Redefining the standard of care for low-grade serous ovarian cancer.

Low-grade serous carcinoma is a rare epithelial ovarian cancer subtype with distinct clinical, histologic, and molecular features. Improved understanding of this disease subtype has prompted recent advances in treatment options. Although low-grade serous carcinoma historically has been treated following a high-grade serous carcinoma paradigm, new data have called into question the utility of platinum retreatment, addressed the possibility of first-line hormonal treatment, and brought forth therapeutic options targeting the MAPK pathway and cyclin D kinase in low-grade tumors. Ongoing research efforts seek to leverage the unique features of low-grade serous carcinoma to refine treatment options for patients with this rare tumor subtype.

Ovarian cancer.

ABSTRACT: Ovarian cancer, a leading cause of cancer deaths, poses challenges due to insidious development and vague signs and symptoms. Risk factors include age, reproductive history, genetic mutations, and environmental factors. Treatment involves surgery, chemotherapy, and targeted therapy, with nursing interventions focusing on symptom management and supportive care.

Synchronous skull base and spinal metastases in a patient with treatment-resistant, high-grade serous adenocarcinoma of tubo-ovarian origin.

Brain metastases (BMs) arising from ovarian cancer remain rare. Spinal cord metastases are even rarer, accounting for just 0.4% of total metastatic spinal cord compressions. In this report, we describe a case of a woman in her 70s who developed sequential brain and spinal cord metastases during her treatment for high-grade serous ovarian cancer, without a germline or somatic BRCA mutation. Following completion of neoadjuvant chemotherapy, interval debulking surgery and adjuvant chemotherapy, relapsed disease was ultimately identified as a single BM, curiously mimicking an acoustic neuroma. Subsequently, spinal cord metastases rapidly developed. Throughout, multidisciplinary team meetings guided decisions on patient management. In this report, we highlight the rarity of such a presentation and discuss the possible role of disease pathophysiology, associated systemic anticancer therapy resistance, and treatment possibilities for both cerebral and spinal metastases.

Special Issue "Ovarian Cancer: Advances on Pathophysiology and Therapies".

Ovarian cancer is a gynecologic cancer with a high mortality rate, and its incidence has increased significantly over the past 50 years [...].

Exosomes in diagnostic and therapeutic applications of ovarian cancer.

Ovarian cancer accounts for more deaths than any other female reproductive tract cancer. The major reasons for the high mortality rates include delayed diagnoses and drug resistance. Hence, improved diagnostic and therapeutic options for ovarian cancer are a pressing need. Extracellular vesicles (EVs), that include exosomes provide hope in both diagnostic and therapeutic aspects. They are natural lipid nanovesicles secreted by all cell types and carry molecules that reflect the status of the parent cell. This facilitates their potential use as biomarkers for an early diagnosis. Additionally, EVs can be loaded with exogenous cargo, and have features such as high stability and favorable pharmacokinetic properties. This makes them ideal for tumor-targeted delivery of biological moieties. The International Society of Extracellular Vesicles (ISEV) based on the Minimal Information for Studies on Extracellular Vesicles (MISEV) recommends the usage of the term "small extracellular vesicles (sEVs)" that includes exosomes for particles that are 30-200 nm in size. However, majority of the studies reported in the literature and relevant to this review have used the term "exosomes". Therefore, this review will use the term "exosomes" interchangeably with sEVs for consistency with the literature and avoid confusion to the readers. This review, initially summarizes the different isolation and detection techniques developed to study ovarian cancer-derived exosomes and the potential use of these exosomes as biomarkers for the early diagnosis of this devastating disease. It addresses the role of exosome contents in the pathogenesis of ovarian cancer, discusses strategies to limit exosome-mediated ovarian cancer progression, and provides options to use exosomes for tumor-targeted therapy in ovarian cancer. Finally, it states future research directions and recommends essential research needed to successfully transition exosomes from the laboratory to the gynecologic-oncology clinic.

Dual­regulated oncolytic adenovirus carrying ERCC1­siRNA gene possesses potent antitumor effect on ovarian cancer cells.

Ovarian cancer is a multifactorial and deadly disease. Despite significant advancements in ovarian cancer therapy, its incidence is on the rise and the molecular mechanisms underlying ovarian cancer invasiveness, metastasis and drug resistance remain largely elusive, resulting in poor prognosis. Oncolytic viruses armed with therapeutic transgenes of interest offer an attractive alternative to chemical drugs, which often face innate and acquired drug resistance. The present study constructed a novel oncolytic adenovirus carrying ERCC1 short interfering (si)RNA, regulated by hTERT and HIF promoters, termed Ad­siERCC1. The findings demonstrated that this oncolytic adenovirus effectively inhibits the proliferation, migration and invasion of ovarian cancer cells. Furthermore, the downregulation of ERCC1 expression by siRNA ameliorates drug resistance to cisplatin (DDP) chemotherapy. It was found that Ad­siERCC1 blocks the cell cycle in the G1 phase and enhances apoptosis through the PI3K/AKT­caspase­3 signaling pathways in SKOV3 cells. The results of the present study highlighted the critical effect of oncolytic virus Ad­siERCC1 in inhibiting the survival of ovarian cancer cells and increasing chemotherapy sensitivity to DDP. These findings underscore the potent antitumor effect of Ad­siERCC1 on ovarian cancers in vivo.

Advances in precision therapy of low-grade serous ovarian cancer: A review.

Low-grade serous ovarian carcinoma (LGSOC) is a rare subtype of ovarian cancer that accounts for approximately 6% to 10% of serous ovarian cancers. The clinical treatment of LGSOC is similar to that of high-grade serous ovarian carcinoma, however, its clinical and molecular characteristics are different from those of high-grade serous ovarian carcinoma. This article reviews the research on gene diagnosis, surgical treatment, chemotherapy, and biological therapy of LGSOC, providing reference for clinical diagnosis and treatment of LGSOC. Surgery is the cornerstone of LGSOC treatment and maximum effort must be made to achieve R0 removal. Although LGSOC is not sensitive to chemotherapy, postoperative platinum-based combination chemotherapy remains the first-line treatment option for LGSOC. Additional clinical trials are needed to confirm the clinical benefits of chemotherapy and explore new chemotherapy protocols. Hormone and targeted therapies may also play important roles. Some patients, particularly those with residual lesions after treatment, may benefit from hormone maintenance therapy after chemotherapy. Targeted therapies, such as MEKi, show good application prospects and are expected to change the treatment pattern of LGSOC. Continuing to further study the genomics of LGSOC, identify its specific gene changes, and combine traditional treatment methods with precision targeted therapy based on second-generation sequencing may be the direction for LGSOC to overcome the treatment bottleneck. In future clinical work, comprehensive genetic testing should be carried out for LGSOC patients to accumulate data for future scientific research, in order to find more effective methods and drugs for the treatment of LGSOC.

Prospects and challenges of CAR-T in the treatment of ovarian cancer.

Ovarian cancer ranks as the seventh most prevalent cancer among women and is considered the most lethal gynecological malignancy on a global scale. The absence of reliable screening techniques, coupled with the insidious onset of nonspecific symptoms, often results in a delayed diagnosis, typically at an advanced stage characterized by peritoneal involvement. Management of advanced tumors typically involves a combination of chemotherapy and cytoreductive surgery. However, the therapeutic arsenal for ovarian cancer patients remains limited, highlighting the unmet need for precise, targeted, and sustained-release pharmacological agents. Genetically engineered T cells expressing chimeric antigen receptors (CARs) represent a promising novel therapeutic modality that selectively targets specific antigens, demonstrating robust and enduring antitumor responses in numerous patients. CAR T cell therapy has exhibited notable efficacy in hematological malignancies and is currently under investigation for its potential in treating various solid tumors, including ovarian cancer. Currently, numerous researchers are engaged in the development of novel CAR-T cells designed to target ovarian cancer, with subsequent evaluation of these candidate cells in preclinical studies. Given the ability of chimeric antigen receptor (CAR) expressing T cells to elicit potent and long-lasting anti-tumor effects, this therapeutic approach holds significant promise for the treatment of ovarian cancer. This review article examines the utilization of CAR-T cells in the context of ovarian cancer therapy.

Targeting the GPI transamidase subunit GPAA1 abrogates the CD24 immune checkpoint in ovarian cancer.

CD24 is frequently overexpressed in ovarian cancer and promotes immune evasion by interacting with its receptor Siglec10, present on tumor-associated macrophages, providing a "don't eat me" signal that prevents targeting and phagocytosis by macrophages. Factors promoting CD24 expression could represent novel immunotherapeutic targets for ovarian cancer. Here, using a genome-wide CRISPR knockout screen, we identify GPAA1 (glycosylphosphatidylinositol anchor attachment 1), a factor that catalyzes the attachment of a glycosylphosphatidylinositol (GPI) lipid anchor to substrate proteins, as a positive regulator of CD24 cell surface expression. Genetic ablation of GPAA1 abolishes CD24 cell surface expression, enhances macrophage-mediated phagocytosis, and inhibits ovarian tumor growth in mice. GPAA1 shares structural similarities with aminopeptidases. Consequently, we show that bestatin, a clinically advanced aminopeptidase inhibitor, binds to GPAA1 and blocks GPI attachment, resulting in reduced CD24 cell surface expression, increased macrophage-mediated phagocytosis, and suppressed growth of ovarian tumors. Our study highlights the potential of targeting GPAA1 as an immunotherapeutic approach for CD24+ ovarian cancers.

Current treatment strategies for ovarian cancer in the East Asian Gynecologic Oncology Trial Group (EAGOT).

Ovarian cancer, notable for its severe prognosis among gynecologic cancers, has seen substantial progress in treatment approaches recently. Enhanced protocols in chemotherapy and the introduction of poly (ADP-ribose) polymerase (PARP) inhibitors for maintenance therapy have markedly improved outcomes for patients with specific genetic profiles, such as those positive for BRCA mutations or exhibiting homologous recombination deficiency (HRD). Additionally, the method of intraperitoneal chemotherapy administration has emerged as a valuable alternative to traditional transvenous routes, showing promise for wider clinical adoption. The field of surgery has also evolved, with increasing exploration into the benefits and feasibility of laparoscopic methods over more invasive traditional surgeries, aiming for complete tumor removal but with reduced patient impact. The hereditary nature of ovarian cancer underscores the importance of genetic testing, which has become integral in tailoring treatment strategies, particularly in determining suitability for PARP inhibitors. The formation of the East Asian Gynecologic Oncology Trial Group (EAGOT) aims to optimize treatment across Japan, Korea, China, and Taiwan. The ovarian cancer committee of EAGOT shared the current policies, focusing on 5 topics: 1) strategies for maintenance therapy after initial surgery and chemotherapy, 2) drug regimens for platinum-sensitive and platinum-resistant recurrence, 3) intraperitoneal chemotherapy, 4) laparoscopic surgery as an alternative to laparotomy, and 5) current status of genetic testing (BRCA, HRD, and panel tests) for ovarian cancer and its prospects. EAGOT's multi-national trials aim to harmonize these evolving treatment strategies, ensuring that the latest and most effective protocols are accessible across the region, thereby significantly impacting patient outcomes in East Asia.

High-Grade Serous Ovarian Cancer during Pregnancy: From Diagnosis to Treatment.

BACKGROUND: Due to the rarity of ovarian cancer diagnosed during pregnancy, the literature on the treatment of subtypes of epithelial ovarian cancer in pregnancy is sparse. The aim of our review was to analyze cases of high-grade serous ovarian cancer in pregnancy. METHODS: The PubMed and Scopus databases were searched for relevant articles published in English between January 2000 and December 2023. The references of all the relevant reviews found were also checked to avoid omitting eligible studies. Information on the all retrieved cases was extracted and reviewed in detail. The most important detail was the subtype of high-grade serous ovarian cancer, which was referred to as serous adenocarcinoma (grade 2 or grade 3) in older cases. RESULTS: We found eleven cases with relevant details of high-grade serous ovarian cancer diagnosed in pregnancy. Despite the small number of cases we found, our study demonstrated the importance of an accurate initial vaginal ultrasound at the first examination in pregnancy and the safety of diagnostic surgery and chemotherapy in pregnancy. CONCLUSIONS: There have not been long-term follow-ups of patients' oncologic and obstetric outcomes. As patients should be comprehensively informed, more detailed case reports or series with longer follow-up periods are needed.

Immunotherapy combined with targeted therapy in advanced small cell carcinoma of the ovary of hypercalcemic type: A case of overall survival lasting for over 5 years.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but highly aggressive ovarian malignant neoplasm lacking a unified clinical management process. Most patients are diagnosed at an advanced stage and have an extremely poor prognosis with an overall probability of survival less than 10 %. Here, we describe the case of a patient with advanced SCCOHT achieved a survival of over 5 years after receiving multiple cycles of immunotherapy combined with anti-angiogenic therapy or CDK4/6 inhibitors. At the same time, we also summarized the case reports and clinical trials of immunotherapy in SCCOHT.

Mesonephric-like adenocarcinoma of the ovary.

Mesonephric-like adenocarcinoma is a new class of rare subtypes of the female reproductive system. Its clinical symptoms are similar to other types of ovarian tumors. The diagnosis is based on pathological and immunohistochemical methods. The main treatment option is surgery combined with chemotherapy. Few cases have been reported at home and abroad. We reported a case of a 45-year-old woman with a cystic solid mass in the left adnexa. The postoperative pathological diagnosis was mesonephric-like adenocarcinoma of the left ovary and mature cystic teratoma (partial infiltration of the small intestine). This case had no specific clinical symptoms. Immunohistochemical findings showed positive results of GATA3, TTF1, CD10, ER, and PR. Paclitaxel and carboplatin chemotherapy were given after the operation. Currently, no specific criteria are available for diagnosis and treatment of the disease. This article aims to improve the understanding of clinicians in this disease and create a basis for clinical diagnosis and treatment.

Targeting and monitoring ovarian cancer invasion with an RNAi and peptide delivery system.

RNA interference (RNAi) therapeutics are an emerging class of medicines that selectively target mRNA transcripts to silence protein production and combat disease. Despite the recent progress, a generalizable approach for monitoring the efficacy of RNAi therapeutics without invasive biopsy remains a challenge. Here, we describe the development of a self-reporting, theranostic nanoparticle that delivers siRNA to silence a protein that drives cancer progression while also monitoring the functional activity of its downstream targets. Our therapeutic target is the transcription factor SMARCE1, which was previously identified as a key driver of invasion in early-stage breast cancer. Using a doxycycline-inducible shRNA knockdown in OVCAR8 ovarian cancer cells both in vitro and in vivo, we demonstrate that SMARCE1 is a master regulator of genes encoding proinvasive proteases in a model of human ovarian cancer. We additionally map the peptide cleavage profiles of SMARCE1-regulated proteases so as to design a readout for downstream enzymatic activity. To demonstrate the therapeutic and diagnostic potential of our approach, we engineered self-assembled layer-by-layer nanoparticles that can encapsulate nucleic acid cargo and be decorated with peptide substrates that release a urinary reporter upon exposure to SMARCE1-related proteases. In an orthotopic ovarian cancer xenograft model, theranostic nanoparticles were able to knockdown SMARCE1 which was in turn reported through a reduction in protease-activated urinary reporters. These LBL nanoparticles both silence gene products by delivering siRNA and noninvasively report on downstream target activity by delivering synthetic biomarkers to sites of disease, enabling dose-finding studies as well as longitudinal assessments of efficacy.

NK-92MI Cells Engineered with Anti-claudin-6 Chimeric Antigen Receptors in Immunotherapy for Ovarian Cancer.

Background: The application of chimeric antigen receptor (CAR) NK cells in solid tumors is hindered by lack of tumor-specific targets and inefficient CAR-NK cell efficacy. Claudin-6 (CLDN6) has been reported to be overexpressed in ovarian cancer and may be an attractive target for CAR-NK cells immunotherapy. However, the feasibility of using anti-CLDN6 CAR-NK cells to treat ovarian cancer remains to be explored. Methods: CLDN6 expression in primary human ovarian cancer, normal tissues and cell lines were detected by immunohistochemistry and western blot. Two types of third-generation CAR NK-92MI cells targeting CLDN6, CLDN6-CAR1 NK-92MI cells with domains containing self-activated elements (NKG2D, 2B4) and CLDN6-CAR2 NK-92MI cells with classical domains (CD28, 4-1BB) were constructed by lentivirus transfection, sorted by flow cytometry and verified by western blot and qPCR. OVCAR-3, SK-OV-3, A2780, Hey and PC-3 cells expressing the GFP and luciferase genes were transduced. Subcutaneous and intraperitoneal tumor models were established via NSG mice. The ability of CLDN6-CAR NK cells to kill CLDN6-positive ovarian cancer cells were evaluated in vitro and in vivo by live cell imaging and bioluminescence imaging. Results: Both CLDN6-CAR1 and CLDN6-CAR2 NK-92MI cells could specifically killed CLDN6-positive ovarian cancer cells (OVCAR-3, SK-OV-3, A2780 and Hey), rather than CLDN6 negative cell (PC-3), in vitro. CLDN6-CAR1 NK-92MI cells with domains containing self-activated elements (NKG2D, 2B4) exhibited stronger cytotoxicity than CLDN6-CAR2 NK-92MI cells with classical domains (CD28, 4-1BB). Furthermore, CLDN6-CAR1 NK cells could effectively eliminate ovarian cancer cells in subcutaneous and intraperitoneal tumor models. More importantly, CAR-NK cells combined with immune checkpoint inhibitors, anti-PD-L1, could synergistically enhance the antitumor efficacy of CLDN6-targeted CAR-NK cells. Conclusions: These results indicate that CLDN6-CAR NK cells possess strong antitumor activity and represent a promising immunotherapeutic modality for ovarian cancer.

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

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

Metastasis of serous ovarian carcinoma to the breast: a case report and review of the literature.

BACKGROUND: Breast metastasis from primary ovarian cancer is rare, with an estimated frequency of 0.07%. More than 110 cases are reported in the literature of metastatic spread of ovarian cancer to the breast and axilla. This entity usually represents aggressive late disease characterized by multi-drug chemoresistance and a poor prognosis with a median survival time of 16 months. Currently no standardized treatment protocol exists for this condition. CASE PRESENTATION: We present a case of a 59-year-old Caucasian female with recurrent high-grade serous ovarian cancer who was diagnosed with symptomatic unilateral breast metastasis while on fourth line chemotherapy with weekly paclitaxel. She was treated with local radiation with 2300 cGy to the right breast with a complete response. She then had a subsequent recurrence in the ipsilateral breast 8 months after completion of post treatment imaging. She remains alive to date approximately 2 years after her initial diagnosis of breast metastasis on seventh line treatment. CONCLUSIONS: Breast metastasis from primary ovarian cancer is rare and represents advanced disease characterized by multi-drug chemoresistance and a poor prognosis. This case describes radiation therapy as a safe, effective treatment option to improve local control and quality of life in these patients, but with limited durability of response.