Journal of Hematology & Oncology

Mirvetuximab soravtansine: current and future applications

Ovarian epithelial cancer (OEC), particularly high-grade serous carcinoma (HGSC), remains a clinical challenge due to its late-stage diagnosis, high recurrence rates, and poor survival outcomes. Mirvetuximab soravtansine (MIRV), an antibody-drug conjugate targeting folate receptor alpha (FRα), has demonstrated promising efficacy in platinum-resistant OEC, particularly in high FRα-expressing populations, as evidenced by key clinical trials such as FORWARD I, FORWARD II, SORAYA, and MIRASOL. These trials highlight MIRV's ability to improve progression-free survival, response rates, and quality of life in advanced disease settings. Emerging data suggest that FRα is also highly expressed in serous tubal intraepithelial carcinoma (STIC), a non-invasive precursor lesion to HGSC. Although MIRV has not yet been studied for STIC management, we propose its potential application in this context to prevent progression to invasive carcinoma, particularly in high-risk populations undergoing risk-reducing bilateral salpingo-oophorectomy. This novel use could bridge the gap between prevention and treatment, offering a proactive strategy for hereditary cancer management. Furthermore, MIRV's therapeutic versatility extends to other FRα-positive tumors, such as endometrial and breast cancers, broadening its clinical relevance. Despite challenges such as accessibility and cost, MIRV represents a significant advancement in precision medicine, with potential to redefine prevention and treatment strategies for hereditary and sporadic cancers.

High-throughput approaches for precision medicine in high-grade serous ovarian cancer

AbstractHigh-grade serous carcinoma (HGSC) is the most prevalent and aggressive subtype of ovarian cancer. The large degree of clinical heterogeneity within HGSC has justified deviations from the traditional one-size-fits-all clinical management approach. However, the majority of HGSC patients still relapse with chemo-resistant cancer and eventually succumb to their disease, evidence that further work is needed to improve patient outcomes. Advancements in high-throughput technologies have enabled novel insights into biological complexity, offering a large potential for informing precision medicine efforts. Here, we review the current landscape of clinical management for HGSC and highlight applications of high-throughput biological approaches for molecular subtyping and the discovery of putative blood-based biomarkers and novel therapeutic targets. Additionally, we present recent improvements in model systems and discuss how their intersection with high-throughput platforms and technological advancements is positioned to accelerate the realization of precision medicine in HGSC.

MiR-509-3 augments the synthetic lethality of PARPi by regulating HR repair in PDX model of HGSOC

Abstract Background PARP inhibitors have been the most promising target drugs with widely proven benefits among ovarian cancer patients. Although platinum-response, HR-related genes, or HRD genomic scar detection are acceptably used in assessment of Olaparib response, there are still evident limitations in the present approaches. Therefore, we aim to investigate more accurate approaches to predict Olaparib sensitivity and effective synergistic treatment strategies. Methods We probed two databases (TCGA and Qilu Hospital) in order to quest novel miRNAs associated with platinum-sensitivity or HR-related genes. Cellular experiments in vitro or in vivo and PDX models were utilized to validate their role in tumor suppression and Olaparib sensitizing. Furthermore, HR gene mutation was analyzed through WES to explore the relation between HR gene mutation and Olaparib response. Results High miR-509-3 expression indicated better response to platinum and longer progression-free and overall survival in two independent ovarian cancer patient cohorts (high vs. low miR-509-3 expression; PFS: TCGA P < 0.05, Qilu P < 0.05; OS: TCGA P < 0.05, Qilu P < 0.01). MiR-509-3 could impair the proliferation, migration, and invasion ability but enhance the sensitivity to Olaparib of ovarian cancer cell in vitro and in vivo by directly targeting HMGA2 and RAD51. In two PDX cases (PDX1 and PDX9), miR-509-3 could significantly increase the sensitivity to Olaparib along with the decrease of RAD51 positive rate (mean tumor weight NC + Olaparib vs. miR-509 + Olaparib; PDX1 P < 0.05, PDX9 P < 0.05). Additionally, in PDX8, miR-509-3 treatment dramatically reversed the Olaparib insensitivity (P < 0.05) by downregulating RAD51 expression. RAD51 functional detection revealed that all Olaparib sensitive cases exhibited low RAD51 positive rate (lesser than 50%) in treated groups. Furthermore, among the four HR gene mutation patients, three harbored HR core gene mutation and were sensitive to Olaparib while the remaining one with non-HR core gene mutation did not respond well to Olaparib. Conclusions MiR-509-3 can sensitize ovarian cancer cells to Olaparib by impeding HR, which makes it a potential target in PARPi synergistic treatment. HR core gene analysis and RAD51 functional detection are prospectively feasible in prediction of PARPi response.

The gynecologic tumor risk related to GLP-1 receptor agonists and SGLT2 inhibitors use: a network meta-analysis of 91 randomized controlled trials

Abstract Background Concerns have emerged regarding the oncogenic potential of glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter 2 (SGLT2) inhibitors, particularly in relation to gynecologic malignancies. To date, no consensus has been reached on regimen-specific risks. This network meta-analysis (NMA) evaluated and compared the incidence of gynecologic tumors associated with various GLP-1 receptor agonists and SGLT2 inhibitors. Methods Following a Cochrane-recommended confirmatory approach, we conducted a frequentist-based NMA using data from randomized controlled trials (RCTs) including female participants. Systematic searches of major databases were conducted through March 3, 2025. The primary outcome was the incidence of gynecologic tumors; drop-out rates served as an acceptability endpoint. Bayesian sensitivity analyses were conducted for validation. Results This NMA included 91 RCTs comprising 224,986 participants (89,558 females). Only high-dose tirzepatide (15mg/week) was associated with significantly increased overall gynecologic tumor risk compared to controls [odds ratio (OR) = 2.37, 95% confidence interval (CI): 1.04–5.39; absolute risk difference= 0.57%; number needed to harm = 176]. Site-specific analysis noticed that both high-dose tirzepatide (15mg/week) (OR = 4.65, 95% CI: 1.28–16.94) and low-dose tirzepatide (5mg/week) (OR = 4.61, 95% CI: 1.07–19.90) were associated with a significantly elevated risk of intra-uterus tumor. No other regimen demonstrated a significant elevation in risk. Conclusions Tirzepatide appears to be associated with gynecologic tumor risk, particularly intra-uterus neoplasms. Given that these agents are frequently prescribed to individuals with predisposing risk factors, personalized risk–benefit evaluation is warranted. However, more data are needed to confirm whether this association is causal and not due to chance/bias or not. Besides, longitudinal research is essential to elucidate underlying mechanisms and guide clinical decision-making. Trial registration: PROSPERO CRD420251003016 The study protocol was approved by the Institutional Review Board of the Tri-Service General Hospital, National Defense Medical Center (TSGHIRB E202516007).

Harnessing extracellular vesicles using liquid biopsy for cancer diagnosis and monitoring: highlights from AACR Annual Meeting 2024

AbstractLiquid biopsy, an advanced technology for analyzing body fluid samples, is gaining traction in cancer diagnostics and monitoring. Blood-based liquid biopsy, particularly focusing on cell-free DNAs (cf-DNAs), circulating tumor cells (CTCs), and extracellular vesicles (EVs), has garnered significant attention. EVs stand out for their potential in tumor diagnosis, prognosis prediction, and treatment response assessment, owing to their stable molecular cargo and clear extraction process. At the recent American Association for Cancer Research (AACR) Annual Meeting 2024, groundbreaking EVs-based liquid biopsy studies showcased promising strides in early detection and diagnosis of various cancers, including breast cancer (BC), high-grade serous ovarian cancer (HGSOC), pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), colon adenocarcinoma (COAD), head and neck cancer (HNC), neuroblastoma, and retinoblastoma (RB). Despite these advancements, challenges persist in translating EVs biomarkers into clinical practice. Overcoming these challenges promises to propel EVs-based liquid biopsy into a new era of personalized precision medicine, revolutionizing cancer detection, monitoring, and treatment.

Participation of the ATR/CHK1 pathway in replicative stress targeted therapy of high-grade ovarian cancer

AbstractOvarian cancer is one of the most lethal gynecologic malignancies reported throughout the world. The initial, standard-of-care, adjuvant chemotherapy in epithelial ovarian cancer is usually a platinum drug, such as cisplatin or carboplatin, combined with a taxane. However, despite surgical removal of the tumor and initial high response rates to first-line chemotherapy, around 80% of women will develop cancer recurrence. Effective strategies, including chemotherapy and new research models, are necessary to improve the prognosis. The replication stress response (RSR) is characteristic of the development of tumors, including ovarian cancer. Hence, RSR pathway and DNA repair proteins have emerged as a new area for anticancer drug development. Although clinical trials have shown poly (ADP-ribose) polymerase inhibitors (PARPi) response rates of around 40% in women who carry a mutation in the BRCA1/2 genes, PARPi is responsible for tumor suppression, but not for complete tumor regression. Recent reports suggest that cells with impaired homologous recombination (HR) activities due to mutations in TP53 gene or specific DNA repair proteins are specifically sensitive to ataxia telangiectasia and Rad3-related protein (ATR) inhibitors. Replication stress activates DNA repair checkpoint proteins (ATR, CHK1), which prevent further DNA damage. This review describes the use of DNA repair checkpoint inhibitors as single agents and strategies combining these inhibitors with DNA-damaging compounds for ovarian cancer therapy, as well as the new platforms used for optimizing ovarian cancer therapy.

The developing landscape of combinatorial therapies of immune checkpoint blockade with DNA damage repair inhibitors for the treatment of breast and ovarian cancers

AbstractThe use of immune checkpoint blockade (ICB) using antibodies against programmed death receptor (PD)-1, PD ligand (PD-L)-1, and cytotoxic T-lymphocyte antigen 4 (CTLA-4) has redefined the therapeutic landscape in solid tumors, including skin, lung, bladder, liver, renal, and breast tumors. However, overall response rates to ICB therapy remain limited in PD-L1-negative patients. Thus, rational and effective combination therapies will be needed to address ICB treatment resistance in these patients, as well as in PD-L1-positive patients who have progressed under ICB treatment. DNA damage repair inhibitors (DDRis) may activate T-cell responses and trigger inflammatory cytokines release and eventually immunogenic cancer cell death by amplifying DNA damage and generating immunogenic neoantigens, especially in DDR-defective tumors. DDRi may also lead to adaptive PD-L1 upregulation, providing a rationale for PD-L1/PD-1 blockade. Thus, based on preclinical evidence of efficacy and no significant overlapping toxicity, some ICB/DDRi combinations have rapidly progressed to clinical testing in breast and ovarian cancers. Here, we summarize the available clinical data on the combination of ICB with DDRi agents for treating breast and ovarian cancers and discuss the mechanisms of action and other lessons learned from translational studies conducted to date. We also review potential biomarkers to select patients most likely to respond to ICB/DDRi combination therapy.

A clinical study of autologous chimeric antigen receptor macrophage targeting mesothelin shows safety in ovarian cancer therapy

CAR-macrophage has promising prospect in treating solid tumors, due to its high infiltration into tumors, and its dual roles in phagocytosis and immune modulation. Here we show the clinical results of CAR-macrophage treatment of two ovarian cancer patients. The CAR-macrophages were produced by introducing a mesothelin targeting CAR to patients' primary peripheral blood mononuclear cell-derived macrophages, and the products were infused to patients intravenously. Our data show good safety of the infusion product, and the efficacy can be further improved. Intraperitoneal infusion of CAR-macrophages has proven effective in treating intraperitoneal tumors in a preclinical model, paving the way for demonstrating proof-of-concept clinical efficacy of CAR-macrophages in the treatment of intraperitoneal tumors.

Global status and attributable risk factors of breast, cervical, ovarian, and uterine cancers from 1990 to 2021

Female-specific cancers, particularly breast, cervical, ovarian, and uterine cancers, account for nearly 40% of all cancers in women. This study aimed to analyze the global epidemiological trends of these cancers from 1990 to 2021, offering insights into their evolving patterns and providing valuable information for health policymakers to allocate healthcare resources more effectively. Data from the Global Burden of Disease Study 2021 (GBD 2021) were used to comprehensively assess the global incidence, mortality, and disability-adjusted life years (DALYs) of female-specific cancers. Age-standardized rates facilitated cross-regional comparisons, accounting for differences in population size and demographics. The socio-demographic index (SDI) was employed to categorize regions and evaluate correlations between cancer burden and economic level. In addition, risk factors attributable to female-specific cancer deaths and DALYs were assessed based on the comparative risk assessment model of the GBD project. From 1990 to 2021, the global burden of female-specific cancers increased at varying rates. In 2021, breast cancer accounted for 2.08 million incident cases, 0.66 million deaths, and 20.25 million DALYs globally. In comparison, cervical, ovarian, and uterine cancers had lower burdens, with 0.67 million, 0.30 million, and 0.47 million incident cases, respectively. Age-standardized rates of breast, ovarian, and uterine cancers showed positive correlations with SDI, while cervical cancer exhibited a negative correlation. Attributable risk factors for breast cancer-associated deaths in 2021 included dietary risks, high body-mass index (BMI), high fasting plasma glucose, alcohol use, tobacco use, and low physical activity. Additional risk factors were unsafe sex and tobacco use for cervical cancer, high BMI and occupational risks for ovarian cancer, and high BMI for uterine cancer. The burden of female-specific cancers has increased in recent decades, with significant demographic and regional discrepancies. These findings highlight the urgent need for targeted public health interventions to mitigate the global impact of these cancers.

VEGF pathway inhibition potentiates PARP inhibitor efficacy in ovarian cancer independent of BRCA status

AbstractPoly ADP-ribose polymerase inhibitors (PARPi) have transformed ovarian cancer (OC) treatment, primarily for tumours deficient in homologous recombination repair. Combining VEGF-signalling inhibitors with PARPi has enhanced clinical benefit in OC. To study drivers of efficacy when combining PARP inhibition and VEGF-signalling, a cohort of patient-derived ovarian cancer xenografts (OC-PDXs), representative of the molecular characteristics and drug sensitivity of patient tumours, were treated with the PARPi olaparib and the VEGFR inhibitor cediranib at clinically relevant doses. The combination showed broad anti-tumour activity, reducing growth of all OC-PDXs, regardless of the homologous recombination repair (HRR) mutational status, with greater additive combination benefit in tumours poorly sensitive to platinum and olaparib. In orthotopic models, the combined treatment reduced tumour dissemination in the peritoneal cavity and prolonged survival. Enhanced combination benefit was independent of tumour cell expression of receptor tyrosine kinases targeted by cediranib, and not associated with change in expression of genes associated with DNA repair machinery. However, the combination of cediranib with olaparib was effective in reducing tumour vasculature in all the OC-PDXs. Collectively our data suggest that olaparib and cediranib act through complementary mechanisms affecting tumour cells and tumour microenvironment, respectively. This detailed analysis of the combined effect of VEGF-signalling and PARP inhibitors in OC-PDXs suggest that despite broad activity, there is no dominant common mechanistic inter-dependency driving therapeutic benefit.