Ovarian cancer (OC) remains the most lethal gynecologic malignancy, and platinum-taxane combination therapy is the global first-line standard of care for advanced disease. However, resistance to platinum-taxane combination therapy is a major clinical barrier in ovarian cancer (OC), yet the molecular basis of dual resistance remains unresolved. Therefore, defining the molecular mechanisms that drive resistance to combined platinum-taxane therapy is essential for identifying new therapeutic targets and improving patient outcomes. We generated matched RNA-seq and ATAC-seq profiles from parental A2780 cells and derivatives exhibiting functional resistance to platinum (CpR), taxane (TxR), or both agents (TxCpR). We integrated differential gene expression with chromatin accessibility, annotated regulatory elements using ENCODE cCREs, and performed motif enrichment to infer candidate transcription factor programs. We found that CpR and TxR cells displayed the expected drug-specific transcriptional profiles. CpR cells upregulated DNA repair genes, whereas TxR cells showed activation of pathways associated with paclitaxel adaptation, including cytoskeletal regulation and ABCB1-mediated efflux. In contrast, TxCpR cells adopted a distinct regulatory state, separate from CpR and TxR. They exhibited broad enhancer remodeling and enriched accessibility at developmental and morphogenesis-associated loci. Motif analysis identified stress-responsive (MAFF (MAF bzip transcription factor F), NFATC4 (Nuclear factor of activated T-cells 4)) and architectural (YY1 (Yin-Yang 1), ZNF549 (Zinc finger protein 549), CTCF (CCCTC-binding Factor)) transcription factors as candidate regulators of this state. Integrated analysis of RNA-seq and ATAC-seq identified TxCpR-associated candidate distal regulatory elements, including an accessible CTCF motif-containing region near AIM2 (Absent in Melanoma 2) gene, highlighting AIM2-proximal regions as candidates for further functional investigation. Dual platinum-taxane resistance is accompanied by integrated transcriptional plasticity and chromatin rewiring, consistent with a regulatory state that is distinct from single-agent resistance. To our knowledge, this dataset represents the first paired transcriptomic–epigenomic map of all four A2780 states, and identifies candidate transcriptional and distal regulatory elements that may be exploited to target multidrug resistance in OC.

Abstract Background: Resistance to platinum-taxane combination therapy is a major clinical barrier in ovarian cancer (OC), yet the molecular determinants of dual resistance remain poorly defined. Single-agent cisplatin- or paclitaxel-resistant models are well characterized, but whether dual resistance represents an additive or fundamentally distinct state is unknown. Methods: We performed paired RNA-seq and ATAC-seq on A2780 parental cells and isogenic cisplatin-resistant (CpR), paclitaxel-resistant (TxR), and dual-resistant (TxCpR) derivatives. Differential expression, chromatin accessibility, motif enrichment, and enhancer-promoter integration analyses were used to identify transcriptional and epigenomic features unique to each resistance state. Results: CpR and TxR cells exhibited expected drug-specific adaptations, including upregulation of DNA repair genes (e.g., MLH1, LIG4) or cytoskeletal regulators and drug-efflux transporters (e.g., ABCB1, ALDH1A1). In contrast, TxCpR cells formed a distinct transcriptional and chromatin state, characterized by a hybrid epithelial-mesenchymal program, activation of developmental pathways, and selective retention of advantageous single-agent resistance traits. ATAC-seq revealed extensive remodeling of distal regulatory elements in TxCpR cells, with enrichment of MAFF, NFATC4, YY1, and ZNF549 motifs, implicating stress-response and chromatin-architectural regulators. Integrative analysis identified TxCpR-specific enhancers, including a CTCF-associated regulatory element near AIM2, suggesting emergent 3D chromatin restructuring that stabilizes dual-resistance transcriptional programs. Conclusions: Dual resistance to cisplatin and paclitaxel is not a composite of single-agent responses but a reprogrammed regulatory state driven by enhancer remodeling and coordinated transcription factor networks. This dataset provides a unique paired RNA-seq/ATAC-seq resource and identifies candidate enhancer and architectural dependencies that may be therapeutically targetable in multidrug-resistant OC. Citation Format: Won-Young Choi, Rachel Perkins, Jisun Kang, Haoxiang Lyu, Matthew S. Jung, Xiaoya Hou, Wei Li, Junming Yue, Wenjing Zhang. Chromatin rewiring and transcriptional plasticity drive a distinct dual-resistant state in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 380.

Platinum-resistant ovarian cancer (PROC) remains a major clinical challenge, with limited effective treatment options and poor survival outcomes. Aberrant activation of the glucocorticoid receptor (GR) signaling pathway promotes tumor progression, chemoresistance, and immune evasion, providing a strong rationale for therapeutic targeting. Selective GR antagonists (SGRAs) represent an emerging novel strategy aimed at blocking this pro-tumorigenic pathway while minimizing off-target effects. Preclinical studies demonstrated that GR blockade restores chemosensitivity, particularly to taxane-based therapies, and may modulate the tumor microenvironment. These findings have translated into clinical evaluation, culminating in the phase 3 ROSELLA trial, which reported that the addition of relacorilant, a SGRA, to nab-paclitaxel significantly improved progression-free and overall survival in patients with recurrent PROC. These results, presented in March 2026, establish GR antagonism as a promising therapeutic strategy and a potential new treatment paradigm in this setting. In this evidence-based review, we summarize the biological basis of GR signaling in ovarian cancer, evaluate the clinical evidence supporting SGRAs, and discuss key challenges for implementation, including biomarker development, safety considerations, and rational combination strategies with chemotherapy, PARP inhibitors, and immunotherapy. We also highlight critical considerations for future clinical trial design to optimize the integration of GR-targeted therapies into the management of ovarian cancer.

ABSTRACT Background Papillary thyroid cancer (PTC) is the most common type of thyroid malignancy. While the prognosis of PTC is generally favorable, some cases exhibit aggressive behavior, leading to metastasis and recurrence. ASAP1 (ArfGAP with SH3, ankyrin repeats, and PH domain 1), an ADP‐ribosylation factor GTPase‐activating protein, has been implicated in tumor metastasis. However, its role in PTC remains unclear. Methods ASAP1 expression in PTC was evaluated using TCGA and GEO databases. Studies in PTC cell lines (MDA‐T32 and MDA‐T85) included lentiviral‐mediated knockdown and overexpression of ASAP1 to assess effects on epithelial–mesenchymal transition (EMT) marker expression, cell proliferation, and invasive capacity. TGFβ pathway activity was examined by p‐SMAD2 Western blotting and luciferase reporter assays. ASAP1‐SMAD2/3 interactions were analyzed using co‐immunoprecipitation (CO‐IP) and immunofluorescence. Results ASAP1 was aberrantly upregulated in PTC. Lentiviral knockdown of ASAP1 in PTC cells suppressed the EMT process. Reduced ASAP1 expression also inhibited cell survival, proliferation, migration, invasion, and the expression of p‐SMAD2 in the TGFβ pathway in PTC cells. Conversely, ASAP1 overexpression reversed these effects. Mechanistically, ASAP1 interacts with the SMAD2/3 complex, forming a positive feedback loop with TGFβ signaling that promotes EMT and cell invasiveness in PTC cells, which suggests its potential role in PTC metastasis. Conclusions These findings suggest that targeting ASAP1 may offer a novel therapeutic strategy to limit PTC metastasis by suppressing EMT and attenuating the TGFβ pathway.

Ovarian cancer (OC) remains a significant health issue for women due to its late diagnosis and chemoresistance. Currently, there is no relevant mouse OC model for preclinical drug screening and treatment. We established a mouse OC cell line model, PC53K, by transforming primary ovarian surface epithelial cells through CRISPR/Cas9-mediated TP53 knockout and simultaneous overexpression of human PTK2 and cMyc. We further developed the paclitaxel-resistant PC53K/TxR cell line. PC53K and PC53K/TxR cell lines were validated in vitro and in vivo in an orthotopic mouse model. We also evaluated the efficacy of two novel tubulin inhibitors, the clinical drug VERU-111 and the preclinical compound SB-216, using the PC53K/TxR model in vitro and in vivo. Mice intrabursally injected with PC53K cells exhibited bloody ascites, aggressive primary tumor growth and widespread metastasis, which faithfully recapitulates the phenotypes of human ovarian serous adenocarcinoma. Additionally, the paclitaxel-resistant PC53K/TxR cell line shows significant higher IC50 for paclitaxel than PC53K cell line, indicating it is a valuable tool for studying OC chemoresistance. Compounds VERU-111 and SB-216 significantly inhibited tumor growth and metastasis in orthotopic OC mouse models by overcoming chemoresistance. This study demonstrates the effectiveness of the PC53K and PC53K/TxR models for preclinical drug screening and validates the potential of VERU-111 and SB-216 in overcoming chemoresistance and treating OC. The development of the PC53K and PC53K/TxR mouse models represents a significant advancement in OC research. By mimicking the genetic profile, aggressive behavior and chemoresistance of human OC, these models provide a robust platform for preclinical drug discovery and development. Ziping Liu, Wenjing Zhang, Xinxin Zhao, Yongshuai Li, Xiaoya Hou, Satyanarayana Pochampally, Shelby Waddell, Shiji Song, Yaohong Wang, Lawrence M. Pfeffer, Duane D. Miller, Junming Yue, Wei Li. A p53-deficient, PTK2/cMyc-driven ovarian cancer mouse model for preclinical drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3922.

Hypothyroidism (HypoTH) is an independent and major risk factor for myocardial infarction (MI). However, long noncoding RNA (lncRNA; ncRNAs>200 bp) mechanisms in the cardiac thyroid hormone (TH) pathway are unclear. An array of in vitro, in vivo, computational, and statistical methods was employed. Paigen high-fat (PHF)-fed homozygous HypoE mice died rapidly (median survival [ms] 26 days) with severe MI, cardiac fibrosis, hypertrophy, inflammation, lipid deposition, and heart failure. So, we used cholate-free PHF diet, which showed more gradual mortality (ms: 41.5 days) with serum HypoTH, cardiac hypertrophy, splenomegaly, and alterations in real-time differential expression of multiple inflammatory/immune left ventricular (LV) lncRNAs, especially the lncRNA, XRik (>2-fold; p<0.05). Oral T3 therapy restored LV contractility, atrial refractory period, expression levels of LV epigenetic enzymes and lncRNAs, especially XRik, without increases in heart rate or hypertrophy. We genetically manipulated XRik using siRNAs, overexpression, and CRISPRa (dCas9)-based activation strategies in HL1 adult mouse myocytes, primary adult mouse ventricular myocytes, and/or primary adult mouse ventricular nonmyocytes (fibroblasts). XRik overexpression improved cell viability against Doxorubicin or H2O2 injury (p<0.05). While XRik siRNA inhibited cardiac cell viability following low-iodine diet-induced HypoTH in control mice, both overexpression and CRISPRa-activation improved cell viability. siRNA-induced increase in proapoptotic Cytochrome C levels was attenuated by T3 (and CRISPRa; p<0.05). Our LV lncRNA-seq-based prediction of XRik ’s interaction with an miRNA was mediated by T3 via dual-luciferase assays. In vivo lentiviral CRISPRa XRik delivery improved LV fractional shortening in cholate-free PHF homozygous HypoE mice without significant adverse effects on hypertrophy or heart rate (p<0.05). LV mRNA-sequencing identified alterations in several genes/transcripts in these mice, which were improved following in vivo XRik CRISPRa. Enrichment analyses showed improvements in genes/transcripts related to pathways including TH synthesis, cardiac contraction, lipid metabolism, ATP/Ca++ binding, inflammation, apoptosis, etc. CRISPRa in vivo also significantly reduced the levels of multiple proinflammatory cytokines (p<0.05). In conclusion, we uncovered a novel mechanism by which T3 regulates XRik in mediating cardioprotection in high-fat-diet-induced atherosclerosis-driven MI.

Deoxyhypusine synthase (DHPS) is an enzyme encoded by the DHPS gene, with high expression in various cancers, including ovarian cancer (OC). DHPS regulates the translation initiation factor EIF5A, and EIF5A2 knockout inhibits OC tumor growth and metastasis by blocking the epithelial-to-mesenchymal transition (EMT) and the TGFβ pathway. In this study, we show that DHPS is amplified in OC patients, and its elevated expression correlates with poor survival. Using lentiviral CRISPR/Cas9 vectors for DHPS knockout, we observed EMT inhibition in SKOV3 and OVCAR8 cells through suppressed hypusination and reduced EIF5A2 expression. Inhibition of DHPS activity with GC7 similarly blocked hypusination and EMT. Disrupting DHPS expression, either genetically or pharmacologically, inhibited primary tumor growth and metastasis in OC mouse models. These findings suggest that targeting DHPS and inhibiting hypusination could be promising strategies for OC treatment.

PD-L1, a key inhibitory immune receptor, has crucial functions in cancer immune evasion, but whether PD-L1 promotes the malignant properties of cervical cancer (CC) cells and the mechanism by which PD-L1 is regulated in CC remains unclear. We report that PD-L1 is overexpressed in CC, and shRNA-mediated PD-L1 depletion suppresses the proliferation, invasion, and tumorigenesis of CC cells. Loss of miR-140/142/340/383 contributes to PD-L1 upregulation. miR-18a enhances PD-L1 levels by targeting PTEN , WNK2 (ERK1/2 pathway inhibitor), and SOX6 (Wnt/β-catenin pathway inhibitor and p53 pathway activator) to activate the PI3K/AKT, MEK/ERK, and Wnt/β-catenin pathways and inhibit the p53 pathway, and miR-18a also directly suppresses the expression of the tumor suppressors BTG3 and RBSP3 (CTDSPL). miR-18a overexpression in CC cells is triggered by OCT4 overexpression. Our data implicate PD-L1 as a novel oncoprotein and indicate that miR-140/142/340/383 and miR-18a are key upstream regulators of PD-L1 and potential targets for CC treatment.

MicroRNAs (miRNAs) can function as either tumor suppressors or oncogenes. This study explores the role of miR-675 in ovarian cancer (OC) using in vitro OC cell lines and an in vivo orthotopic mouse model. We demonstrate that miR-675 expression inhibits primary tumor growth and metastasis by targeting TGFβ1, suppressing epithelial to mesenchymal transition (EMT), and attenuating the TGFβ signaling pathway. Functional assays revealed significant inhibition of cell proliferation, migration, and invasion by miR-675. In addition, miR-675 synergistically enhanced the apoptotic effect of paclitaxel and carboplatin, suggesting potential for combination therapy of miRNA-675 with chemotherapeutic agents. In vivo studies using orthotopic injection of miR-675 expressing and control OC cells in NSG mice demonstrated significant inhibition of primary OC growth and metastasis. These findings indicate that miR-675 is a promising therapeutic target for OC treatment.

MicroRNAs (miRNAs) can function as either tumor suppressors or oncogenes. This study explores the role of miR-675 in ovarian cancer (OC) using in vitro OC cell lines and an in vivo orthotopic mouse model. We demonstrate that miR-675 expression inhibits primary tumor growth and metastasis by targeting TGFI31, suppressing epithelial to mesenchymal transition (EMT), and attenuating the TGFI3 signaling pathway. Functional assays revealed significant inhibition of cell proliferation, migration, and invasion by miR-675. In addition, miR-675 synergistically enhanced the apoptotic effect of paclitaxel and carboplatin, suggesting potential for combination therapy of miRNA-675 with chemotherapeutic agents. In vivo studies using orthotopic injection of miR-675 expressing and control OC cells in NSG mice demonstrated significant inhibition of primary OC growth and metastasis. These findings indicate that miR-675 is a promising therapeutic target for OC treatment.

Ovarian cancer is the most lethal gynecological malignancy, with a 5-year survival rate of approximately 50%. The dismal prognosis is due in part to metastatic disease and acquired drug resistance to conventional chemotherapies such as taxanes. Colchicine binding site inhibitors (CBSIs) are attractive alternatives to taxanes because they could potentially achieve oral bioavailability and overcome drug resistance associated with the prolonged use of taxanes. VERU-111 is one of the most advanced CBSIs that is orally available, potent, and well tolerated and has shown good efficacy in several preclinical solid tumor models. Here, we demonstrate for the first time the in vitro potency of VERU-111 as well as its efficacy at inhibiting tumor growth and metastasis in an orthotopic ovarian cancer mouse model. VERU-111 has nanomolar potency against ovarian cancer cell lines and strongly inhibits colony formation, proliferation, invasion, and migration. VERU-111 disrupts microtubule formation to induce mitotic catastrophe and ultimately apoptosis in a concentration-dependent manner. The efficacy of VERU-111 was comparable with standard chemotherapy paclitaxel, the current first-line treatment of ovarian cancer, with no observed synergy with combination paclitaxel + VERU-111 treatment. In vivo, VERU-111 markedly suppressed ovarian tumor growth and completely suppressed distant organ metastasis. Together, these results support VERU-111 for its potential as a novel therapy for ovarian cancer, particularly for late-stage metastatic disease. SIGNIFICANCE STATEMENT: VERU-111 is an investigational new drug and has comparable efficacy as paclitaxel in suppressing tumor cell proliferation, colony formation, and migration in ovarian cancer models in vitro and has potent in vivo antitumor and antimetastatic activity in an orthotopic ovarian cancer mouse model. VERU-111 has low systemic toxicity and, unlike paclitaxel, is orally bioavailable and is not a substrate for the major drug efflux transporters, making it a promising and attractive alternative to taxane-based therapy.

The application of extracellular vehicles (EVs), particularly exosomes, is rapidly expanding in the field of medicine, thanks to their remarkable properties as natural carriers of biological cargo. This study investigates utilization of exosomes derived from stromal cells of tumor adjacent normal tissues (NAF-EXs) for personalized medicine, which can be derived at the time of diagnosis by endoscopic ultrasound. Herein, we showcase that EXs derived from NAFs demonstrate differential bio-physical characteristics, efficient cellular internalization, drug loading efficiency, pancreatic tumor targeting and delivery of payloads. NAF-derived EXs (NAF-EXs) were used for loading ormeloxifene (ORM), a potent anti-cancer and desmoplasia inhibitor as a model drug. We found that ORM maintains normal fibroblast cell phenotype and renders them incompatible to be triggered for a CAF-like phenotype, which may be due to regulation of Ca2+ influx in fibroblast cells. NAF-EXs-ORM effectively blocked oncogenic signaling pathways involved in desmoplasia and epithelial mesenchymal transition (EMT) and repressed tumor growth in xenograft mouse model. In conclusion, our data suggests preferential tropism of NAF-EXs for PDAC tumors, thus imply feasibility of developing a novel personalized medicine for PDAC patients using autologous NAF-EXs for improved therapeutic outcome. Additionally, it provides the opportunity of utilizing this biological scaffold for effective therapeutics in combination with standard therapeutic regimen.

Abstract A major clinical challenge in cancer treatment is to prevent and treat metastatic disease. Despite the significant advancements in targeted therapy and immunotherapy, chemotherapeutic drugs, including taxanes, remain one of the mainline systemic treatment options for several major cancer types. However, the prolonged use of taxanes has been associated with the development of multidrug resistance, dose-limiting hematopoietic toxicity, and neurotoxicity, frequently presenting as persistent peripheral neuropathy. In addition, these drugs have limited blood-brain barrier penetration, and thus they are not effective in treating brain tumors or brain metastases from other cancer types, particularly breast cancer metastases. We have developed a new generation of tubulin inhibitors, termed colchicine binding site inhibitors (CBSIs). Unlike taxanes, these compounds bind to the colchicine site in tubulin, structurally less complex than taxanes which enables fine-tuning of physical-chemical properties, and shows the ability to overcome acquired drug resistance to existing taxane drugs. One of the best inhibitors in this class of compounds is SB-216. We have solved the high-resolution crystal structure of SB-216 in a complex with tubulin protein (PDB: 6X1F) and confirmed its mode of action. Extensive preclinical evaluations of SB-216 in a number of tumor models, including taxane-resistant prostate cancer, melanoma, ovarian cancer, and triple-negative breast cancer, indicated that SB-216 is highly potent in suppressing both primary tumor growth and tumor metastases. Importantly, SB-216 shows high brain penetration and shows efficacy in suppressing brain metastases from triple-negative breast cancer. SB-216 also has good drug-like properties and shows strong promise as a new generation of tubulin inhibitor for systemic cancer treatments, not only in brain metastasis from non-CNS tumors but also potentially be useful for brain tumors such as glioma. The work is supported by NIH/NCI grants R01CA14876 and R01CA276152 and the DoD grant HT9425-23-1-0216. Citation Format: Kelli L. Adeleye, Satyanarayana Pochampally, Raisa Krutilina, Rui Wang, Junming Yue, Tiffany Seagroves, Duane D.Miller, Wei Li. Discovery of a potent and brain-penetrable tubulin inhibitor SB-216 that shows efficacy in primary tumor growth and brain metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr A019.

Supplementary Figure 3. (A) ATX and LPA receptor profiling in B16F10 cells transduced with GFP lentivirus using quantitative real-time PCR. Data are expressed as mean {plus minus} SD of an experiment performed twice in quadruplicates. (B) Representative images of lungs harvested at day 21 from mice that were injected with PBS (left panel, control) and mice that were injected with 1 x 105 GFP-expressing B16F10 cells (right panel). Arrow denotes a single fluorescent tumor nodule on lung surface. Scale bar = 200 microns.

Supplementary Table 1. Primer sequences used in quantitative Real-Time PCR analysis.

Background Cancer-testis antigens (CTAs) are often expressed in tumor and testicular tissues but not in other normal tissues. To date, there has been no comprehensive study of the expression and clinical significance of CTA genes associated with endometrial cancer (EC) development. Additionally, the clinical relevance, biological role, and molecular mechanisms of the CTA gene TTK protein kinase ( TTK ) in EC are yet to be fully understood. Methods Using bioinformatics methods, we comprehensively investigated the genomic, transcriptomic, and epigenetic changes associated with aberrant TTK overexpression in EC samples from the TCGA database. We further investigated the mechanisms of the lower survival associated with TTK dysregulation using single-cell data of EC samples from the GEO database. Cell functional assays were used to confirm the biological roles of TTK in EC cells. Results We identified 80 CTA genes that were more abundant in EC than in normal tissues, and high expression of TTK was significantly linked with lower survival in EC patients. Furthermore, ROC analysis revealed that TTK could accurately distinguish stage I EC tissues from benign endometrial samples, suggesting that TTK has the potential to be a biomarker for early EC detection. We found TTK overexpression was more prevalent in EC patients with high-grade, advanced tumors, serous carcinoma, and TP53 alterations. Furthermore, in EC tissue, TTK expression showed a strong positive correlation with EMT-related genes. With single-cell transcriptome data, we identified a proliferative cell subpopulation with high expression of TTK and known epithelial–mesenchymal transition (EMT)-related genes and transcription factors. When proliferative cells were grouped according to TTK expression levels, the overexpressed genes in the TTK high group were shown to be functionally involved in the control of chemoresistance. Utilizing shRNA to repress TTK expression in EC cells resulted in substantial decreases in cell proliferation, invasion, EMT, and chemoresistance. Further research identified microRNA-21 (miR-21) as a key downstream regulator of TTK-induced EMT and chemoresistance. Finally, the TTK inhibitor AZ3146 was effective in reducing EC cell growth and invasion and enhancing the apoptosis of EC cells generated by paclitaxel. Conclusion Our findings establish the clinical significance of TTK as a new biomarker for EC and an as-yet-unknown carcinogenic function. This present study proposes that the therapeutic targeting of TTK might provide a viable approach for the treatment of EC.

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Supplementary Figure 5. ATX and LPA receptor profiling in isolated rat alveolar type I-like (A) or type II (B) epithelial cells. Note that expression levels in type II alveolar cells are approximately 10-fold lower than in type I-like cells. Data presented are representative of an experiment performed three times in quadruplicates and are expressed as mean {plus minus} SD.