD-1 blockade in murine HGSOC models. Thus, NK cells and CD8⁺ T cells engage in a functional interplay of immunological relevance. Moreover, the NKG2A-HLA-E axis represents a clinically actionable immunological checkpoint in tumors with impaired NK cell functions.
2025-12-11 | Fueling the Seed: Growth Factors and Cytokines Driving Cancer Stem Cells in Gynecological Malignancies.
Gynecological cancers remain a major global health burden due to their high incidence, molecular heterogeneity, and frequent resistance to conventional therapies. Beyond well-established genetic alterations and targeted treatments, growing attention has been directed toward the role of cancer stem cells (CSCs), a rare tumor subpopulation with self-renewal, differentiation, and tumor-initiating capacities. CSCs are sustained by a specialized microenvironment, the cancer stem cell niche, where growth factors, cytokines, hypoxia, and stromal interactions converge to promote stemness, chemoresistance, and metastatic potential. In breast cancer, signaling axes such as EGFR, IGF, TGFβ, and HGF/c-Met critically regulate CSC expansion, particularly in aggressive subtypes like triple-negative tumors. In ovarian cancer, factors including HGF, VEGFA, IGF, and stromal-derived BMPs drive CSC plasticity and contribute to relapse after platinum therapy. Endometrial CSCs are supported by pathways involving TGFβ, BMP2, and Netrin-4/c-Myc signaling, while in cervical cancer, VEGF, IGF-1, Gremlin-1, and TGFβ-mediated circuits enhance stem-like phenotypes and drug resistance. Cytokine-driven inflammation, especially via IL-3, IL-6, IL-8, IL-10, and CCL5, further fosters CSC survival and immune evasion across gynecologic malignancies. Preclinical studies demonstrate that targeting growth factors and cytokine signaling, through monoclonal antibodies, receptor inhibitors, small molecules, or cytokine modulation, can reduce CSC frequency, restore chemosensitivity, and enhance immunotherapy efficacy. This review highlights the interplay between CSCs, growth factors, and cytokines as central to tumor progression and relapses, emphasizing their translational potential as therapeutic targets in precision oncology for gynecological cancers.
other
2026-06-06 | Cancer immunotherapy with oncolytic myxoma virus.
Viruses have been developed as oncolytic immunotherapy agents due to their ability to target and kill cancer cells while sparing normal cells. Additionally, engineered oncolytic viruses (OVs) can alter the immunosuppressive tumor microenvironment, making other cancer therapies more favorable. Many candidate OVs are currently in clinical trials as monotherapy or in combination with other cancer therapeutics. Oncolytic myxoma virus (MYXV), a member of the Poxviridae family that infects only leporids in nature and causes no infection to humans or other animals, has been developed as an oncolytic immunotherapy agent. MYXV selectively infects cancer cells due to the accumulation of mutations and the absence of functional antiviral responses within these cells. The large dsDNA genome of MYXV is amenable to the deletion of non-essential immunomodulatory genes and to the insertion of multiple immunostimulatory transgenes with antitumor properties. The systemic and local administration of engineered MYXV promotes changes within the tumor microenvironment that reverse immunosuppression and improve immune activation and infiltration. These cancer tropism and immune activation properties, combined with the absence of preexisting antibodies, led to the testing of MYXV in various types of preclinical cancer models, including pancreatic cancer, glioblastoma, ovarian cancer, melanoma, small cell lung cancer, and hematological malignancies. This review highlights the current progress with the development of MYXV as an immunotherapeutic agent.
2026-02-20 | Efficacy of chimeric antigen receptor natural killer cells in treatment of ovarian cancer. A meta-analysis of pre-clinical studies.
Chimeric antigen receptor (CAR) therapies have expanded beyond T-cells with addition of natural killer (NK) cells. In ovarian cancer, long-term survival remains poor with the rising need for new therapies. Therefore, this meta-analysis evaluated the pre-clinical efficacy of emerging CAR-NK therapies in ovarian cancer models. Following PRISMA-guidelines and registered protocol (PROSPERO, CRD420251131530), literature from PubMed, Web of Science, and Scopus was retrieved till 30-06-2025 for pre-clinical in-vivo studies of CAR-NK therapy in ovarian cancer. Studies without in-vivo components or human CAR-NK were excluded. Primary outcomes were ratio of means (ROM) for tumor burden and median survival ratio (MSR). Data was analyzed in JASP™ and risk of bias (RoB) was determined using SYRCLE's RoB tool for animal studies. Fourteen experiments (21 CAR-NK groups) were included. CAR-NK significantly reduced tumor burden versus untreated controls (ROM 0.09 [0.03-0.32], p < 0.001) and unmodified/mock NK-cells (ROM 0.18 [0.08-0.42], p < 0.001). Survival was significantly prolonged (MSR 1.67 [1.31-2.14] vs. control; 1.40 [1.08-1.83] vs. unmodified/mock NK, both p < 0.05). Subgroup analyses revealed no significant modifiers, though trends favored mesothelin-targeted and NK-92-based CARs. Limited safety data indicated no cytokine release syndrome or graft-versus-host disease. Small sample size in subgroup analyses and unclear RoB in certain areas are some limitations of this study. However, the pooled estimates were robust to sensitivity analyses and relatively insignificant heterogeneity in survival outcomes could be important for poor long-term survival in ovarian cancers. CAR-NK demonstrates potential pre-clinical efficacy in ovarian cancer models, outperforming naive NK-cells with a consistent survival benefit.
2026-01-21 | Dual Targeting of Mutant p53 and SNRPD2 via Engineered Exosomes Modulates Alternative Splicing to Suppress Ovarian Cancer.
Mutation of the tumor suppressor gene TP53 promotes ovarian cancer progression and therapeutic resistance. Whether mutant p53 (mtp53) regulates alternative splicing and how this regulation can be exploited for cancer therapy remain unclear. Here, small nuclear ribonucleoprotein D2 polypeptide (SNRPD2) as a binding partner of mtp53 is identified. SNRPD2 is highly expressed in ovarian cancer and associated with an unfavorable prognosis. The overexpression of SNRPD2 promotes, whereas its depletion inhibits, the growth and migration of ovarian cancer cells. Mechanistically, mtp53 cooperates with SNRPD2 to facilitate the assembly of the Sm/SMN protein complex, an essential component of the spliceosome, modulating alternative splicing of pre-mRNAs. Specifically, the co-depletion of mtp53 and SNRPD2 reduces the level of OTUD3 oncogenic transcripts while increasing its tumor suppressor counterparts through an exon-skipping event. Moreover, therapeutic engineered exosomes are developed with their surfaces decorated with iRGD and their interiors loaded with siRNAs targeting mtp53 and SNRPD2. These exosomes effectively suppress the growth of ovarian cancer cells and enhance their sensitivity to chemotherapy in vivo. Collectively, this study uncovers that mtp53 and SNRPD2 cooperatively regulate alternative splicing to drive ovarian cancer progression, and co-targeting these two molecules via engineered exosomes represents a potential therapeutic strategy for ovarian cancer.
2025-11-28 | Antibody Generation Using Cancer-Derived Small Extracellular Vesicles (sEVs): A Platform for Targeted Cancer Therapy and Potential Personalized Applications.
Despite advances in tumor-targeting therapies, drug delivery efficiency to solid tumors remains low in most preclinical studies, highlighting the need for more effective targeting ligands. A novel method is developed to generate tumor-targeting monoclonal antibodies (mAbs) using cancer-derived small extracellular vesicles (sEVs), which inherit the structural and functional features of their parent cells. sEVs isolated from human ovarian carcinoma cell lines (OVCAR-8) are injected into mice to elicit an immune response. Hybridoma technology is used to generate mAbs, which are screened for either high specificity or cytotoxicity toward OVCAR-8 cells. Two lead mAbs are individually decorated onto paclitaxel-loaded CD8⁺ T cell-derived sEVs (antibody-functionalized TSEV/P; AB-TSEV/P), and the resulting formulations are evaluated in OVCAR-8 tumor-bearing mice. Both AB-TSEV/P formulations significantly reduce tumor growth without affecting body weight. Biodistribution studies using IR780-loaded AB-TSEV reveal enhanced tumor accumulation compared to non-targeted controls. RNA sequencing and spatial transcriptomics show that antibody-decorated sEVs induce transcriptional changes associated with immune activation and tumor suppression. This antibody generation strategy enables cancer cell-specific targeting and supports its application in targeted cancer therapy and personalized oncology.
2025-11-27 | Oncolytic Vaccinia Virus Expressing HSP70 shRNA Exerts Anti-Tumor Effects in Human Ovarian Cancer via Triggering the Autophagy-ROS Feedback Loop and Immune Activation.
Heat shock protein 70 (HSP70) represents a promising target for cancer therapy. Oncolytic vaccinia virus (oncoVV) mediates tumor regression through direct oncolysis and immune activation. However, the anti-tumor potential of HSP70-silenced oncoVV (oncoVV-shHSP70) remains unexplored. Here, we demonstrate that oncoVV-shHSP70 achieves superior tumor regression in ovarian cancer models (cell lines, immunodeficient mice and humanized mice) via dual mechanisms including enhancing apoptosis, autophagy flux, ROS generation, and immune reprogramming. Notably, we found that oncoVV-shHSP70 triggers an autophagy-ROS feedback loop that amplifies viral replication and pro-inflammatory cytokine expression. Crucially, in humanized mice, oncoVV-shHSP70 induced spatial redistribution of cytotoxic T cells, expanding tumor-infiltrating hCD8+hGZMB+ populations. These findings position oncoVV-shHSP70 as a promising viro-immunotherapy that co-opts HSP70 silencing to potentiate both direct oncolysis and anti-tumor immunity, providing a preclinical rationale for viro-immunotherapy in solid tumors.
small molecules
2026-09-29 | Case Report: Primary ovarian pulmonary-type small cell neuroendocrine carcinoma mimicking benign adnexal torsion: a diagnostic challenge.
Small cell carcinoma of the ovary, pulmonary type (SCCOPT), is a rare and aggressive ovarian neuroendocrine carcinoma. Because its clinical and radiological features overlap with benign adnexal conditions and metastatic neuroendocrine tumors, preoperative diagnosis remains challenging. Here, we report a rare case of SCCOPT presenting as acute abdomen associated with adnexal torsion, tumor rupture, and hemoperitoneum, which complicated recognition of the underlying malignancy. A woman in her early 60s presented with acute lower abdominal pain, abdominal distension, and syncope. Pelvic magnetic resonance imaging revealed a complex cystic-solid adnexal mass. Emergency laparoscopy demonstrated left adnexal torsion, tumor rupture, active bleeding, and approximately 550 mL of hemoperitoneum. Histopathological examination revealed a high-grade small cell neuroendocrine carcinoma. Immunohistochemical analysis supported the diagnosis of SCCOPT, showing positivity for synaptophysin, chromogranin A, and CD56, with negative TTF-1 expression, loss of Rb expression, and retained SMARCA4 expression. Postoperative evaluation, including PET-CT, gastroscopy, and colonoscopy, showed no evidence of an extra-ovarian primary tumor. Tumor-blood sequencing identified an HRD-negative/BRCA-wild-type profile and a somatic TP53 mutation, further supporting the high-grade neuroendocrine phenotype. The patient underwent surgical staging followed by six cycles of carboplatin plus etoposide chemotherapy and remained without clinically evident recurrence at the latest follow-up. SCCOPT may initially present as an acute gynecological emergency and mimic benign adnexal torsion, potentially delaying recognition of malignancy. Accurate diagnosis requires integration of clinical presentation, imaging findings, histopathology, immunophenotyping, molecular alterations, and exclusion of extra-ovarian primary sites. This case emphasizes the importance of considering ovarian malignancy, including SCCOPT, in postmenopausal women presenting with acute adnexal events.
2026-09-25 | Converting lysosomes into photothermal organelles enables nanoparticle-free tumor ablation via intracellular vapor bubbles.
Photothermal nanomaterials enable precise tumor ablation but face limitations in biodistribution, tissue penetration, toxicity, and biodegradability. Here, we present a unique concept for nanoparticle-free photothermal therapy based on the lysosomal entrapment of cationic amphiphilic small molecular dyes for spatially controlled vapor bubble (VB)-mediated tumor cell ablation. This strategy, which exploits a universal biological and physical effect, uses intracellular pH gradients for extensive local dye enrichment in acidified organelles, transforming them into transient endogenous nanosized photothermal reactors for subsequent light activation. Using sunitinib, a clinically approved lysosomotropic anticancer drug, and the commercially available dye LysoTracker Deep Red, lacking intrinsic anticancer activity, we demonstrate pulsed laser-induced VB formation from dye-enriched lysosomal compartments, leading to selective photomechanical disruption of various ex vivo cancer cell models across two-dimensional (2D) cultures, 3D spheroids, patient-derived neuroblastoma tumoroids, and tumor fragments from a patient with ovarian carcinoma. This approach allows precise, low-fluence, and wavelength-tunable cancer tissue ablation without the need for synthetic photoresponsive nanoparticles.
2026-09-01 | Identification of New Putative Autotaxin Inhibitors via Structure-Based Virtual Screening and Evaluation of Their Antiproliferative Properties Against Ovarian and Breast Cancer Cells.
Autotaxin (ATX), a lysophospholipase D playing an important role in several inflammatory diseases, as well as in tumor invasion, progression, and metastasis, is an attractive therapeutic target. Herein, we report a virtual screening study of an in-house molecular database. In silico simulations highlighted five putative ATX inhibitors. The enzyme assay showed that compound 3 achieves inhibition potency in the submicromolar range (IC50 = 0.534 µM), whereas all the other test compounds proved to be moderate (2) or weak (1, 4, and 5) inhibitors of ATX at 10 µM concentration. These compounds, evaluated for the in vitro antiproliferative activity in four ATX-expressing cancer cell lines, namely the ovarian cancer cell lines A2780 and SK-OV-3, the breast cancer cells MCF-7, and immortalized mouse embryonic fibroblast cell line NIH/3T3, demonstrated preliminary phenotypic effects, inhibiting cell proliferation with IC50 values mostly in the low micromolar range. Compound 4 (IC50 = 11.5 µM against SK-OV-3) significantly reduced the motility of SK-OV-3 ovarian carcinoma cells in the wound-healing assay, suggesting that it may represent a hit structure for the development of potential antimetastatic agents.
2026-08-19 | Case Report: Personalized therapy in gynecological neuroendocrine neoplasm: a case of BRCA2-mutated ovarian neuroendocrine carcinoma treated with PARP-inhibitor.
Neuroendocrine neoplasms (NENs) of the female genital tract are rare and typically aggressive malignancies, accounting for only 1-2% of gynecologic tumors. The majority (54%) are located in the cervix. Ovarian neuroendocrine carcinomas (O-NECs) represent less than 1% of all ovarian cancers and 16% of all gynecologic NENS; these tumors are associated with poor prognosis, with an overall survival (OS) ranging from 11 to 20 months and progression-free survival (PFS) between 12-14.71 months. To date, approximately 923 cases have been reported in the literature and owing to their rarity no standardized treatment protocols have been established. We retrospectively reviewed all cases of NENs of female genital tract treated at the Gynecologic Oncology Unit of Fondazione IRCCS Istituto Nazionale Tumori of Milan, Italy. Moreover, we describe an interesting case of a 66-year-old woman with O-NEC and harboring a BRCA2 mutation. Patient achieved a pathological complete response following platinum-based chemotherapy and subsequently received a maintenance therapy with PARP-inhibitor. From 2005 to June 2025, a total of 42 women with NENs of the female genital tract were treated at the Gynecologic Oncology Unit of Fondazione IRCCS Istituto Nazionale Tumori of Milan (Italy): 59% originated from cervix, 29% from endometrium and 12% from ovaries. Median OS and PFS of patients with O-NEC were consistent with literature data (15 and 11 months, respectively); all patients underwent surgery followed by platinum-etoposide chemotherapy and then follow up. In May 2024, a 66-year-old woman underwent exploratory laparoscopy for a large pelvic mass (121×83×137 mm) associated with hemoperitoneum, bilateral grade 3 hydronephrosis and rectum infiltration. Final histopathological diagnosis was of small cell ovarian neuroendocrine carcinoma (SCNEC), FIGO stage IV, due to the presence of the hepatic metastasis. Next-generation sequencing (NGS) performed on tumor tissue revealed a pathogenetic BRCA2 mutation. Following multidisciplinary tumor board discussion, patient received 4 cycles of carboplatin-etoposide chemotherapy with an excellent radiological response and significant tumor marker reduction (CA125: 477→9.4 U/ml; NSE: 629→8.9 ng/mL; CEA: 560→16.9 ng/mL). The histopathology report, performed after interval debulking surgery, confirmed a complete pathological response. She completed systemic treatment with two additional cycles of chemotherapy and then, she started compassionate-use maintenance therapy with PARP inhibitor based on the presence of the BRCA2 mutation. Today, after 12 months to the end of chemotherapy, patient has not evidence of recurrence disease, she is in good clinical condition and maintenance treatment with PARP inhibitor is still ongoing. To the best of our knowledge, only 1 prior case of BRCA2-mutated O-NEC patient treated with PARP-inhibitor has been reported in literature, with a PFS of 2 months, suggesting limited efficacy of PARP inhibitors in this setting. However, our case may indicate a potential benefit in selected patients. O-NECs are rare and poorly characterized malignancies, lacking standardized diagnostic and therapeutic protocols. Therefore, comprehensive characterization of individual cases is crucial to improve knowledge and patient outcomes. This case highlights the pivotal role of molecular profiling in identifying candidates for personalized therapeutic approaches. Further experiences are needed to expand current knowledge and evaluate the potential benefit of PARP inhibitors in BRCA-mutated O-NEC patients.
2026-07-24 | Atranorin suppresses the LUCAT1/STAT3 axis to induce ferroptotic cell death in ovarian cancer.
Ovarian cancer remains the most lethal gynecological malignancy and represents a major cause of cancer-related mortality among women worldwide. Despite advances in therapeutic strategies, treatment efficacy is frequently limited by systemic toxicity, chemoresistance, and disease recurrence, highlighting the urgent need for novel, mechanism-based targeted therapies with improved safety profiles. In the present study, we investigated the anti-cancer activity of atranorin (ATR), a naturally derived small-molecule compound, with a particular focus on its ability to induce ferroptosis by modulation of the LUCAT1/STAT3 signaling axis. Human ovarian cancer cell lines (OVCAR-3 and SKOV-3) and normal ovarian surface epithelial (OSE) cells were employed to evaluate cytotoxic selectivity and mechanistic effects. ATR selectively inhibited proliferation of ovarian cancer cells while exerting minimal cytotoxicity toward normal OSE cells. Mechanistic analyses demonstrated that ATR significantly suppressed LUCAT1 and STAT3 expression at both mRNA and protein levels, as confirmed by qRT-PCR and Western blotting. Concomitantly, ATR upregulated ferroptosis-related genes and proteins. Biochemical assessments revealed increased intracellular reactive oxygen species (ROS), elevated malondialdehyde (MDA) and iron accumulation, and depletion of glutathione (GSH), collectively indicating activation of ferroptotic cell death. Furthermore, ATR significantly impaired migratory and invasive capacities of ovarian cancer cells. Collectively, our findings identify ATR as a compound capable of inducing biochemical features consistent with ferroptosis in ovarian cancer through suppression of the LUCAT1/STAT3 axis. These results uncover a previously uncharacterized mechanistic pathway underlying ATR-mediated anti-tumor effect and support its potential development as a targeted therapeutic candidate for ovarian cancer management.
proteins
2026-09-07 | Integrating Tumor Targeting and Half-Life Extension into a Dual-Surfaced Single-Domain ADAPT Protein.
Folate receptor alpha (FRα) is frequently overexpressed in ovarian cancer while showing limited expression in healthy tissues. Targeting of FRα has been extensively investigated using antibody-based therapies but less so with small scaffold proteins. Small scaffold proteins represent an alternative approach with potential advantages such as site-specific conjugation and deep tumor penetration but are limited by a short half-life. Here, we describe the development of a dual-surfaced ADAPT scaffold protein (6 kDa) with simultaneous bispecificity for FRα and albumin. Using combinatorial libraries and phage display, we identified a candidate, termed ADAPT22, with high isoform selectivity and subnanomolar affinity for FRα (KD = 0.8 nM), paired with a low nanomolar affinity for albumin (KD = 2.4 nM). Importantly, ADAPT22 is able to interact with both targets simultaneously, truly combining extended retention in blood via albumin association and tumor targeting via FRα within a single-domain protein. The simultaneous nature was verified in vitro to soluble proteins and to FRα-positive cells and in vivo using a mouse xenograft model. In mice, ADAPT22 demonstrated markedly extended blood retention, reduced renal uptake, and specific accumulation in FRα-positive tumors, confirming simultaneous dual-surface binding. To the best of our knowledge, this is the smallest half-life extended affinity protein designed for therapeutic targeting of FRα.
2026-03-06 | Micropeptide YG-6 encoded by exosomal LINC01123 derived from highly migratory ovarian cancer cells promotes tumor progression.
BACKGROUND: Intercellular crosstalk plays a pivotal role in tumor progression and metastasis. Exosomes can package long non-coding RNAs (lncRNAs) to mediate extracellular communication. Although exosome research in various cancers has made remarkable progress, it remains unclear in ovarian cancer (OC) whether the cellular communication between OC cells with different metastatic potentials influences progression via exosomal-lncRNA. Besides, lncRNA can encode functional micropeptides, yet the association between OC and micropeptides encoded by exosomal-derived lncRNA has not been reported. METHODS: OC cell-derived exosomes were characterized using transmission electron microscopy, nanoparticle tracking analysis, and WB. Exosomal lncRNA sequencing results of highly migratory OC cells (HMOs) and low migratory OC cells (LMOs) were analyzed, and LINC01123 was selected for further study. The effect of exosome LINC01123 on the function of LMOs was detected by the co-culture experiment. Bioinformatics prediction, mass spectrometry (MS), WB, and a series of functional experiments showed that LINC01123 encodes a small 59 aa peptide, named YG-6 (LINC01123 Yield peptide Gaining metastasis function: ORF no.6). Immunofluorescence, qPCR, WB, immunohistochemistry, and MS analysis were used to detect the endogenous expression of YG-6 in OC cells and tissues. The function of YG-6 in OC was investigated by detecting cell migration ability and observing tumor metastasis in nude mice. Mechanistically, the relationship between the YG-6 and ACTC1 in OC was verified by Co-Immunoprecipitation, WB, MS, immunofluorescence, and functional experiment. RESULTS: LINC01123 was significantly up-regulated in exosomes derived from HMOs and was readily internalized by LMOs, promoting their malignant behavior. Interestingly, LINC01123 encodes a small peptide composed of 59 amino acids, named YG-6, which exhibits endogenous high expression in OC cells and tissues. Functional experiments demonstrated that LINC01123 promotes tumor progression by encoding the peptide YG-6, rather than via an RNA-dependent mechanism. Furthermore, we identified ACTC1 as a binding protein of YG-6, which can synergistically activate the focal adhesion signaling pathway together with YG-6, thereby promoting the migration and adhesion of LMOs. CONCLUSIONS: Our findings not only demonstrate the YG-6 peptide encoded by LINC01123 as a potential prognostic biomarker for OC but also uncover a new mechanism of OC progression driven by YG-6 peptides.
2025-12-09 | Pan-cancer profiling links C1orf50 to DNA repair and immune modulation in ovarian cancer.
C1orf50 encodes a small, evolutionarily conserved protein, the function of which remains unclear. Its significance across various human cancers, particularly its specific role in ovarian cancer within an immunogenomic context, is not yet fully understood. Utilizing The Cancer Genome Atlas and single-cell RNA sequencing (scRNA-seq) public datasets, we conducted a comprehensive profiling of C1orf50 across multiple cancer types, with a particular focus on ovarian cancer, to investigate its associations with copy-number status, genomic instability, tumor programs, and the immune microenvironment. Across cancer types, copy-number gain or amplification of C1orf50 was most frequent in ovarian cancer and closely tracked with higher messenger RNA levels. Higher C1orf50 expression was associated with a greater tumor mutational burden and homologous recombination deficiency, as indicated by gene-set patterns that suggested heightened cell-cycle and cellular stress responses accompanied by reduced oxidative phosphorylation, enrichment of regulatory T cells, and depletion of resting memory CD4 T cells. In ovarian cancer, focal events at chromosome 1p34.2 were accompanied by stepwise increases in C1orf50 expression by clinical stage and were linked to higher tumor mutational burden, homologous recombination deficiency, and greater loss of heterozygosity, together with more frequent gene alterations in BRCA1 or BRCA2. Immune composition clustered into profiles consistent with an immunosuppressive context in tumors with higher C1orf50 expression. The scRNA-seq data further revealed that cancer cells enhanced immune-suppressive interactions with various immune cell populations and diminished antigen-presentation signals. Analyses of genomic instability in ovarian cancer suggested mutational processes compatible with base-substitution patterns associated with cytidine deaminase activity and with insertion-deletion patterns characteristic of homologous recombination failure, while transcript-level patterns pointed to a broad downshift of canonical DNA repair activity with apparent compensatory adjustments in related pathways rather than a uniform change in any single pathway. The overexpression of C1orf50 characterizes an aggressive immunogenomic phenotype in ovarian cancer, distinguished by genomic instability, impaired DNA repair mechanisms, and extensive immunosuppression. These findings indicate that C1orf50 warrants consideration as a potential biomarker and a prospective target for therapeutic investigation. Furthermore, they advocate for the progression to prospective validation and functional studies to ascertain its clinical significance.
2025-11-08 | Tβ4-17 peptide enhances the chemo-sensitivity of ovarian cancer cells to DDP by affecting NF-κB signaling pathway.
Ovarian cancer is a gynecologic malignancy with high mortality and poor prognosis. Chemoresistance is a key cause of ovarian cancer recurrence and metastasis. It has been found that some bioactive peptides can inhibit the growth and metastasis of cancer cells and promote cell apoptosis, thus exerting anti-cancer effects. Tβ4-17 is a small polypeptide that we selected using ITRAQ technology, and its precursor protein is thymosin β4. This study mainly investigated its effect in combination with cisplatin (DDP) on the proliferation, migration and apoptosis of ovarian cancer resistant cells and related molecular mechanisms. Our results showed that Tβ4-17 peptide combined with DDP significantly inhibited the proliferation and migration of drug resistance cells in ovarian cancer, promoted apoptosis, and increased the chemo-sensitivity of ovarian cancer cells to DDP. In addition, qRT-PCR and Western blot showed that NF-κB was significantly highly expressed in DDP-resistant cells of ovarian cancer. After application of NF-κB inhibitors and activators, Western blot, CCK8, EDU fluorescence proliferation assay, and cell scratch assay showed that Tβ4-17 peptide down-regulated NF-κB p65 protein expression and inhibited cell proliferation and migration. In conclusion, our study demonstrates that Tβ4-17 peptide enhances the sensitivity of ovarian cancer cells to DDP by down-regulating NF-κB expression.
2025-07-13 | MYC Regulates a DNA Repair Gene Expression Program in Small Cell Carcinoma of the Ovary, Hypercalcemic Type.
SCCOHT is an aggressive and often fatal cancer that belongs to the ~20% of cancers defined by mutations to subunits of the SWI/SNF chromatin remodeling complex. In SCCOHT, mutations to the SMARCA4 gene, which encodes the SWI/SNF ATPase BRG1, are sufficient to impair SWI/SNF function. This single genetic lesion leads to a cascade of events that promote tumorigenesis, some of which may involve the intersection of SWI/SNF with oncogenic pathways such as those regulated by the MYC oncogene. In SCCOHT tumors and other cancers marked by SWI/SNF subunit mutation, MYC target genes are recurrently activated, pointing to a relationship between SWI/SNF and MYC that has yet to be fully explored. In this study, we investigate the contribution of MYC to SCCOHT biology by performing a combination of chromatin binding and transcriptome assays in genetically engineered SCCOHT cell lines, with subsequent validation using patient tumor expression data. We find that MYC binds to thousands of active promoters in the BIN-67 SCCOHT cell line and that the depletion of MYC results in a broad range of gene expression changes with a notable effect on the expression of genes related to DNA repair. We uncover an MYC-regulated DNA repair gene expression program in BIN-67 cells that is antagonized by BRG1 reintroduction. Finally, we identify a DNA repair gene signature that is upregulated in SCCOHT tumors and in tumors defined by loss of the SWI/SNF subunit SNF5. Collectively, these data implicate MYC as a robust regulator of DNA repair gene expression in SCCOHT and lay a foundation for future studies focused on interrogating the relationship between BRG1 and MYC.
oligonucleotides
2026-06-17 | Developing a pan cancer therapy based on DISE-inducing short RNAs.
RNA interference (RNAi) regulates gene expression through small RNAs that act via Argonaute-containing RNA-induced silencing complexes (RISCs). We previously found that short RNAs with G-rich 6mer seeds (e.g., GGGGGC and G5C) can kill cells by targeting C-rich 3' UTR seed matches in essential survival genes (SGs), a mechanism termed death induced by survival gene elimination (DISE). To assess therapeutic potential, we systemically delivered two DISE-inducing sRNAs, sG5C and sCAG (based on CAG trinucleotide repeats), using lipopolyplexes (LPPs) composed of low-molecular-weight polyethyleneimines and lipids. In mouse ovarian and prostate cancer models and a rat hepatocellular carcinoma model, LPP-delivered small RNAs (sRNAs) markedly reduced or eliminated tumors without harming normal tissues. Predicted SG targets were engaged in tumors. Transcriptomic analyses across 10 major human cancers showed that many sG5C-targeted SGs are consistently upregulated in tumors and increase with stage, revealing a therapeutic window. These results support LPP-delivered DISE-inducing sRNAs as a promising pan-cancer therapy.
2026-05-10 | Disruption of the SNRPF-DDX24-E2F4 Feedback Loop Uncouples Splicing and Transcriptional Regulation to Suppress Ovarian Cancer Progression.
Ovarian cancer (OC) remains a major cause of gynecologic cancer mortality, with progress in targeted therapy limited by an incomplete understanding of post-transcriptional oncogenic drivers. Dysregulated RNA splicing-particularly intron retention (IR)-is increasingly recognized as a key driver of tumor progression. Here, integrated transcriptomic and proteomic analyses identify SNRPF, a core spliceosomal component, as a potent oncogenic driver in OC. SNRPF is highly expressed in tumor specimens, and its overexpression predicts poor patient survival. Silencing SNRPF suppresses proliferation, invasion, and xenograft growth. IR-focused analysis reveals that SNRPF depletion induces intron 6 retention in DDX24, disrupting the Helicase_C domain and generating premature termination codons that activate nonsense-mediated decay (NMD), thereby reducing DDX24 protein abundance and markedly impairing its oncogenic function. DDX24 depletion similarly promotes intron 2 retention in E2F4, causing NMD-mediated downregulation. Notably, E2F4 directly binds the SNRPF promoter, forming a self-sustaining "SNRPF-DDX24-E2F4" axis linking splicing and transcriptional regulation. Antisense oligonucleotide-mediated inhibition of SNRPF disrupts this feedback loop, downregulates DDX24 and E2F4 via IR, and significantly impairs tumor growth in vitro, in vivo, and in patient-derived xenografts. These findings define a splicing-transcription coupling mechanism in OC and position SNRPF as a promising therapeutic target.
2026-04-04 | Single-cell transcriptomics reveals FXR1 as an actionable target for siRNA therapy in ovarian cancer.
Ovarian cancer is one of the leading causes of cancer-related mortality among women and remains exceptionally difficult to manage and treat effectively in the clinic. Fragile X-related protein 1 (FXR1) is highly amplified and overexpressed in ovarian and several other cancers. FXR1 is a key regulator of the translation of multiple oncogenes and therefore represents a vulnerable target for cancer therapy. RNA interference (RNAi) of FXR1 using a locked nucleic acid (LNA) form of siRNA (siFXR1-LNA) inhibits tumor growth, ascites formation, and metastasis of ovarian cancer more efficiently than the native form of FXR1 siRNA in vivo. LNA modification of siRNA improves resistance to RNase mediated degradation and enhances tumor tissue uptake of siRNA with robust inhibition of target mRNA in tumor tissues. Single-cell RNA sequencing (scRNA-seq) analysis of ascites composed of tumor, stromal, and immune cells analysis reveals that FXR1 silencing suppresses tumor cell proliferation and reduces tumor-promoting M2-like macrophages. FXR1 silencing also increases cytotoxic T cells, NK cells, and dendritic cells with anti-tumor characteristics in vivo. Collectively, our data establishes FXR1 as an important regulator of oncogenic processes in cancer tissues and serves as a therapeutic liability. Therefore, FXR1 silencing in tumor tissues provides an effective strategy to treat tumors expressing high levels of FXR1.
2025-12-09 | Synergistic effect study on the co-delivery of paclitaxel and SiRNA targeting STMN1 based on MPDA nanoparticles in the therapy of ovarian cancer.
Ovarian cancer is one of the most prevalent gynecologic malignancies and ranks as a leading cause of death in female cancers. Chemotherapy remains the primary treatment modality, however, the development of chemoresistance poses a significant obstacle in ovarian cancer therapy, contributing to its high mortality rate. In this paper, we report a multifunctional nanoparticle that enables laser-controlled release of co-loaded paclitaxel (PTX) and STMN1 siRNA for synergistic combination therapy. This nanoparticle can improve the microtubule stability by interfering the expression of STMN1, thereby increasing the sensitivity to PTX, blocking cells in the G2/M phase, and ultimately leading to cancer cell death. Additionally, it exhibits enhanced bioavailability, reduced systemic toxicity, and photothermal properties suitable for in vivo imaging. Our nanoparticle offers an innovative strategy for the concurrent therapy and monitoring of ovarian cancer, enhancing therapeutic efficacy and diagnostic precision.
2025-11-27 | Engineered NK92 cell-derived exosomes inhibit ovarian cancer progression by degrading GPRC5A.
Natural killer (NK) 92 (NK92) cells are critical immune-effectors with established roles in treating metastatic and hematological malignancies. Owing to the substantial adverse effects, including cytokine release syndrome, associated with NK92 cell therapy, research interest has pivoted toward the safer and potentially more efficient exosome-based approaches. However, the composition, properties, and functions of NK92 cell-derived exosomes remain largely unknown. In this study, NK92 cell-derived exosomes were isolated via ultracentrifugation. Small RNA sequencing and proteomic sequencing were performed on both the cells and their exosomes. To enhance exosome targeting to tumor cells, the tLyP-1 targeting peptide was displayed on NK92 cell surfaces through genetic engineering. The mechanism underlying tumor therapy mediated by NK92 cell-derived exosomes was investigated through in vitro and in vivo experiments. Additionally, we designed a cholesterol-modified ABCB1 siRNA that adsorbs onto exosome surfaces and enters recipient cells to silence target genes. First, small RNA sequencing and proteomic analysis of NK92 cells and NK92 cell-derived exosomes revealed that the exosomes retained the anti-tumor activity of parental NK cells, inhibiting tumor progression by modulating apoptosis, proliferation, and metastasis. Second, tLyP-1-modified exosomes exhibited enhanced tumor-targeting specificity and exerted anti-tumor effects via the miR-31-5p-GPRC5A axis. Furthermore, NK92 cell-derived exosomes effectively delivered ABCB1 siRNA into recipient cells, mediating efficient gene silencing to sensitize chemoresistant ovarian cancer cells to therapeutic agents. Overall, this study provides a novel strategy to treat ovarian cancer through the preparation of genetically modified NK92 cell-derived exosomes loaded with RNA interference.
antibodies
2026-05-22 | Assessment of delta-like ligand 3 (DLL3) immunostaining in neuroendocrine tumors of the gynecological tract and comparing expression with other high-grade gynecological malignancies.
Neuroendocrine tumors (NETs) of the gynecologic tract are diagnostically challenging because of their heterogeneity. Delta-like ligand 3 (DLL3), an inhibitory Notch receptor ligand, is frequently overexpressed in NETs and has emerged as a potential diagnostic and therapeutic target. This study evaluated DLL3 expression in 76 paraffin-embedded tissue samples from 74 patients, including cervical and ovarian small cell carcinomas/NETs, cervical large cell carcinoma/NET, metastatic NETs, dedifferentiated/undifferentiated carcinomas, carcinosarcomas, and high-grade serous carcinomas. DLL3 positivity was defined by cytoplasmic staining and assessed by staining intensity (0-3+) and percentage of positive tumor cells. DLL3 expression was detected in 83% of cervical small cell carcinomas/NETs, 67% of ovarian small cell carcinomas/NETs, and 100% of cervical large-cell carcinoma/NETs, all showing strong (3+) staining and seen in 5% to 100% of the tumor cells. Metastatic NETs demonstrated lower expression (14%, 3+), which was seen in 90% of the tumor cells. Among dedifferentiated/undifferentiated carcinomas, 60% showed DLL3 positivity in scattered undifferentiated foci with staining intensities ranging from 1+ to 3+. DLL3 expression was also identified in 62% of carcinosarcomas within scattered foci of sarcomatous areas, with 2+ to 3+ intensity. In contrast, high-grade serous carcinomas lacked DLL3 expression. These findings demonstrate frequent DLL3 expression in gynecologic NETs and selected dedifferentiated malignancies, supporting DLL3 as a promising diagnostic marker and potential therapeutic target in gynecologic cancers.
2026-05-10 | The case for tumour-agnostic reimbursement of dual immunotherapy.
Barjesteh van Waalwijk van Doorn-Khosrovani and colleagues raise important questions about this recommendation for tumour-agnostic reimbursement of nivolumab and ipilimumab in Australia. We respectfully offer a counterpoint and endorse the broad coverage. In 2025, Pharmaceutical Benefits Advisory Committee (PBAC) proposed that prescribing nivolumab and ipilimumab be guided by clinical judgement informed by the best available evidence for undefined "immunotherapy-sensitive" advanced or metastatic cancers, and, in January 2026 made a similar recommendation for pembrolizumab. Patients with rare and ultra-rare cancers, including but not limited to angiosarcoma, alveolar soft part sarcoma, gestational trophoblastic disease, small cell carcinoma of the ovary (hypercalcemic type), and adrenocortical carcinoma, face profound unmet need. Within many of these diseases, a subset of patients derives substantial benefit from immunotherapy. For example, the SWOG DART (Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors) trial, the largest prospective evaluation of nivolumab plus ipilimumab in rare/ultra-rare cancers, demonstrated clinically meaningful activity across multiple histologies, without biomarker selection. Notably, some patients with metastatic disease remain disease-free years after treatment, outcomes rarely achieved with chemotherapy or supportive care in refractory settings. Therefore, concerns that biomarker-agnostic approval signals an evidentiary retreat overlook both our incomplete understanding immune sensitivity and the global access limits to comprehensive genomic testing. Importantly, clinical judgement is not arbitrary; it reflects training, experience, ethical reasoning, and patient-centred decision making. The question is whether demanding perfect evidence should prevent access to potentially transformative treatment. Grounded in evidence and expertise, PBAC's decision prioritises meaningful access to effective therapy for patients with few alternatives.
2026-04-21 | ZW191, an FRα-Targeted Topoisomerase 1 Inhibitor ADC with a Differentiated Antitumor Efficacy and Tolerability Profile.
Multiple antibody-drug conjugates (ADC) are approved for the treatment of human cancers, yet there remains significant potential for design improvements through iterative learnings from nonclinical and clinical experience. ZW191 is a clinical-stage ADC bearing a novel topoisomerase I inhibitor payload and targeted to the clinically validated tumor antigen folate receptor α (FRα). The nonclinical activity and tolerability profiles of ZW191 were assessed in vitro and in vivo, focusing on properties of its antibody and payload components. ZW191 has a highly differentiated efficacy and tolerability profile, markedly improving on the FDA-approved FRα-targeted ADC mirvetuximab soravtansine in its activity in tumors with both high and low levels of FRα in multiple patient-derived xenograft models of ovarian cancer, endometrial cancer, non-small cell lung cancer, and triple-negative breast cancer. ZW191's novel FRα-targeting antibody demonstrates unique binding properties and is superior to multiple other clinical-stage ADC antibodies in its internalization, payload delivery, and penetration through 3D tumor spheroids. ZW191's novel payload drives strong antitumor activity in vitro, including bystander activity. Furthermore, ZW191 is effective in vivo in combination with clinically relevant standard-of-care drugs carboplatin, bevacizumab, and paclitaxel. ZW191's best-in-class tolerability profile in Good Laboratory Practice nonhuman primate toxicity studies is owing to its payload's moderate potency-an ADC feature that we show from a clinical landscape analysis allows for higher dosing in humans. ZW191 demonstrates favorable preclinical efficacy and tolerability. This differentiated profile is supported by initial clinical data, potentially positioning ZW191 to meaningfully improve responses and substantially widen the targetable patient population over standard-of-care treatment.
2026-04-18 | NKG2A inhibition promotes NK cell-CD8+ T cell interactions to improve anticancer immunity in ovarian carcinoma.
Natural killer (NK) cells contribute to tumor immunosurveillance, yet their heterogeneity across cancer types remains incompletely understood. Transcriptomic, spatial, and functional assays reveal that non-small cell lung carcinoma (NSCLC) is enriched in NK cells that mediate clinically relevant effector functions, whereas high-grade serous ovarian carcinoma (HGSOC) contains dysfunctional NK cells that express co-inhibitory receptors including NKG2A. Analysis of HGSOC patient samples and syngeneic mouse models indicates a crosstalk between NK cells and CD8⁺ T cells critical for effective antitumor immunity. Depletion of either population leads to phenotypic impairment of the reciprocal one. Blocking NKG2A restores NK cell cytotoxicity and promotes CD8⁺ T cell responses, significantly improving the efficacy of PD-1 blockade in murine HGSOC models. Thus, NK cells and CD8⁺ T cells engage in a functional interplay of immunological relevance. Moreover, the NKG2A-HLA-E axis represents a clinically actionable immunological checkpoint in tumors with impaired NK cell functions.
2025-12-11 | Fueling the Seed: Growth Factors and Cytokines Driving Cancer Stem Cells in Gynecological Malignancies.
Gynecological cancers remain a major global health burden due to their high incidence, molecular heterogeneity, and frequent resistance to conventional therapies. Beyond well-established genetic alterations and targeted treatments, growing attention has been directed toward the role of cancer stem cells (CSCs), a rare tumor subpopulation with self-renewal, differentiation, and tumor-initiating capacities. CSCs are sustained by a specialized microenvironment, the cancer stem cell niche, where growth factors, cytokines, hypoxia, and stromal interactions converge to promote stemness, chemoresistance, and metastatic potential. In breast cancer, signaling axes such as EGFR, IGF, TGFβ, and HGF/c-Met critically regulate CSC expansion, particularly in aggressive subtypes like triple-negative tumors. In ovarian cancer, factors including HGF, VEGFA, IGF, and stromal-derived BMPs drive CSC plasticity and contribute to relapse after platinum therapy. Endometrial CSCs are supported by pathways involving TGFβ, BMP2, and Netrin-4/c-Myc signaling, while in cervical cancer, VEGF, IGF-1, Gremlin-1, and TGFβ-mediated circuits enhance stem-like phenotypes and drug resistance. Cytokine-driven inflammation, especially via IL-3, IL-6, IL-8, IL-10, and CCL5, further fosters CSC survival and immune evasion across gynecologic malignancies. Preclinical studies demonstrate that targeting growth factors and cytokine signaling, through monoclonal antibodies, receptor inhibitors, small molecules, or cytokine modulation, can reduce CSC frequency, restore chemosensitivity, and enhance immunotherapy efficacy. This review highlights the interplay between CSCs, growth factors, and cytokines as central to tumor progression and relapses, emphasizing their translational potential as therapeutic targets in precision oncology for gynecological cancers.
other
2026-06-06 | Cancer immunotherapy with oncolytic myxoma virus.
Viruses have been developed as oncolytic immunotherapy agents due to their ability to target and kill cancer cells while sparing normal cells. Additionally, engineered oncolytic viruses (OVs) can alter the immunosuppressive tumor microenvironment, making other cancer therapies more favorable. Many candidate OVs are currently in clinical trials as monotherapy or in combination with other cancer therapeutics. Oncolytic myxoma virus (MYXV), a member of the Poxviridae family that infects only leporids in nature and causes no infection to humans or other animals, has been developed as an oncolytic immunotherapy agent. MYXV selectively infects cancer cells due to the accumulation of mutations and the absence of functional antiviral responses within these cells. The large dsDNA genome of MYXV is amenable to the deletion of non-essential immunomodulatory genes and to the insertion of multiple immunostimulatory transgenes with antitumor properties. The systemic and local administration of engineered MYXV promotes changes within the tumor microenvironment that reverse immunosuppression and improve immune activation and infiltration. These cancer tropism and immune activation properties, combined with the absence of preexisting antibodies, led to the testing of MYXV in various types of preclinical cancer models, including pancreatic cancer, glioblastoma, ovarian cancer, melanoma, small cell lung cancer, and hematological malignancies. This review highlights the current progress with the development of MYXV as an immunotherapeutic agent.
2026-02-20 | Efficacy of chimeric antigen receptor natural killer cells in treatment of ovarian cancer. A meta-analysis of pre-clinical studies.
Chimeric antigen receptor (CAR) therapies have expanded beyond T-cells with addition of natural killer (NK) cells. In ovarian cancer, long-term survival remains poor with the rising need for new therapies. Therefore, this meta-analysis evaluated the pre-clinical efficacy of emerging CAR-NK therapies in ovarian cancer models. Following PRISMA-guidelines and registered protocol (PROSPERO, CRD420251131530), literature from PubMed, Web of Science, and Scopus was retrieved till 30-06-2025 for pre-clinical in-vivo studies of CAR-NK therapy in ovarian cancer. Studies without in-vivo components or human CAR-NK were excluded. Primary outcomes were ratio of means (ROM) for tumor burden and median survival ratio (MSR). Data was analyzed in JASP™ and risk of bias (RoB) was determined using SYRCLE's RoB tool for animal studies. Fourteen experiments (21 CAR-NK groups) were included. CAR-NK significantly reduced tumor burden versus untreated controls (ROM 0.09 [0.03-0.32], p < 0.001) and unmodified/mock NK-cells (ROM 0.18 [0.08-0.42], p < 0.001). Survival was significantly prolonged (MSR 1.67 [1.31-2.14] vs. control; 1.40 [1.08-1.83] vs. unmodified/mock NK, both p < 0.05). Subgroup analyses revealed no significant modifiers, though trends favored mesothelin-targeted and NK-92-based CARs. Limited safety data indicated no cytokine release syndrome or graft-versus-host disease. Small sample size in subgroup analyses and unclear RoB in certain areas are some limitations of this study. However, the pooled estimates were robust to sensitivity analyses and relatively insignificant heterogeneity in survival outcomes could be important for poor long-term survival in ovarian cancers. CAR-NK demonstrates potential pre-clinical efficacy in ovarian cancer models, outperforming naive NK-cells with a consistent survival benefit.
2026-01-21 | Dual Targeting of Mutant p53 and SNRPD2 via Engineered Exosomes Modulates Alternative Splicing to Suppress Ovarian Cancer.
Mutation of the tumor suppressor gene TP53 promotes ovarian cancer progression and therapeutic resistance. Whether mutant p53 (mtp53) regulates alternative splicing and how this regulation can be exploited for cancer therapy remain unclear. Here, small nuclear ribonucleoprotein D2 polypeptide (SNRPD2) as a binding partner of mtp53 is identified. SNRPD2 is highly expressed in ovarian cancer and associated with an unfavorable prognosis. The overexpression of SNRPD2 promotes, whereas its depletion inhibits, the growth and migration of ovarian cancer cells. Mechanistically, mtp53 cooperates with SNRPD2 to facilitate the assembly of the Sm/SMN protein complex, an essential component of the spliceosome, modulating alternative splicing of pre-mRNAs. Specifically, the co-depletion of mtp53 and SNRPD2 reduces the level of OTUD3 oncogenic transcripts while increasing its tumor suppressor counterparts through an exon-skipping event. Moreover, therapeutic engineered exosomes are developed with their surfaces decorated with iRGD and their interiors loaded with siRNAs targeting mtp53 and SNRPD2. These exosomes effectively suppress the growth of ovarian cancer cells and enhance their sensitivity to chemotherapy in vivo. Collectively, this study uncovers that mtp53 and SNRPD2 cooperatively regulate alternative splicing to drive ovarian cancer progression, and co-targeting these two molecules via engineered exosomes represents a potential therapeutic strategy for ovarian cancer.
2025-11-28 | Antibody Generation Using Cancer-Derived Small Extracellular Vesicles (sEVs): A Platform for Targeted Cancer Therapy and Potential Personalized Applications.
Despite advances in tumor-targeting therapies, drug delivery efficiency to solid tumors remains low in most preclinical studies, highlighting the need for more effective targeting ligands. A novel method is developed to generate tumor-targeting monoclonal antibodies (mAbs) using cancer-derived small extracellular vesicles (sEVs), which inherit the structural and functional features of their parent cells. sEVs isolated from human ovarian carcinoma cell lines (OVCAR-8) are injected into mice to elicit an immune response. Hybridoma technology is used to generate mAbs, which are screened for either high specificity or cytotoxicity toward OVCAR-8 cells. Two lead mAbs are individually decorated onto paclitaxel-loaded CD8⁺ T cell-derived sEVs (antibody-functionalized TSEV/P; AB-TSEV/P), and the resulting formulations are evaluated in OVCAR-8 tumor-bearing mice. Both AB-TSEV/P formulations significantly reduce tumor growth without affecting body weight. Biodistribution studies using IR780-loaded AB-TSEV reveal enhanced tumor accumulation compared to non-targeted controls. RNA sequencing and spatial transcriptomics show that antibody-decorated sEVs induce transcriptional changes associated with immune activation and tumor suppression. This antibody generation strategy enables cancer cell-specific targeting and supports its application in targeted cancer therapy and personalized oncology.
2025-11-27 | Oncolytic Vaccinia Virus Expressing HSP70 shRNA Exerts Anti-Tumor Effects in Human Ovarian Cancer via Triggering the Autophagy-ROS Feedback Loop and Immune Activation.
Heat shock protein 70 (HSP70) represents a promising target for cancer therapy. Oncolytic vaccinia virus (oncoVV) mediates tumor regression through direct oncolysis and immune activation. However, the anti-tumor potential of HSP70-silenced oncoVV (oncoVV-shHSP70) remains unexplored. Here, we demonstrate that oncoVV-shHSP70 achieves superior tumor regression in ovarian cancer models (cell lines, immunodeficient mice and humanized mice) via dual mechanisms including enhancing apoptosis, autophagy flux, ROS generation, and immune reprogramming. Notably, we found that oncoVV-shHSP70 triggers an autophagy-ROS feedback loop that amplifies viral replication and pro-inflammatory cytokine expression. Crucially, in humanized mice, oncoVV-shHSP70 induced spatial redistribution of cytotoxic T cells, expanding tumor-infiltrating hCD8+hGZMB+ populations. These findings position oncoVV-shHSP70 as a promising viro-immunotherapy that co-opts HSP70 silencing to potentiate both direct oncolysis and anti-tumor immunity, providing a preclinical rationale for viro-immunotherapy in solid tumors.
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Drug Discovery Landscape
2 orphan drug designations for Small cell carcinoma of the ovary.
2 orphan drug designations for Small cell carcinoma of the ovary.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Rinatabart sesutecan | antibodies | EMA | Genmab A/S | |
Rezatapopt | small molecules | EMA | Scendea (NL) B.V. |
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