ImportanceDespite similar histologic appearance among high-grade serous ovarian cancers (HGSOCs), clinical observations suggest vast differences in gross appearance. There is currently no systematic framework by which to classify HGSOCs according to their gross morphologic characteristics.ObjectiveTo develop and characterize a gross morphologic classification system for HGSOC.Design, Setting, and ParticipantsThis cohort study included patients with suspected advanced-stage ovarian cancer who presented between April 1, 2013, and August 5, 2016, to the University of Texas MD Anderson Cancer Center, a large referral center. Patients underwent laparoscopic assessment of disease burden before treatment and received a histopathologic diagnosis of HGSOC. Researchers assigning morphologic subtype and performing molecular analyses were blinded to clinical outcomes. Data analysis was performed between April 2020 and November 2021.ExposuresGross tumor morphologic characteristics.Main Outcomes and MeasuresClinical outcomes and multiomic profiles of representative tumor samples of type I or type II morphologic subtypes were compared.ResultsOf 112 women (mean [SD] age 62.7 [9.7] years) included in the study, most patients (84% [94]) exhibited a predominant morphologic subtype and many (63% [71]) had a uniform morphologic subtype at all involved sites. Compared with those with uniform type I morphologic subtype, patients with uniform type II morphologic subtype were more likely to have a favorable Fagotti score (83% [19 of 23] vs 46% [22 of 48]; P = .004) and thus to be triaged to primary tumor reductive surgery. Similarly, patients with uniform type II morphologic subtype also had significantly higher mean (SD) estimated blood loss (639 [559; 95% CI, 391-887] mL vs 415 [527; 95% CI, 253-577] mL; P = .006) and longer mean (SD) operative time (408 [130; 95% CI, 350-466] minutes vs 333 [113; 95% CI, 298-367] minutes; P = .03) during tumor reductive surgery. Type I tumors had enrichment of epithelial-mesenchymal transition (false discovery rate [FDR] q-value, 3.10 × 10−24), hypoxia (FDR q-value, 1.52 × 10−5), and angiogenesis pathways (FDR q-value, 2.11 × 10−2), whereas type II tumors had enrichment of pathways related to MYC signaling (FDR q-value, 2.04 × 10−9) and cell cycle progression (FDR q-value, 1.10 × 10−5) by integrated proteomic and transcriptomic analysis. Abundances of metabolites and lipids also differed between the 2 morphologic subtypes.Conclusions and RelevanceThis study identified 2 novel, gross morphologic subtypes of HGSOC, each with unique clinical features and molecular signatures. The findings may have implications for triaging patients to surgery or chemotherapy, identifying outcomes, and developing tailored therapeutic strategies.
Background: The incidence of venous thromboembolism (VTE) in patients with ovarian cancer is higher than most solid tumors, ranging between 10–30%, and a diagnosis of VTE in this patient population is associated with worse oncologic outcomes. The tumor-specific molecular factors that may lead to the development of VTE are not well understood. Objectives: The aim of this study was to identify molecular features present in ovarian tumors of patients with VTE compared to those without. Methods: We performed a multiplatform omics analysis incorporating RNA and DNA sequencing, quantitative proteomics, as well as immune cell profiling of high-grade serous ovarian carcinoma (HGSC) samples from a cohort of 32 patients with or without VTE. Results: Pathway analyses revealed upregulation of both inflammatory and coagulation pathways in the VTE group. While DNA whole-exome sequencing failed to identify significant coding alterations between the groups, the results of an integrated proteomic and RNA sequencing analysis indicated that there is a relationship between VTE and the expression of platelet-derived growth factor subunit B (PDGFB) and extracellular proteins in tumor cells, namely collagens, that are correlated with the formation of thrombosis. Conclusions: In this comprehensive analysis of HGSC tumor tissues from patients with and without VTE, we identified markers unique to the VTE group that could contribute to development of thrombosis. Our findings provide additional insights into the molecular alterations underlying the development of VTE in ovarian cancer patients and invite further investigation into potential predictive biomarkers of VTE in ovarian cancer.
CRM1 inhibitors have demonstrated antitumor effects in ovarian and other cancers; however, rational combinations are largely unexplored. We performed a high-throughput drug library screen to identify drugs that might combine well with selinexor in ovarian cancer. Next, we tested the combination of selinexor with the top hit from the drug screen in vitro and in vivo. Finally, we assessed for mechanisms underlying the identified synergy using reverse phase protein arrays (RPPA). The drug library screen assessing 688 drugs identified olaparib (a PARP inhibitor) as the most synergistic combination with selinexor. Synergy was further demonstrated by MTT assays. In the A2780luc ip1 mouse model, the combination of selinexor and olaparib yielded significantly lower tumor weight and fewer tumor nodules compared with the control group (P < 0.04 and P < 0.03). In the OVCAR5 mouse model, the combination yielded significantly fewer nodules (P = 0.006) and markedly lower tumor weight compared with the control group (P = 0.059). RPPA analysis indicated decreased expression of DNA damage repair proteins and increased expression of tumor suppressor proteins in the combination treatment group. Collectively, our preclinical findings indicate that combination with selinexor to expand the utility and efficacy of PARP inhibitors in ovarian cancer warrants further exploration.
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Background: GP-2250, a novel analog of taurultam (TRLT), has emerged as a potent anti-neoplastic drug; however, the mechanisms underlying its effects are not well understood. Here, we investigated the mechanism of action and the biological effects of GP-2250 using in vitro and in vivo models. Methods: We carried out a series of in vitro experiments including MTT assay, Annexin V/PI assay, colony formation assay, reverse-phase protein array (RPPA), and HRLC/IC analysis to determine the biological activity of GP-2250 and investigate the mechanism of action. In vivo experiments were carried out to determine the therapeutic efficacy of GP-2250 alone and in combination with standard-of-care drugs (e.g., paclitaxel, cisplatin topotecan, and poly ADP-ribose polymerases (PARP) inhibitors. Results: We investigated the cytotoxic effect of GP-2250 in 10 ovarian cancer cell lines and found that HRD ovarian cancer cells (e.g., Kuramochi, OVCAR4, and OVCAR8) were more vulnerable to GP-2250 than HRP ovarian cancer cells (e.g., A2780 and OVCAR5). In addition, GP-2250 combination with a PARP inhibitor showed the most synergistic effects. There was no difference among the PARP inhibitors (e.g., olaparib, niraparib, and rucaparib) with regard to the combinatorial effect with GP-2250. RPPA analyses revealed that GP-2250 inhibited hypoxia-inducible factor-1α, AKT, and mTOR activation and expression level. Ultra-high resolution mass spectrometry (HRMS) analysis also revealed that hexokinase2 activity and expression was significantly reduced by GP-2250 treatment. Furthermore, GP-2250 also reduced glycolysis and ATP synthesis in cancer cells. In vivo pharmacodynamic experiment using the OVCAR8 mouse model demonstrated that a dose of 500 mg/kg GP-2250 was the most effective in downregulating AKT and mTOR activation and expression In the in vivo therapy experiment using an orthotopic mouse model, a combination of GP-2250 and PARP inhibitors (olaparib, niraparib, or rucaparib) or bevacizumab showed a significant reduction of tumor weights (0.16 ± 0.05 g, 0.13 ± 0.06 g, 0.29 ± 0.05 g, and 0.07 ± 0.03 g, respectively) and nodules (1.56 ± 0.44, 1.89 ± 0.59, 3.11 ± 0.59, and 0.78 ±0.2, respectively) compared to those treated with a vehicle (tumor weight, 0.95 ± 0.1 g and nodules, 8.4 ± 0.65) or the monotherapy groups, GP-2250 (tumor weight, 2.9 ± 0.48 g, and nodules, 2.9 ± 0.48), olaparib (tumor weight, 0.53 ± 0.09 g, and nodules, 3.3 ± 0.64), niraparib (tumor weight, 0.38 ± 0.05 g, and nodules, 3.4 ± 0.44), rucaprib, (tumor weight, 0.52 ± 0.1 g, and nodules, 4.85 ± 0.79), and bevacizumab (tumor weight, 0.43 ± 0.08 g, and nodules, 3.8 ± 0.71), respectively. Conclusions: Taken together, our data indicate that GP-2250 exerts profound effects on tumor metabolism and combination with PARP inhibitors or bevacizumab showed promising anti-tumor efficacy. These findings could have implications for the clinical development of GP-2250. Citation Format: Mark S. Kim, Deanna Glassman, Adrian Lankenau Ahumada, Emine Bayraktar, Nicholas B. Jennings, Robiya Joseph, Sanghoon Lee, Robert L. Coleman, Anil K. Sood. Mechanisms and rational combinations with gp-2250, a novel oxathiazine derivative, in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 528.
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