126 results on '"Mangala LS"'
Search Results
2. EphA2- and HDAC-Targeted Combination Therapy in Endometrial Cancer.
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Joseph R, Dasari SK, Umamaheswaran S, Mangala LS, Bayraktar E, Rodriguez-Aguayo C, Wu Y, Nguyen N, Powell RT, Sobieski M, Liu Y, Kim MS, Corvigno S, Foster K, Hanjra P, Vu TC, Chowdhury MA, Amero P, Stephan C, Lopez-Berestein G, Westin SN, and Sood AK
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- Animals, Female, Humans, Mice, Apoptosis, Cell Line, Tumor, Panobinostat pharmacology, Panobinostat therapeutic use, Phosphatidylinositol 3-Kinases, Molecular Targeted Therapy, Endometrial Neoplasms drug therapy, Endometrial Neoplasms genetics, Endometrial Neoplasms pathology, Histone Deacetylase Inhibitors therapeutic use, Receptor, EphA2 antagonists & inhibitors
- Abstract
Endometrial cancer is the most frequent malignant tumor of the female reproductive tract but lacks effective therapy. EphA2, a receptor tyrosine kinase, is overexpressed by various cancers including endometrial cancer and is associated with poor clinical outcomes. In preclinical models, EphA2-targeted drugs had modest efficacy. To discover potential synergistic partners for EphA2-targeted drugs, we performed a high-throughput drug screen and identified panobinostat, a histone deacetylase inhibitor, as a candidate. We hypothesized that combination therapy with an EphA2 inhibitor and panobinostat leads to synergistic cell death. Indeed, we found that the combination enhanced DNA damage, increased apoptosis, and decreased clonogenic survival in Ishikawa and Hec1A endometrial cancer cells and significantly reduced tumor burden in mouse models of endometrial carcinoma. Upon RNA sequencing, the combination was associated with downregulation of cell survival pathways, including senescence, cyclins, and cell cycle regulators. The Axl-PI3K-Akt-mTOR pathway was also decreased by combination therapy. Together, our results highlight EphA2 and histone deacetylase as promising therapeutic targets for endometrial cancer.
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- 2024
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3. Enhancing oral delivery of plant-derived vesicles for colitis.
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Liu Y, Ahumada AL, Bayraktar E, Schwartz P, Chowdhury M, Shi S, Sebastian MM, Khant H, de Val N, Bayram NN, Zhang G, Vu TC, Jie Z, Jennings NB, Rodriguez-Aguayo C, Swain J, Stur E, Mangala LS, Wu Y, Nagaraju S, Ermias B, Li C, Lopez-Berestein G, Braam J, and Sood AK
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- Mice, Animals, Hydrogen-Ion Concentration, Polymethacrylic Acids chemistry, Administration, Oral, Drug Delivery Systems, Colitis chemically induced, Colitis drug therapy
- Abstract
Plant-derived vesicles (PDVs) are attractive for therapeutic applications, including as potential nanocarriers. However, a concern with oral delivery of PDVs is whether they would remain intact in the gastrointestinal tract. We found that 82% of cabbage PDVs were destroyed under conditions mimicking the upper digestive tract. To overcome this limitation, we developed a delivery method whereby lyophilized Eudragit S100-coated cabbage PDVs were packaged into a capsule (Cap-cPDVs). Lyophilization and suspension of PDVs did not have an appreciable impact on PDV structure, number, or therapeutic effect. Additionally, packaging the lyophilized Eudragit S100-coated PDVs into capsules allowed them to pass through the upper gastrointestinal tract for delivery into the colon better than did suspension of PDVs in phosphate-buffered saline. Cap-cPDVs showed robust therapeutic effect in a dextran sulfate sodium-induced colitis mouse model. These findings could have broad implications for the use of PDVs as orally delivered nanocarriers of natural therapeutic plant compounds or other therapeutics., Competing Interests: Declaration of Competing Interest A.K.S.: scientific consulting (Kiyatec, GSK, Merck, Onxeo, ImmunoGen, Iylon); shareholder (Biopath)., (Copyright © 2023 Elsevier B.V. All rights reserved.)
- Published
- 2023
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4. Overcoming adaptive resistance to anti-VEGF therapy by targeting CD5L.
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LaFargue CJ, Amero P, Noh K, Mangala LS, Wen Y, Bayraktar E, Umamaheswaran S, Stur E, Dasari SK, Ivan C, Pradeep S, Yoo W, Lu C, Jennings NB, Vathipadiekal V, Hu W, Chelariu-Raicu A, Ku Z, Deng H, Xiong W, Choi HJ, Hu M, Kiyama T, Mao CA, Ali-Fehmi R, Birrer MJ, Liu J, Zhang N, Lopez-Berestein G, de Franciscis V, An Z, and Sood AK
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- Humans, Bevacizumab pharmacology, Bevacizumab therapeutic use, Antibodies, Monoclonal pharmacology, Angiogenesis Inhibitors pharmacology, Angiogenesis Inhibitors therapeutic use, Apoptosis Regulatory Proteins, Receptors, Scavenger, Vascular Endothelial Growth Factor A genetics, Vascular Endothelial Growth Factor A metabolism, Neoplasms drug therapy, Neoplasms genetics
- Abstract
Antiangiogenic treatment targeting the vascular endothelial growth factor (VEGF) pathway is a powerful tool to combat tumor growth and progression; however, drug resistance frequently emerges. We identify CD5L (CD5 antigen-like precursor) as an important gene upregulated in response to antiangiogenic therapy leading to the emergence of adaptive resistance. By using both an RNA-aptamer and a monoclonal antibody targeting CD5L, we are able to abate the pro-angiogenic effects of CD5L overexpression in both in vitro and in vivo settings. In addition, we find that increased expression of vascular CD5L in cancer patients is associated with bevacizumab resistance and worse overall survival. These findings implicate CD5L as an important factor in adaptive resistance to antiangiogenic therapy and suggest that modalities to target CD5L have potentially important clinical utility., (© 2023. The Author(s).)
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- 2023
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5. Combination of EphA2- and Wee1-Targeted Therapies in Endometrial Cancer.
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Dasari SK, Joseph R, Umamaheswaran S, Mangala LS, Bayraktar E, Rodriguez-Aguayo C, Wu Y, Nguyen N, Powell RT, Sobieski M, Liu Y, Chowdhury MA, Amero P, Stephan C, Lopez-Berestein G, Westin SN, and Sood AK
- Subjects
- Animals, Female, Humans, Mice, Apoptosis, Cell Cycle Proteins metabolism, Cell Line, Tumor, Cell Proliferation, Antineoplastic Agents therapeutic use, Endometrial Neoplasms drug therapy, Protein Kinase Inhibitors therapeutic use, Protein-Tyrosine Kinases antagonists & inhibitors, Receptor, EphA2 antagonists & inhibitors, Molecular Targeted Therapy
- Abstract
EphA2 tyrosine kinase is upregulated in many cancers and correlated with poor survival of patients, including those with endometrial cancer. EphA2-targeted drugs have shown modest clinical benefit. To improve the therapeutic response to such drugs, we performed a high-throughput chemical screen to discover novel synergistic partners for EphA2-targeted therapeutics. Our screen identified the Wee1 kinase inhibitor, MK1775, as a synergistic partner to EphA2, and this finding was confirmed using both in vitro and in vivo experiments. We hypothesized that Wee1 inhibition would sensitize cells to EphA2-targeted therapy. Combination treatment decreased cell viability, induced apoptosis, and reduced clonogenic potential in endometrial cancer cell lines. In vivo Hec1A and Ishikawa-Luc orthotopic mouse models of endometrial cancer showed greater anti-tumor responses to combination treatment than to either monotherapy. RNASeq analysis highlighted reduced cell proliferation and defective DNA damage response pathways as potential mediators of the combination's effects. In conclusion, our preclinical findings indicate that Wee1 inhibition can enhance the response to EphA2-targeted therapeutics in endometrial cancer; this strategy thus warrants further development.
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- 2023
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6. Broad-acting therapeutic effects of miR-29b-chitosan on hypertension and diabetic complications.
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Jensen DM, Han P, Mangala LS, Lopez-Berestein G, Sood AK, Liu J, Kriegel AJ, Usa K, Widlansky ME, and Liang M
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- Mice, Humans, Animals, Angiotensin II adverse effects, Mice, Knockout, ApoE, Disease Models, Animal, Fibrosis, Mice, Inbred Strains, Thiolester Hydrolases, MicroRNAs genetics, MicroRNAs metabolism, Chitosan, Hypertension genetics, Hypertension therapy, Diabetes Complications, Diabetes Mellitus
- Abstract
MicroRNA miR-29 promotes endothelial function in human arterioles in part by targeting LYPLA1 and increasing nitric oxide production. In addition, miR-29 is a master inhibitor of extracellular matrix gene expression, which may attenuate fibrosis but could also weaken tissue structure. The goal of this study was to test whether miR-29 could be developed as an effective, broad-acting, and safe therapeutic. Substantial accumulation of miR-29b and effective knockdown of Lypla1 in several mouse tissues were achieved using a chitosan-packaged, chemically modified miR-29b mimic (miR-29b-CH-NP) injected systemically at 200 μg/kg body weight. miR-29b-CH-NP, injected once every 3 days, significantly attenuated angiotensin II-induced hypertension. In db/db mice, miR-29b-CH-NP treatment for 12 weeks decreased cardiac and renal fibrosis and urinary albuminuria. In uninephrectomized db/db mice, miR-29b-CH-NP treatment for 20 weeks significantly improved myocardial performance index and attenuated proteinuria. miR-29b-CH-NP did not worsen abdominal aortic aneurysm in ApoE knockout mice treated with angiotensin II. miR-29b-CH-NP caused aortic root fibrotic cap thinning in ApoE knockout mice fed a high-cholesterol and high-fat diet but did not worsen the necrotic zone or mortality. In conclusion, systemic delivery of low-dose miR-29b-CH-NP is an effective therapeutic for several forms of cardiovascular and renal disease in mice., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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7. Corrigendum to "PTGER3 induces ovary tumorigenesis and confers resistance to cisplatin therapy through up-regulation Ras-MAPK/Erk-ETS1-ELK1/CFTR1 axis" [EBioMedicine 40 (2019) 290-304].
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Rodriguez-Aguayo C, Bayraktar E, Ivan C, Aslan B, Mai J, He G, Mangala LS, Jiang D, Nagaraja AS, Ozpolat B, Chavez-Reyes A, Ferrari M, Mitra R, Siddik ZH, Shen H, Yang X, Sood AK, and Lopez-Berestein G
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- 2022
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8. Molecular Analysis of Short- versus Long-Term Survivors of High-Grade Serous Ovarian Carcinoma.
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Stur E, Bayraktar E, Dal Molin GZ, Wu SY, Mangala LS, Yao H, Wang Y, Ram PT, Corvigno S, Chen H, Liang H, Tworoger SS, Levine DA, Lutgendorf SK, Liu J, Moore KN, Baggerly KA, Karlan BY, and Sood AK
- Abstract
Despite having similar histologic features, patients with high-grade serous ovarian carcinoma (HGSC) often experience highly variable outcomes. The underlying determinants for long-term survival (LTS, ≥10 years) versus short-term survival (STS, <3 years) are largely unknown. The present study sought to identify molecular predictors of LTS for women with HGSC. A cohort of 24 frozen HGSC samples was collected (12 LTS and 12 STS) and analyzed at DNA, RNA, and protein levels. OVCAR5 and OVCAR8 cell lines were used for in vitro validation studies. For in vivo studies, we injected OVCAR8 cells into the peritoneal cavity of female athymic nude mice. From RNAseq analysis, 11 genes were found to be differentially expressed between the STS and LTS groups (fold change > 2; false discovery rate < 0.01). In the subsequent validation cohort, transmembrane protein 62 (TMEM62) was found to be related to LTS. CIBERSORT analysis showed that T cells (follicular helper) were found at higher levels in tumors from LTS than STS groups. In vitro data using OVCAR5 and OVCAR8 cells showed decreased proliferation with TMEM62 overexpression and positive correlation with a longevity-regulating pathway (KEGG HSA04213) at the RNA level. In vivo analysis using the OVCAR8-TMEM62-TetON model showed decreased tumor burden in mice with high- vs. low-expressing TMEM62 tumors. Our results demonstrate that restoring TMEM62 may be a novel approach for treatment of HGSC. These findings may have implications for biomarker and intervention strategies to help improve patient outcomes
- Published
- 2022
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9. Author Correction: Tuning microtubule dynamics to enhance cancer therapy by modulating FER-mediated CRMP2 phosphorylation.
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Zheng Y, Sethi R, Mangala LS, Taylor C, Goldsmith J, Wang M, Masuda K, Carrami EM, Mannion D, Miranda F, Herrero-Gonzalez S, Hellner K, Chen F, Alsaadi A, Albukhari A, Fotso DC, Yau C, Jiang D, Pradeep S, Rodriguez-Aguayo C, Lopez-Berestein G, Knapp S, Gray NS, Campo L, Myers KA, Dhar S, Ferguson D, Bast RC Jr, Sood AK, von Delft F, and Ahmed AA
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- 2022
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10. Targeting CCR2 + macrophages with BET inhibitor overcomes adaptive resistance to anti-VEGF therapy in ovarian cancer.
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Wu Y, Jennings NB, Sun Y, Dasari SK, Bayraktar E, Corvigno S, Stur E, Glassman D, Mangala LS, Lankenau Ahumada A, Westin SN, Sood AK, and Hu W
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- Animals, Carcinoma, Ovarian Epithelial metabolism, Cell Line, Tumor, Humans, Macrophages, Mice, Receptors, CCR2 metabolism, Antineoplastic Agents pharmacology, Ovarian Neoplasms pathology
- Abstract
Purpose: Tumor-associated macrophages (TAMs) are known to contribute to adaptive resistance to anti-vascular endothelial growth factor (VEGF) antibody (AVA) therapy in ovarian cancer. BET (bromodomain and extra-terminal domain) inhibitors (BETi) may have unique roles in targeting TAMs. Our objective was to examine the effects of BETi on TAMs, especially in the context of enhancing the efficacy of AVA therapy., Methods: We conducted a series of in vitro (MTT assay, apoptosis, flow cytometry, and RNA sequencing) and in vivo (xenograft ovarian cancer model) experiments to determine the biological effects of BETi combined with AVA in ovarian cancer. For statistical analysis, a two-tailed Student's t test (equal variance) or ANOVA was used for multiple groups' comparison, and p < 0.05 was considered significant., Results: BETi resulted in a dose-dependent decrease in cell viability and induced apoptosis (p < 0.01) in ovarian cancer cells (SKOV3ip1, OVCAR5, and OVCAR8). Treatment with BETi significantly increased apoptosis in THP-1 monocytes and macrophages (PMA-differentiated THP-1; p < 0.01). Furthermore, BETi selectively induced greater apoptosis in M2-like macrophages (PMA and IL-4, IL-13-differentiated THP-1) (31.3%-36.1%) than in M1-like macrophages (PMA and LPS-differentiated THP-1) (12.4%-18.5%) (p < 0.01). Flow cytometry revealed that the percentage of M1-like macrophages (CD68
+ /CD80+ ) was significantly increased after treatment with low-dose BETi (ABBV-075 0.1 µM; p < 0.05), whereas the percentage of CD68+ /CCR2+ macrophages was significantly decreased (p < 0.001); these findings suggest that BETi may selectively inhibit the survival of CCR2+ macrophages and re-polarize the macrophages into an M1-like phenotype. RNA-seq analysis revealed that BETi selectively targeted macrophage infiltration-related cytokines/chemokines in ovarian cancer (adjusted p < 0.05 and Log2 fold change ≥ 1.5). Finally, using in vivo ovarian cancer models, compared with control or monotherapy, the combination of BETi (ABBV-075) and bevacizumab resulted in greater inhibition of tumor growth and macrophage infiltration (p < 0.05) and longer survival of tumor-bearing mice (p < 0.001)., Conclusions: Our findings indicate a previously unrecognized role for BETi in selectively targeting CCR2+ TAMs and enhancing the efficacy of AVA therapy in ovarian cancer., (© 2021. The Author(s).)- Published
- 2022
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11. Author Correction: Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma.
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Thaker PH, Han LY, Kamat AA, Arevalo JM, Takahashi R, Lu C, Jennings NB, Armaiz-Pena G, Bankson JA, Ravoori M, Merritt WM, Lin YG, Mangala LS, Kim TJ, Coleman RL, Landen CN, Li Y, Felix E, Sanguino AM, Newman RA, Lloyd M, Gershenson DM, Kundra V, Lopez-Berestein G, Lutgendorf SK, Cole SW, and Sood AK
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- 2021
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12. Gene Body Methylation of the Lymphocyte-Specific Gene CARD11 Results in Its Overexpression and Regulates Cancer mTOR Signaling.
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McGuire MH, Dasari SK, Yao H, Wen Y, Mangala LS, Bayraktar E, Ma W, Ivan C, Shoshan E, Wu SY, Jonasch E, Bar-Eli M, Wang J, Baggerly KA, and Sood AK
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- Animals, Female, Humans, Mice, Mice, Nude, Prognosis, Signal Transduction, Transfection, CARD Signaling Adaptor Proteins metabolism, DNA Methylation genetics, Lymphocytes metabolism, TOR Serine-Threonine Kinases metabolism
- Abstract
Investigations into the function of nonpromoter DNA methylation have yielded new insights into epigenetic regulation of gene expression. Previous studies have highlighted the importance of distinguishing between DNA methylation in discrete functional regions; however, integrated nonpromoter DNA methylation and gene expression analyses across a wide number of tumor types and corresponding normal tissues have not been performed. Through integrated analysis of gene expression and DNA methylation profiles, we examined 32 tumor types and identified 57 tumor suppressors and oncogenes out of 260 genes exhibiting a correlation of > 0.5 between gene body methylation and gene expression in at least one tumor type. The lymphocyte-specific gene CARD11 exhibits robust association between gene body methylation and expression across 19 of 32 tumor types examined. It is significantly overexpressed in kidney renal cell carcinoma (KIRC) and lung adenocarcinoma (LUAD) tumor tissues in comparison with respective control samples; and is significantly associated with lower overall survival in KIRC. Contrary to its canonical function in lymphocyte NFκB activation, CARD11 activates the mTOR pathway in KIRC and LUAD, resulting in suppressed autophagy. Furthermore, demethylation of a CpG island within the gene body of CARD11 decreases gene expression. Collectively, our study highlights how DNA methylation outside the promoter region can impact tumor progression. IMPLICATIONS: Our study describes a novel regulatory role of gene body DNA methylation-dependent CARD11 expression on mTOR signaling and its impact on tumor progression., (©2021 American Association for Cancer Research.)
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- 2021
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13. MEK inhibition overcomes resistance to EphA2-targeted therapy in uterine cancer.
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Wu Y, Huang J, Ivan C, Sun Y, Ma S, Mangala LS, Fellman BM, Urbauer DL, Jennings NB, Ram P, Coleman RL, Hu W, and Sood AK
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- Animals, Apoptosis drug effects, Cell Line, Tumor, Dasatinib administration & dosage, Drug Resistance, Neoplasm, Female, Humans, MAP Kinase Signaling System physiology, Mice, Pyridones administration & dosage, Pyridones therapeutic use, Pyrimidinones administration & dosage, Pyrimidinones therapeutic use, Receptor, EphA2 physiology, Dasatinib therapeutic use, Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors, Receptor, EphA2 antagonists & inhibitors, Uterine Neoplasms drug therapy
- Abstract
Background: Our pilot clinical study of EphA2 inhibitor (dasatinib) plus paclitaxel and carboplatin showed interesting clinical activity in endometrial cancer with manageable toxicity. However, the underlying mechanisms of dasatinib resistance in uterine cancer are unknown. Here, we investigated potential mechanisms underlying resistance to EphA2 inhibitors in uterine cancer and examined the anti-tumor activity of EphA2 inhibitors alone and in combination with a MEK inhibitor., Methods: We evaluated the antitumor activity of EphA2 inhibitors plus a MEK inhibitor using in vitro and in vivo orthotopic models of uterine cancer., Results: EphA2 inhibitor induced MAPK in dasatinib-resistant uterine cancer cells (HEC-1A and Ishikawa) and BRAF/CRAF heterodimerization in HEC-1A cells. EphA2 inhibitor and trametinib significantly increased apoptosis in cancer cells resistant to EphA2 inhibitors compared with controls (p < 0.01). An in vivo study with the orthotopic HEC-1A model showed significantly greater antitumor response to combination treatment compared with dasatinib alone (p < 0.01). Combination treatment increased EphrinA1 and BIM along with decreased pMAPK, Jagged 1, and c-MYC expression in dasatinib-resistant cells. In addition, Spearman analysis using the TCGA data revealed that upregulation of EphA2 was significantly correlated with JAG1, MYC, NOTCH1, NOTCH3 and HES1 expression (p < 0.001, r = 0.25-0.43). Specifically, MAP3K15 and the NOTCH family genes were significantly related to poor clinical outcome in patients with uterine cancer., Conclusions: These findings indicate that the MAPK pathway is activated in dasatinib-resistant uterine cancer cells and that EphrinA1-mediated MEK inhibition overcomes dasatinib resistance. Dual targeting of both EphA2 and MEK, combined with chemotherapy, should be considered for future clinical development., Competing Interests: Declaration of Competing Interest AKS reports consulting for KIYATEC, Merck, and Astra Zeneca; being a stock holder in Bio-Path Holdings, and receiving research funding from MTrap. RLC reports grants from AstraZeneca, Roche/Genentech, Merck, Clovis Oncology, Esperance Pharmaceuticals, and AbbVie and reports serving as an advisor to AstraZeneca, Roche/Genentech, Janssen, OncoMed, Merck, Clovis Oncology, Esperance Pharmaceuticals, Tesaro, GamaMabs Pharma, Pfizer, Genmab, Agenus, Incyte, and AbbVie. WH reports research funding from Geistlich Pharma AG. The remaining authors have no conflicts of interest to declare., (Copyright © 2021 Elsevier Inc. All rights reserved.)
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- 2021
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14. CD63-mediated cloaking of VEGF in small extracellular vesicles contributes to anti-VEGF therapy resistance.
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Ma S, Mangala LS, Hu W, Bayaktar E, Yokoi A, Hu W, Pradeep S, Lee S, Piehowski PD, Villar-Prados A, Wu SY, McGuire MH, Lara OD, Rodriguez-Aguayo C, LaFargue CJ, Jennings NB, Rodland KD, Liu T, Kundra V, Ram PT, Ramakrishnan S, Lopez-Berestein G, Coleman RL, and Sood AK
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- Aged, Animals, Bevacizumab pharmacology, Bevacizumab therapeutic use, Cell Line, Tumor, Cell Proliferation, Disease Models, Animal, Extracellular Vesicles ultrastructure, Female, Humans, Mice, Mice, Nude, Middle Aged, Neovascularization, Pathologic metabolism, Neovascularization, Pathologic pathology, Ovarian Neoplasms drug therapy, Protein Isoforms metabolism, Signal Transduction, Vascular Endothelial Growth Factor A metabolism, Vascular Endothelial Growth Factor Receptor-2 metabolism, Extracellular Vesicles metabolism, Tetraspanin 30 metabolism, Vascular Endothelial Growth Factor A antagonists & inhibitors
- Abstract
Despite wide use of anti-vascular endothelial growth factor (VEGF) therapy for many solid cancers, most individuals become resistant to this therapy, leading to disease progression. Therefore, new biomarkers and strategies for blocking adaptive resistance of cancer to anti-VEGF therapy are needed. As described here, we demonstrate that cancer-derived small extracellular vesicles package increasing quantities of VEGF and other factors in response to anti-VEGF therapy. The packaging process of VEGF into small extracellular vesicles (EVs) is mediated by the tetraspanin CD63. Furthermore, small EV-VEGF (eVEGF) is not accessible to anti-VEGF antibodies and can trigger intracrine VEGF signaling in endothelial cells. eVEGF promotes angiogenesis and enhances tumor growth despite bevacizumab treatment. These data demonstrate a mechanism where VEGF is partitioned into small EVs and promotes tumor angiogenesis and progression. These findings have clinical implications for biomarkers and therapeutic strategies for ovarian cancer., Competing Interests: Declaration of interests R.L.C. has received grant funding from Genentech, Merck, Janssen Pharmaceutical, Clovis Oncology, AstraZeneca, and AbbVie and serves as an investigator on the scientific steering committees for Tesaro, Clovis Oncology, AstraZeneca, and AbbVie. A.K.S. a consultant for KIYATEC, Merck, and AstraZeneca, has received research funding from M-Trap, and is a BioPath Holdings shareholder., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2021
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15. Editor's Note: Functional Roles of Src and Fgr in Ovarian Carcinoma.
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Kim HS, Han HD, Armaiz-Pena GN, Stone RL, Nam EJ, Lee JW, Shahzad MMK, Nick AM, Lee SJ, Roh JW, Nishimura M, Mangala LS, Bottsford-Miller J, Gallick GE, Lopez-Berestein G, and Sood AK
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- 2021
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16. Editor's Note: Therapeutic Targeting of ATP7B in Ovarian Carcinoma.
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Mangala LS, Zuzel V, Schmandt R, Leshane ES, Halder JB, Armaiz-Pena GN, Spannuth WA, Tanaka T, Shahzad MMK, Lin YG, Nick AM, Danes CG, Lee JW, Jennings NB, Vivas-Mejia PE, Wolf JK, Coleman RL, Siddik ZH, Lopez-Berestein G, Lutsenko S, and Sood AK
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- 2021
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17. Editor's Note: Dopamine Blocks Stress-mediated Ovarian Carcinoma Growth.
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Moreno-Smith M, Lu C, Shahzad MMK, Pena GNA, Allen JK, Stone RL, Mangala LS, Han HD, Kim HS, Farley D, Berestein GL, Cole SW, Lutgendorf SK, and Sood AK
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- 2021
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18. Editor's Note: Targeted Gene Silencing Using RGD-Labeled Chitosan Nanoparticles.
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Han HD, Mangala LS, Lee JW, Shahzad MMK, Kim HS, Shen D, Nam EJ, Mora EM, Stone RL, Lu C, Lee SJ, Roh JW, Nick AM, Lopez-Berestein G, and Sood AK
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- 2021
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19. Inactivating Mutations of the IK Gene Weaken Ku80/Ku70-Mediated DNA Repair and Sensitize Endometrial Cancer to Chemotherapy.
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Gao C, Jin G, Forbes E, Mangala LS, Wang Y, Rodriguez-Aguayo C, Amero P, Bayraktar E, Yan Y, Lopez-Berestein G, Broaddus RR, Sood AK, Xue F, and Zhang W
- Abstract
IK is a mitotic factor that promotes cell cycle progression. Our previous investigation of 271 endometrial cancer (EC) samples from the Cancer Genome Atlas (TCGA) dataset showed IK somatic mutations were enriched in a cluster of patients with high-grade and high-stage cancers, and this group had longer survival. This study provides insight into how IK somatic mutations contribute to EC pathophysiology. We analyzed the somatic mutational landscape of IK gene in 547 EC patients using expanded TCGA dataset. Co-immunoprecipitation and mass spectrometry were used to identify protein interactions. In vitro and in vivo experiments were used to evaluate IK's role in EC. The patients with IK-inactivating mutations had longer survival during 10-year follow-up. Frameshift and stop-gain were common mutations and were associated with decreased IK expression. IK knockdown led to enrichment of G2/M phase cells, inactivation of DNA repair signaling mediated by heterodimerization of Ku80 and Ku70, and sensitization of EC cells to cisplatin treatment. IK/Ku80 mutations were accompanied by higher mutation rates and associated with significantly better overall survival. Inactivating mutations of IK gene and loss of IK protein expression were associated with weakened Ku80/Ku70-mediated DNA repair, increased mutation burden, and better response to chemotherapy in patients with EC.
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- 2021
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20. Combined VEGFR and MAPK pathway inhibition in angiosarcoma.
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Wagner MJ, Lyons YA, Siedel JH, Dood R, Nagaraja AS, Haemmerle M, Mangala LS, Chanana P, Lazar AJ, Wang WL, Ravi V, Holland EC, and Sood AK
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- Animals, Apoptosis, Biomarkers, Tumor genetics, Cell Proliferation, Hemangiosarcoma metabolism, Hemangiosarcoma pathology, Humans, Mice, Mice, Nude, Prognosis, Pyridones administration & dosage, Pyrimidinones administration & dosage, Quinazolines administration & dosage, Transcriptome, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Antineoplastic Combined Chemotherapy Protocols pharmacology, Biomarkers, Tumor metabolism, Gene Expression Regulation, Neoplastic drug effects, Hemangiosarcoma drug therapy, MAP Kinase Signaling System drug effects, Vascular Endothelial Growth Factor Receptor-2 antagonists & inhibitors
- Abstract
Angiosarcoma is an aggressive malignancy of endothelial cells that carries a high mortality rate. Cytotoxic chemotherapy can elicit clinical responses, but the duration of response is limited. Sequencing reveals multiple mutations in angiogenesis pathways in angiosarcomas, particularly in vascular endothelial growth factor (VEGFR) and mitogen-activated protein kinase (MAPK) signaling. We aimed to determine the biological relevance of these pathways in angiosarcoma. Tissue microarray consisting of clinical formalin-fixed paraffin embedded tissue archival samples were stained for phospho- extracellular signal-regulated kinase (p-ERK) with immunohistochemistry. Angiosarcoma cell lines were treated with the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, pan-VEGFR inhibitor cediranib, or combined trametinib and cediranib and viability was assessed. Reverse phase protein array (RPPA) was performed to assess multiple oncogenic protein pathways. SVR angiosarcoma cells were grown in vivo and gene expression effects of treatment were assessed with whole exome RNA sequencing. MAPK signaling was found active in over half of clinical angiosarcoma samples. Inhibition of MAPK signaling with the MEK inhibitor trametinib decreased the viability of angiosarcoma cells. Combined inhibition of the VEGF and MAPK pathways with cediranib and trametinib had an additive effect in in vitro models, and a combinatorial effect in an in vivo model. Combined treatment led to smaller tumors than treatment with either agent alone. RNA-seq demonstrated distinct expression signatures between the trametinib treated tumors and those treated with both trametinib and cediranib. These results indicate a clinical study of combined VEGFR and MEK inhibition in angiosarcoma is warranted.
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- 2021
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21. Improving vascular maturation using noncoding RNAs increases antitumor effect of chemotherapy.
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Mangala LS, Wang H, Jiang D, Wu SY, Somasunderam A, Volk DE, Lokesh GLR, Li X, Pradeep S, Yang X, Haemmerle M, Rodriguez-Aguayo C, Nagaraja AS, Rupaimoole R, Bayraktar E, Bayraktar R, Li L, Tanaka T, Hu W, Ivan C, Gharpure KM, McGuire MH, Thiviyanathan V, Zhang X, Maiti SN, Bulayeva N, Choi HJ, Dorniak PL, Cooper LJ, Rosenblatt KP, Lopez-Berestein G, Gorenstein DG, and Sood AK
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- 2021
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22. Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens.
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Nagaraja AS, Dood RL, Armaiz-Pena G, Kang Y, Wu SY, Allen JK, Jennings NB, Mangala LS, Pradeep S, Lyons Y, Haemmerle M, Gharpure KM, Sadaoui NC, Rodriguez-Aguayo C, Ivan C, Wang Y, Baggerly K, Ram P, Lopez-Berestein G, Liu J, Mok SC, Cohen L, Lutgendorf SK, Cole SW, and Sood AK
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- 2021
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23. ATP11B mediates platinum resistance in ovarian cancer.
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Moreno-Smith M, Halder JB, Meltzer PS, Gonda TA, Mangala LS, Rupaimoole R, Lu C, Nagaraja AS, Gharpure KM, Kang Y, Rodriguez-Aguayo C, Vivas-Mejia PE, Zand B, Schmandt R, Wang H, Langley RR, Jennings NB, Ivan C, Coffin JE, Armaiz GN, Bottsford-Miller J, Kim SB, Halleck MS, Hendrix MJ, Bornman W, Bar-Eli M, Lee JS, Siddik ZH, Lopez-Berestein G, and Sood AK
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- 2021
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24. Gain-of-function p53 protein transferred via small extracellular vesicles promotes conversion of fibroblasts to a cancer-associated phenotype.
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Ma S, McGuire MH, Mangala LS, Lee S, Stur E, Hu W, Bayraktar E, Villar-Prados A, Ivan C, Wu SY, Yokoi A, Dasari SK, Jennings NB, Liu J, Lopez-Berestein G, Ram P, and Sood AK
- Subjects
- Animals, Colorectal Neoplasms metabolism, Female, HT29 Cells, Humans, Mice, Mice, Knockout, Cancer-Associated Fibroblasts metabolism, Extracellular Vesicles genetics, Extracellular Vesicles metabolism, Extracellular Vesicles transplantation, Gain of Function Mutation, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism
- Abstract
Tumor and stromal interactions consist of reciprocal signaling through cytokines, growth factors, direct cell-cell interactions, and extracellular vesicles (EVs). Small EVs (≤200 nm) have been considered critical messengers of cellular communication during tumor development. Here, we demonstrate that gain-of-function (GOF) p53 protein can be packaged into small EVs and transferred to fibroblasts. GOF p53 protein is selectively bound by heat shock protein 90 (HSP90), a chaperone protein, and packaged into small EVs. Inhibition of HSP90 activity blocks packaging of GOF, but not wild-type, p53 in small EVs. GOF p53-containing small EVs result in their conversion to cancer-associated fibroblasts. In vivo studies reveal that GOF p53-containing small EVs can enhance tumor growth and promote fibroblast transformation into a cancer-associated phenotype. These findings provide a better understanding of the complex interactions between cancer and stromal cells and may have therapeutic implications., Competing Interests: Declaration of interests A.K.S. a consultant for Kiyatec, Astra Zeneca, and Merck, has received research funding from M-Trap, and is a Bio-Path Holdings stockholder. The remaining authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2021
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25. The hidden role of paxillin: localization to nucleus promotes tumor angiogenesis.
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Noh K, Bach DH, Choi HJ, Kim MS, Wu SY, Pradeep S, Ivan C, Cho MS, Bayraktar E, Rodriguez-Aguayo C, Dasari SK, Stur E, Mangala LS, Lopez-Berestein G, and Sood AK
- Subjects
- Animals, Female, Humans, Mice, Apoptosis, Cell Proliferation, Disease Progression, Mice, Nude, Prognosis, src-Family Kinases genetics, src-Family Kinases metabolism, Survival Rate, Tissue Plasminogen Activator genetics, Tissue Plasminogen Activator metabolism, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Cell Nucleus metabolism, Gene Expression Regulation, Neoplastic, Neovascularization, Pathologic genetics, Neovascularization, Pathologic metabolism, Neovascularization, Pathologic pathology, Ovarian Neoplasms blood supply, Ovarian Neoplasms genetics, Ovarian Neoplasms metabolism, Paxillin antagonists & inhibitors, Paxillin genetics, Paxillin metabolism
- Abstract
Paxillin (PXN), a key component of the focal adhesion complex, has been associated with cancer progression, but the underlying mechanisms are poorly understood. The purpose of this study was to elucidate mechanisms by which PXN affects cancer growth and progression, which we addressed using cancer patient data, cell lines, and orthotopic mouse models. We demonstrated a previously unrecognized mechanism whereby nuclear PXN enhances angiogenesis by transcriptionally regulating SRC expression. SRC, in turn, increases PLAT expression through NF-ĸB activation; PLAT promotes angiogenesis via LRP1 in endothelial cells. PXN silencing in ovarian cancer mouse models reduced angiogenesis, tumor growth, and metastasis. These findings provide a new understanding of the role of PXN in regulating tumor angiogenesis and growth.
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- 2021
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26. Assessment of In Vivo siRNA Delivery in Cancer Mouse Models.
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Mangala LS, Rodriguez-Aguayo C, Bayraktar E, Jennings NB, Lopez-Berestein G, and Sood AK
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- Animals, Gene Silencing, Mice, Neoplasms genetics, Neoplasms therapy, RNA Interference, RNA, Small Interfering metabolism, Tissue Distribution, RNA, Small Interfering genetics
- Abstract
RNA interference (RNAi) has rapidly become a powerful tool for target discovery and therapeutics. Small interfering RNAs (siRNAs) are highly effective in mediating sequence-specific gene silencing. However, the major obstacle for using siRNAs for cancer therapeutics is their systemic delivery from the administration site to target cells in vivo. This chapter describes approaches to deliver siRNA effectively for cancer treatment and discusses in detail the current methods to assess pharmacokinetics and biodistribution of siRNAs in vivo., (© 2021. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2021
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27. Correction: Paclitaxel Sensitivity of Ovarian Cancer Can be Enhanced by Knocking Down Pairs of Kinases that Regulate MAP4 Phosphorylation and Microtubule Stability.
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Yang H, Mao W, Rodriguez-Aguayo C, Mangala LS, Bartholomeusz G, Iles LR, Jennings NB, Ahmed AA, Sood AK, Lopez-Berestein G, Lu Z, and Bast RC Jr
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- 2020
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28. Sustained Adrenergic Activation of YAP1 Induces Anoikis Resistance in Cervical Cancer Cells.
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Li Y, Yang S, Sadaoui NC, Hu W, Dasari SK, Mangala LS, Sun Y, Zhao S, Wang L, Liu Y, Ramondetta LM, Li K, Lu C, Kang Y, Cole SW, Lutgendorf SK, and Sood AK
- Abstract
Chronic stress-related hormones modulate tumor pathogenesis at multiple levels; however, the molecular pathways involved in stress and cervical cancer progression are not well understood. We established a preclinical orthotopic mouse model of cervical cancer and used the model to show that daily restraint stress increased tumor growth and metastatic tumor burden. Exposure to norepinephrine significantly protected cervical cancer cells from anoikis. We demonstrated that YAP1 was dephosphorylated and translocated from the cytoplasm to the nucleus by norepinephrine, a process initiated by ADRB2/cAMP/protein kinase A activation. Furthermore, anoikis resistance and YAP1 activation induced by norepinephrine could be rescued by a broad β-adrenergic receptor antagonist, propranolol. Collectively, our results provide a pivotal molecular pathway for disrupting pro-tumor neuroendocrine signaling in cervical cancer., Competing Interests: Declaration of Interests A.K.S.: Consulting (Merck, Kiyatec), shareholder (BioPath), research funding (M-Trap)., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2020
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29. Therapeutic efficacy of liposomal Grb2 antisense oligodeoxynucleotide (L-Grb2) in preclinical models of ovarian and uterine cancer.
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Lara OD, Bayraktar E, Amero P, Ma S, Ivan C, Hu W, Wang Y, Mangala LS, Dutta P, Bhattacharya P, Ashizawa AT, Lopez-Berestein G, Rodriguez-Aguayo C, and Sood AK
- Abstract
Background: Adaptor proteins such as growth factor receptor-bound protein-2 (Grb2) play important roles in cancer cell signaling. In the present study, we examined the biological effects of liposomal antisense oligodeoxynucleotide that blocks Grb2 expression (L-Grb2) in gynecologic cancer models., Materials and Methods: Murine orthotopic models of ovarian (OVCAR5 and SKOV3ip1) and uterine (Hec1a) cancer were used to study the biological effects of L-Grb2 on tumor growth. In vitro experiments (cell viability assay, Western blot analysis, siRNA transfection, and reverse phase protein array) were carried out to elucidate the mechanisms and potential predictors of tumor response to L-Grb2., Findings: Treatment with L-Grb2 decreased tumor growth and metastasis in orthotopic models of ovarian cancer (OVCAR5, SKOV3ip1) by reducing angiogenesis and increasing apoptosis at a dose of 15 mg/kg with no effect on mouse body weight. Treatment with L-Grb2 and paclitaxel led to the greatest decrease in tumor weight (mean ± SEM, 0.17 g ± 0.10 g) compared with that in control mice (0.99 g ± 0.35 g). We also observed a reduction in tumor burden after treatment with L-Grb2 and the anti-VEGF antibody B-20 (86% decrease in tumor weight compared with that in controls). Ovarian cancer cells with ErbB2 amplification (OVCAR8 and SKOV3ip1) were the most sensitive to Grb2 downregulation. Reverse phase protein array analysis identified significant dysregulation of metabolites (LDHA, GAPDH, and TCA intermediates) in ovarian cancer cells after Grb2 downregulation., Interpretation: L-Grb2 has therapeutic efficacy in preclinical models of ovarian and uterine cancer. These findings support further clinical development of L-Grb2., Competing Interests: CONFLICTS OF INTEREST A.K. Sood is an advisor for KIYATEC and Merck, is a Bio-Path Holdings, Inc., stockholder, and has received research funding from MTrap.
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- 2020
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30. Author Correction: Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression.
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Rupaimoole R, Wu SY, Pradeep S, Ivan C, Pecot CV, Gharpure KM, Nagaraja AS, Armaiz-Pena GN, McGuire M, Zand B, Dalton HJ, Filant J, Miller JB, Lu C, Sadaoui NC, Mangala LS, Taylor M, van den Beucken T, Koch E, Rodriguez-Aguayo C, Huang L, Bar-Eli M, Wouters BG, Radovich M, Ivan M, Calin GA, Zhang W, Lopez-Berestein G, and Sood AK
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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- 2020
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31. Retraction Note: miR-34a blocks osteoporosis and bone metastasis by inhibiting osteoclastogenesis and Tgif2.
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Krzeszinski JY, Wei W, Huynh H, Jin Z, Wang X, Chang TC, Xie XJ, He L, Mangala LS, Lopez-Berestein G, Sood AK, Mendell JT, and Wan Y
- Abstract
A Retraction to this paper has been published and can be accessed via a link at the top of the paper.
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- 2020
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32. Correction: Therapeutic targeting of Id2 reduces growth of human colorectal carcinoma in the murine liver.
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Gray MJ, Dallas NA, Van Buren G, Xia L, Yang AD, Somcio RJ, Gaur P, Mangala LS, Vivas-Mejia PE, Fan F, Sanguino AM, Gallick GE, Lopez-Berestein G, Sood AK, and Ellis LM
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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- 2020
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33. miRNA551b-3p Activates an Oncostatin Signaling Module for the Progression of Triple-Negative Breast Cancer.
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Parashar D, Geethadevi A, Aure MR, Mishra J, George J, Chen C, Mishra MK, Tahiri A, Zhao W, Nair B, Lu Y, Mangala LS, Rodriguez-Aguayo C, Lopez-Berestein G, Camara AKS, Liang M, Rader JS, Ramchandran R, You M, Sood AK, Kristensen VN, Mills GB, Pradeep S, and Chaluvally-Raghavan P
- Subjects
- Animals, Carcinogenesis genetics, Carcinogenesis pathology, Cell Line, Tumor, Cell Movement genetics, Cell Nucleus metabolism, Cell Proliferation genetics, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Humans, Mice, Nude, MicroRNAs genetics, Molecular Targeted Therapy, Neoplasm Invasiveness, STAT3 Transcription Factor metabolism, Transcription, Genetic, Transcriptional Activation genetics, Up-Regulation genetics, beta Karyopherins metabolism, Disease Progression, MicroRNAs metabolism, Oncostatin M metabolism, Signal Transduction, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms pathology
- Abstract
Genomic amplification of 3q26.2 locus leads to the increased expression of microRNA 551b-3p (miR551b-3p) in triple-negative breast cancer (TNBC). Our results demonstrate that miR551b-3p translocates to the nucleus with the aid of importin-8 (IPO8) and activates STAT3 transcription. As a consequence, miR551b upregulates the expression of oncostatin M receptor (OSMR) and interleukin-31 receptor-α (IL-31RA) as well as their ligands OSM and IL-31 through STAT3 transcription. We defined this set of genes induced by miR551b-3p as the "oncostatin signaling module," which provides oncogenic addictions in cancer cells. Notably, OSM is highly expressed in TNBC, and the elevated expression of OSM associates with poor outcome in estrogen-receptor-negative breast cancer patients. Conversely, targeting miR551b with anti-miR551b-3p reduced the expression of the OSM signaling module and reduced tumor growth, as well as migration and invasion of breast cancer cells., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2019
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34. A-to-I-edited miRNA-379-5p inhibits cancer cell proliferation through CD97-induced apoptosis.
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Xu X, Wang Y, Mojumdar K, Zhou Z, Jeong KJ, Mangala LS, Yu S, Tsang YH, Rodriguez-Aguayo C, Lu Y, Lopez-Berestein G, Sood AK, Mills GB, and Liang H
- Subjects
- Animals, Antigens, CD genetics, Cell Line, Tumor, Cell Proliferation, Female, Mice, Neoplasms pathology, Receptors, G-Protein-Coupled genetics, Antigens, CD physiology, Apoptosis, MicroRNAs physiology, Neoplasms therapy, RNA Editing, Receptors, G-Protein-Coupled physiology
- Abstract
Both miRNAs and A-to-I RNA editing, a widespread nucleotide modification mechanism, have recently emerged as key players in cancer pathophysiology. However, the functional impact of RNA editing of miRNAs in cancer remains largely unexplored. Here, we focused on an ADAR2-catalyzed RNA editing site within the miR-379-5p seed region. This site was under-edited in tumors relative to normal tissues, with a high editing level being correlated with better patient survival times across cancer types. We demonstrated that in contrast to wild-type miRNA, edited miR-379-5p inhibited cell proliferation and promoted apoptosis in diverse tumor contexts in vitro, which was due to the ability of edited but not wild-type miR-379-5p to target CD97. Importantly, through nanoliposomal delivery, edited miR-379-5p mimics significantly inhibited tumor growth and extended survival of mice. Our study indicates a role of RNA editing in diversifying miRNA function during cancer progression and highlights the translational potential of edited miRNAs as a new class of cancer therapeutics.
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- 2019
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35. Identifying and targeting angiogenesis-related microRNAs in ovarian cancer.
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Chen X, Mangala LS, Mooberry L, Bayraktar E, Dasari SK, Ma S, Ivan C, Court KA, Rodriguez-Aguayo C, Bayraktar R, Raut S, Sabnis N, Kong X, Yang X, Lopez-Berestein G, Lacko AG, and Sood AK
- Subjects
- Angiogenesis Inhibitors pharmacology, Animals, Carcinoma, Ovarian Epithelial blood supply, Carcinoma, Ovarian Epithelial pathology, Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic drug effects, HEK293 Cells, Humans, Mice, Mice, Nude, Molecular Targeted Therapy methods, Neovascularization, Pathologic drug therapy, Ovarian Neoplasms blood supply, Ovarian Neoplasms pathology, RNA, Small Interfering pharmacology, RNA, Small Interfering therapeutic use, Xenograft Model Antitumor Assays, Angiogenesis Inhibitors therapeutic use, Carcinoma, Ovarian Epithelial drug therapy, Carcinoma, Ovarian Epithelial genetics, MicroRNAs antagonists & inhibitors, MicroRNAs genetics, Neovascularization, Pathologic genetics, Ovarian Neoplasms drug therapy, Ovarian Neoplasms genetics
- Abstract
Current anti-angiogenic therapy for cancer is based mainly on inhibition of the vascular endothelial growth factor pathway. However, due to the transient and only modest benefit from such therapy, additional approaches are needed. Deregulation of microRNAs (miRNAs) has been demonstrated to be involved in tumor angiogenesis and offers opportunities for a new therapeutic approach. However, effective miRNA-delivery systems are needed for such approaches to be successful. In this study, miRNA profiling of patient data sets, along with in vitro and in vivo experiments, revealed that miR-204-5p could promote angiogenesis in ovarian tumors through THBS1. By binding with scavenger receptor class B type 1 (SCARB1), reconstituted high-density lipoprotein-nanoparticles (rHDL-NPs) were effective in delivering miR-204-5p inhibitor (miR-204-5p-inh) to tumor sites to suppress tumor growth. These results offer a new understanding of miR-204-5p in regulating tumor angiogenesis.
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- 2019
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36. Activating p53 family member TAp63: A novel therapeutic strategy for targeting p53-altered tumors.
- Author
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Gunaratne PH, Pan Y, Rao AK, Lin C, Hernandez-Herrera A, Liang K, Rait AS, Venkatanarayan A, Benham AL, Rubab F, Kim SS, Rajapakshe K, Chan CK, Mangala LS, Lopez-Berestein G, Sood AK, Rowat AC, Coarfa C, Pirollo KF, Flores ER, and Chang EH
- Subjects
- Animals, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Binding Sites, Cell Line, Tumor, Cell Movement drug effects, Cisplatin pharmacology, Cisplatin therapeutic use, Drug Resistance, Neoplasm drug effects, Female, Humans, Liposomes, Mice, Mice, Nude, MicroRNAs administration & dosage, MicroRNAs genetics, MicroRNAs metabolism, Neoplasm Invasiveness prevention & control, Protein Isoforms genetics, Signal Transduction drug effects, Transcription Factors metabolism, Transfection, Tumor Suppressor Protein p53 metabolism, Tumor Suppressor Proteins metabolism, Xenograft Model Antitumor Assays, MicroRNAs therapeutic use, Mutation, Missense, Ovarian Neoplasms drug therapy, Ovarian Neoplasms genetics, Transcription Factors genetics, Transcriptional Activation genetics, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Proteins genetics
- Abstract
Background: Over 96% of high-grade ovarian carcinomas and 50% of all cancers are characterized by alterations in the p53 gene. Therapeutic strategies to restore and/or reactivate the p53 pathway have been challenging. By contrast, p63, which shares many of the downstream targets and functions of p53, is rarely mutated in cancer., Methods: A novel strategy is presented for circumventing alterations in p53 by inducing the tumor-suppressor isoform TAp63 (transactivation domain of tumor protein p63) through its direct downstream target, microRNA-130b (miR-130b), which is epigenetically silenced and/or downregulated in chemoresistant ovarian cancer., Results: Treatment with miR-130b resulted in: 1) decreased migration/invasion in HEYA8 cells (p53 wild-type) and disruption of multicellular spheroids in OVCAR8 cells (p53-mutant) in vitro, 2) sensitization of HEYA8 and OVCAR8 cells to cisplatin (CDDP) in vitro and in vivo, and 3) transcriptional activation of TAp63 and the B-cell lymphoma (Bcl)-inhibitor B-cell lymphoma 2-like protein 11 (BIM). Overexpression of TAp63 was sufficient to decrease cell viability, suggesting that it is a critical downstream effector of miR-130b. In vivo, combined miR-130b plus CDDP exhibited greater therapeutic efficacy than miR-130b or CDDP alone. Mice that carried OVCAR8 xenograft tumors and were injected with miR-130b in 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) liposomes had a significant decrease in tumor burden at rates similar to those observed in CDDP-treated mice, and 20% of DOPC-miR-130b plus CDDP-treated mice were living tumor free. Systemic injections of scL-miR-130b plus CDDP in a clinically tested, tumor-targeted nanocomplex (scL) improved survival in 60% and complete remissions in 40% of mice that carried HEYA8 xenografts., Conclusions: The miR-130b/TAp63 axis is proposed as a new druggable pathway that has the potential to uncover broad-spectrum therapeutic options for the majority of p53-altered cancers., (© 2019 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)
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- 2019
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37. Author Correction: miR-34a blocks osteoporosis and bone metastasis by inhibiting osteoclastogenesis and Tgif2.
- Author
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Krzeszinski JY, Wei W, Huynh H, Jin Z, Wang X, Chang TC, Xie XJ, He L, Mangala LS, Lopez-Berestein G, Sood AK, Mendell JT, and Wan Y
- Abstract
Change history: In this Letter, the citation to 'Fig. 4e, f' in the main text should be 'Fig. 3e, f'. This has not been corrected online.
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- 2019
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38. Quaking orchestrates a post-transcriptional regulatory network of endothelial cell cycle progression critical to angiogenesis and metastasis.
- Author
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Azam SH, Porrello A, Harrison EB, Leslie PL, Liu X, Waugh TA, Belanger A, Mangala LS, Lopez-Berestein G, Wilson HL, McCann JV, Kim WY, Sood AK, Liu J, Dudley AC, and Pecot CV
- Subjects
- Animals, Cell Cycle physiology, Cell Movement genetics, Cell Proliferation genetics, Cells, Cultured, Cyclin D1 genetics, Disease Progression, Female, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Mice, Mice, Nude, Neoplasm Metastasis genetics, Neoplasms blood supply, Neoplasms genetics, Neovascularization, Pathologic pathology, RNA Interference physiology, Cell Cycle genetics, Gene Regulatory Networks genetics, Human Umbilical Vein Endothelial Cells physiology, Neoplasms pathology, Neovascularization, Pathologic genetics, RNA-Binding Proteins physiology
- Abstract
Angiogenesis is critical to cancer development and metastasis. However, anti-angiogenic agents have only had modest therapeutic success, partly due to an incomplete understanding of tumor endothelial cell (EC) biology. We previously reported that the microRNA (miR)-200 family inhibits metastasis through regulation of tumor angiogenesis, but the underlying molecular mechanisms are poorly characterized. Here, using integrated bioinformatics approaches, we identified the RNA-binding protein (RBP) quaking (QKI) as a leading miR-200b endothelial target with previously unappreciated roles in the tumor microenvironment in lung cancer. In lung cancer samples, both miR-200b suppression and QKI overexpression corresponded with tumor ECs relative to normal ECs, and QKI silencing phenocopied miR-200b-mediated inhibition of sprouting. Additionally, both cancer cell and endothelial QKI expression in patient samples significantly corresponded with poor survival and correlated with angiogenic indices. QKI supported EC function by stabilizing cyclin D1 (CCND1) mRNA to promote EC G1/S cell cycle transition and proliferation. Both nanoparticle-mediated RNA interference of endothelial QKI expression and palbociclib blockade of CCND1 function potently inhibited metastasis in concert with significant effects on tumor vasculature. Altogether, this work demonstrates the clinical relevance and therapeutic potential of a novel, actionable miR/RBP axis in tumor angiogenesis and metastasis.
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- 2019
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39. GnRH-R-Targeted Lytic Peptide Sensitizes BRCA Wild-type Ovarian Cancer to PARP Inhibition.
- Author
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Ma S, Pradeep S, Villar-Prados A, Wen Y, Bayraktar E, Mangala LS, Kim MS, Wu SY, Hu W, Rodriguez-Aguayo C, Leuschner C, Liang X, Ram PT, Schlacher K, Coleman RL, and Sood AK
- Subjects
- Animals, BRCA1 Protein genetics, Cell Proliferation drug effects, Cisplatin pharmacology, DNA Damage drug effects, Doxorubicin pharmacology, Drug Resistance, Neoplasm genetics, Female, Gene Expression Regulation, Neoplastic drug effects, Humans, Mice, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology, Paclitaxel pharmacology, Peptides chemical synthesis, Phthalazines pharmacology, Piperazines pharmacology, Receptors, LHRH antagonists & inhibitors, Xenograft Model Antitumor Assays, Ovarian Neoplasms drug therapy, Peptides pharmacology, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Receptors, LHRH genetics
- Abstract
EP-100 is a synthetic lytic peptide that specifically targets the gonadotropin-releasing hormone receptor on cancer cells. To extend the utility of EP-100, we aimed to identify effective combination therapies with EP-100 for ovarian cancer and explore potential mechanisms of this combination. A series of in vitro (MTT assay, immunoblot analysis, reverse-phase protein array, comet assay, and immunofluorescence staining) and in vivo experiments were carried out to determine the biological effects of EP-100 alone and in combination with standard-of-care drugs. EP-100 decreased the viability of ovarian cancer cells and reduced tumor growth in orthotopic mouse models. Of five standard drugs tested (cisplatin, paclitaxel, doxorubicin, topotecan, and olaparib), we found that the combination of EP-100 and olaparib was synergistic in ovarian cancer cell lines. Further experiments revealed that combined treatment of EP-100 and olaparib significantly increased the number of nuclear foci of phosphorylated histone H2AX. In addition, the extent of DNA damage was significantly increased after treatment with EP-100 and olaparib in comet assay. We performed reverse-phase protein array analyses and identified that the PI3K/AKT pathway was inhibited by EP-100, which we validated with in vitro experiments. In vivo experiment using the HeyA8 mouse model demonstrated that mice treated with EP-100 and olaparib had lower tumor weights (0.06 ± 0.13 g) than those treated with a vehicle (1.19 ± 1.09 g), EP-100 alone (0.62 ± 0.78 g), or olaparib alone (0.50 ± 0.63 g). Our findings indicate that combining EP-100 with olaparib is a promising therapeutic strategy for ovarian cancer., (©2019 American Association for Cancer Research.)
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- 2019
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40. PTGER3 induces ovary tumorigenesis and confers resistance to cisplatin therapy through up-regulation Ras-MAPK/Erk-ETS1-ELK1/CFTR1 axis.
- Author
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Rodriguez-Aguayo C, Bayraktar E, Ivan C, Aslan B, Mai J, He G, Mangala LS, Jiang D, Nagaraja AS, Ozpolat B, Chavez-Reyes A, Ferrari M, Mitra R, Siddik ZH, Shen H, Yang X, Sood AK, and Lopez-Berestein G
- Subjects
- Antineoplastic Agents pharmacology, Apoptosis drug effects, Apoptosis genetics, Biomarkers, Cell Cycle drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Cell Transformation, Neoplastic metabolism, Female, Gene Knockdown Techniques, Gene Silencing, Humans, Immunohistochemistry, Models, Biological, Ovarian Neoplasms drug therapy, Ovarian Neoplasms pathology, Proto-Oncogene Protein c-ets-1 metabolism, Receptors, Prostaglandin E, EP3 Subtype metabolism, Cell Transformation, Neoplastic genetics, Cisplatin pharmacology, Drug Resistance, Neoplasm genetics, Ovarian Neoplasms etiology, Ovarian Neoplasms metabolism, Receptors, Prostaglandin E, EP3 Subtype genetics, Signal Transduction drug effects
- Abstract
Background: Inflammatory mediator prostaglandin E2-prostaglandin E2 receptor EP3 (PTGER3) signaling is critical for tumor-associated angiogenesis, tumor growth, and chemoresistance. However, the mechanism underlying these effects in ovarian cancer is not known., Methods: An association between higher tumoral expression of PTGER3 and shorter patient survival in the ovarian cancer dataset of The Cancer Genome Atlas prompted investigation of the antitumor effects of PTGER3 downmodulation. PTGER3 mRNA and protein levels were higher in cisplatin-resistant ovarian cancer cells than in their cisplatin-sensitive counterparts., Findings: Silencing of PTGER3 via siRNA in cancer cells was associated with decreased cell growth and less invasiveness, as well as cell-cycle arrest and increased apoptosis, mediated through the Ras-MAPK/Erk-ETS1-ELK1/CFTR1 axis. Furthermore, sustained PTGER3 silencing with multistage vector and liposomal 2'-F-phosphorodithioate-siRNA-mediated silencing of PTGER3 combined with cisplatin resulted in robust antitumor effects in cisplatin-resistant ovarian cancer models., Interpretation: These findings identify PTGER3 as a potential therapeutic target in chemoresistant ovarian cancers expressing high levels of this oncogenic protein. FUND: National Institutes of Health/National Cancer Institute, USA., (Copyright © 2018. Published by Elsevier B.V.)
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- 2019
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41. PRKRA /PACT Expression Promotes Chemoresistance of Mucinous Ovarian Cancer.
- Author
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Hisamatsu T, McGuire M, Wu SY, Rupaimoole R, Pradeep S, Bayraktar E, Noh K, Hu W, Hansen JM, Lyons Y, Gharpure KM, Nagaraja AS, Mangala LS, Mitamura T, Rodriguez-Aguayo C, Eun YG, Rose J, Bartholomeusz G, Ivan C, Lee JS, Matsuo K, Frumovitz M, Wong KK, Lopez-Berestein G, and Sood AK
- Subjects
- Adenocarcinoma, Mucinous genetics, Adenocarcinoma, Mucinous metabolism, Animals, Cell Line, Tumor, Cell Survival, DEAD-box RNA Helicases metabolism, Female, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, Mice, MicroRNAs genetics, Ovarian Neoplasms genetics, Ovarian Neoplasms metabolism, Oxaliplatin, Proto-Oncogene Proteins genetics, RNA, Small Interfering pharmacology, Receptor Protein-Tyrosine Kinases genetics, Ribonuclease III metabolism, Axl Receptor Tyrosine Kinase, Adenocarcinoma, Mucinous pathology, Drug Resistance, Neoplasm, Ovarian Neoplasms pathology, RNA-Binding Proteins genetics, RNA-Binding Proteins metabolism, Up-Regulation
- Abstract
For mucinous ovarian cancer (MOC), standard platinum-based therapy is largely ineffective. We sought to identify possible mechanisms of oxaliplatin resistance of MOC and develop strategies to overcome this resistance. A kinome-based siRNA library screen was carried out using human MOC cells to identify novel targets to enhance the efficacy of chemotherapy. In vitro and in vivo validations of antitumor effects were performed using mouse MOC models. Specifically, the role of PRKRA /PACT in oxaliplatin resistance was interrogated. We focused on PRKRA , a known activator of PKR kinase, and its encoded protein PACT because it was one of the five most significantly downregulated genes in the siRNA screen. In orthotopic mouse models of MOC, we observed a significant antitumor effect of PRKRA siRNA plus oxaliplatin. In addition, expression of miR-515-3p was regulated by PACT-Dicer interaction, and miR-515-3p increased the sensitivity of MOC to oxaliplatin. Mechanistically, miR-515-3p regulated chemosensitivity, in part, by targeting AXL. The PRKRA /PACT axis represents an important therapeutic target in MOC to enhance sensitivity to oxaliplatin., (©2018 American Association for Cancer Research.)
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- 2019
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42. Paclitaxel Sensitivity of Ovarian Cancer Can be Enhanced by Knocking Down Pairs of Kinases that Regulate MAP4 Phosphorylation and Microtubule Stability.
- Author
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Yang H, Mao W, Rodriguez-Aguayo C, Mangala LS, Bartholomeusz G, Iles LR, Jennings NB, Ahmed AA, Sood AK, Lopez-Berestein G, Lu Z, and Bast RC Jr
- Subjects
- Animals, Antineoplastic Agents, Phytogenic pharmacology, Apoptosis drug effects, Biomarkers, Cell Cycle genetics, Cell Line, Tumor, Disease Models, Animal, Female, Gene Knockdown Techniques, Genes, BRCA1, Genes, BRCA2, Genes, p53, Humans, Mice, Mutation, Ovarian Neoplasms drug therapy, Phosphorylation, RNA, Small Interfering genetics, Xenograft Model Antitumor Assays, p38 Mitogen-Activated Protein Kinases metabolism, Drug Resistance, Neoplasm genetics, Microtubule-Associated Proteins metabolism, Microtubules metabolism, Ovarian Neoplasms genetics, Ovarian Neoplasms metabolism, Paclitaxel pharmacology, Protein Kinases genetics
- Abstract
Purpose: Most patients with ovarian cancer receive paclitaxel chemotherapy, but less than half respond. Pre-treatment microtubule stability correlates with paclitaxel response in ovarian cancer cell lines. Microtubule stability can be increased by depletion of individual kinases. As microtubule stability can be regulated by phosphorylation of microtubule-associated proteins (MAPs), we reasoned that depletion of pairs of kinases that regulate phosphorylation of MAPs could induce microtubule stabilization and paclitaxel sensitization. Experimental Design: Fourteen kinases known to regulate paclitaxel sensitivity were depleted individually in 12 well-characterized ovarian cancer cell lines before measuring proliferation in the presence or absence of paclitaxel. Similar studies were performed by depleting all possible pairs of kinases in six ovarian cancer cell lines. Pairs that enhanced paclitaxel sensitivity across multiple cell lines were studied in depth in cell culture and in two xenograft models. Results: Transfection of siRNA against 10 of the 14 kinases enhanced paclitaxel sensitivity in at least six of 12 cell lines. Dual knockdown of IKBKB/STK39 or EDN2/TBK1 enhanced paclitaxel sensitivity more than silencing single kinases. Sequential knockdown was superior to concurrent knockdown. Dual silencing of IKBKB/STK39 or EDN2/TBK1 stabilized microtubules by inhibiting phosphorylation of p38 and MAP4, inducing apoptosis and blocking cell cycle more effectively than silencing individual kinases. Knockdown of IKBKB/STK39 or EDN2/TBK1 enhanced paclitaxel sensitivity in two ovarian xenograft models. Conclusions: Sequential knockdown of dual kinases increased microtubule stability by decreasing p38-mediated phosphorylation of MAP4 and enhanced response to paclitaxel in ovarian cancer cell lines and xenografts, suggesting a strategy to improve primary therapy. Clin Cancer Res; 24(20); 5072-84. ©2018 AACR ., (©2018 American Association for Cancer Research.)
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- 2018
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43. Bone protection by inhibition of microRNA-182.
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Inoue K, Deng Z, Chen Y, Giannopoulou E, Xu R, Gong S, Greenblatt MB, Mangala LS, Lopez-Berestein G, Kirsch DG, Sood AK, Zhao L, and Zhao B
- Subjects
- Animals, Arthritis, Rheumatoid complications, Arthritis, Rheumatoid metabolism, Autocrine Communication, Bone Resorption etiology, Female, Homeostasis, Male, Mice, Inbred C57BL, Mice, Transgenic, MicroRNAs antagonists & inhibitors, Monocytes physiology, Bone Resorption prevention & control, Interferon-beta metabolism, MicroRNAs metabolism, Osteogenesis, eIF-2 Kinase metabolism
- Abstract
Targeting microRNAs recently shows significant therapeutic promise; however, such progress is underdeveloped in treatment of skeletal diseases with osteolysis, such as osteoporosis and rheumatoid arthritis (RA). Here, we identified miR-182 as a key osteoclastogenic regulator in bone homeostasis and diseases. Myeloid-specific deletion of miR-182 protects mice against excessive osteoclastogenesis and bone resorption in disease models of ovariectomy-induced osteoporosis and inflammatory arthritis. Pharmacological treatment of these diseases with miR-182 inhibitors completely suppresses pathologic bone erosion. Mechanistically, we identify protein kinase double-stranded RNA-dependent (PKR) as a new and essential miR-182 target that is a novel inhibitor of osteoclastogenesis via regulation of the endogenous interferon (IFN)-β-mediated autocrine feedback loop. The expression levels of miR-182, PKR, and IFN-β are altered in RA and are significantly correlated with the osteoclastogenic capacity of RA monocytes. Our findings reveal a previously unrecognized regulatory network mediated by miR-182-PKR-IFN-β axis in osteoclastogenesis, and highlight the therapeutic implications of miR-182 inhibition in osteoprotection.
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- 2018
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44. FABP4 as a key determinant of metastatic potential of ovarian cancer.
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Gharpure KM, Pradeep S, Sans M, Rupaimoole R, Ivan C, Wu SY, Bayraktar E, Nagaraja AS, Mangala LS, Zhang X, Haemmerle M, Hu W, Rodriguez-Aguayo C, McGuire M, Mak CSL, Chen X, Tran MA, Villar-Prados A, Pena GA, Kondetimmanahalli R, Nini R, Koppula P, Ram P, Liu J, Lopez-Berestein G, Baggerly K, S Eberlin L, and Sood AK
- Subjects
- Animals, Cell Line, Tumor, Fatty Acid-Binding Proteins genetics, Female, Gene Expression Regulation, Neoplastic genetics, Gene Expression Regulation, Neoplastic physiology, Humans, Mice, Mice, Nude, MicroRNAs genetics, MicroRNAs metabolism, Neoplasm Invasiveness genetics, Neoplasm Invasiveness pathology, Ovarian Neoplasms genetics, Fatty Acid-Binding Proteins metabolism, Ovarian Neoplasms metabolism, Ovarian Neoplasms pathology
- Abstract
The standard treatment for high-grade serous ovarian cancer is primary debulking surgery followed by chemotherapy. The extent of metastasis and invasive potential of lesions can influence the outcome of these primary surgeries. Here, we explored the underlying mechanisms that could increase metastatic potential in ovarian cancer. We discovered that FABP4 (fatty acid binding protein) can substantially increase the metastatic potential of cancer cells. We also found that miR-409-3p regulates FABP4 in ovarian cancer cells and that hypoxia decreases miR-409-3p levels. Treatment with DOPC nanoliposomes containing either miR-409-3p mimic or FABP4 siRNA inhibited tumor progression in mouse models. With RPPA and metabolite arrays, we found that FABP4 regulates pathways associated with metastasis and affects metabolic pathways in ovarian cancer cells. Collectively, these findings demonstrate that FABP4 is functionally responsible for aggressive patterns of disease that likely contribute to poor prognosis in ovarian cancer.
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- 2018
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45. ATP11B mediates platinum resistance in ovarian cancer.
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Moreno-Smith M, Halder JB, Meltzer PS, Gonda TA, Mangala LS, Rupaimoole R, Lu C, Nagaraja AS, Gharpure KM, Kang Y, Rodriguez-Aguayo C, Vivas-Mejia PE, Zand B, Schmandt R, Wang H, Langley RR, Jennings NB, Ivan C, Coffin JE, Armaiz GN, Bottsford-Miller J, Kim SB, Halleck MS, Hendrix MJ, Bornman W, Bar-Eli M, Lee JS, Siddik ZH, Lopez-Berestein G, and Sood AK
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- 2018
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46. Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction.
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Allen JK, Armaiz-Pena GN, Nagaraja AS, Sadaoui NC, Ortiz T, Dood R, Ozcan M, Herder DM, Haemmerle M, Gharpure KM, Rupaimoole R, Previs RA, Wu SY, Pradeep S, Xu X, Han HD, Zand B, Dalton HJ, Taylor M, Hu W, Bottsford-Miller J, Moreno-Smith M, Kang Y, Mangala LS, Rodriguez-Aguayo C, Sehgal V, Spaeth EL, Ram PT, Wong STC, Marini FC, Lopez-Berestein G, Cole SW, Lutgendorf SK, De Biasi M, and Sood AK
- Subjects
- Animals, Cell Line, Tumor, Cyclic AMP metabolism, Female, Guanine Nucleotide Exchange Factors metabolism, Humans, Membrane Glycoproteins metabolism, Mice, Neoplasms mortality, Peripheral Nerves metabolism, Peripheral Nerves pathology, Receptor, trkB metabolism, Signal Transduction, Tumor Microenvironment physiology, Xenograft Model Antitumor Assays, Brain-Derived Neurotrophic Factor metabolism, Feedback, Physiological, Neoplasms pathology, Norepinephrine metabolism, Receptors, Adrenergic, beta-3 metabolism
- Abstract
Mounting clinical and preclinical evidence supports a key role for sustained adrenergic signaling in the tumor microenvironment as a driver of tumor growth and progression. However, the mechanisms by which adrenergic neurotransmitters are delivered to the tumor microenvironment are not well understood. Here we present evidence for a feed-forward loop whereby adrenergic signaling leads to increased tumoral innervation. In response to catecholamines, tumor cells produced brain-derived neurotrophic factor (BDNF) in an ADRB3/cAMP/Epac/JNK-dependent manner. Elevated BDNF levels in the tumor microenvironment increased innervation by signaling through host neurotrophic receptor tyrosine kinase 2 receptors. In patients with cancer, high tumor nerve counts were significantly associated with increased BDNF and norepinephrine levels and decreased overall survival. Collectively, these data describe a novel pathway for tumor innervation, with resultant biological and clinical implications. Significance: Sustained adrenergic signaling promotes tumor growth and metastasis through BDNF-mediated tumoral innervation. Cancer Res; 78(12); 3233-42. ©2018 AACR ., (©2018 American Association for Cancer Research.)
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- 2018
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47. Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens.
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Nagaraja AS, Dood RL, Armaiz-Pena G, Kang Y, Wu SY, Allen JK, Jennings NB, Mangala LS, Pradeep S, Lyons Y, Haemmerle M, Gharpure KM, Sadaoui NC, Rodriguez-Aguayo C, Ivan C, Wang Y, Baggerly K, Ram P, Lopez-Berestein G, Liu J, Mok SC, Cohen L, Lutgendorf SK, Cole SW, and Sood AK
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- 2018
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48. Improving vascular maturation using noncoding RNAs increases antitumor effect of chemotherapy.
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Mangala LS, Wang H, Jiang D, Wu SY, Somasunderam A, Volk DE, Lokesh GLR, Li X, Pradeep S, Yang X, Haemmerle M, Rodriguez-Aguayo C, Nagaraja AS, Rupaimoole R, Bayraktar E, Bayraktar R, Li L, Tanaka T, Hu W, Ivan C, Gharpure KM, McGuire MH, Thiviyanathan V, Zhang X, Maiti SN, Bulayeva N, Choi HJ, Dorniak PL, Cooper LJ, Rosenblatt KP, Lopez-Berestein G, Gorenstein DG, and Sood AK
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- 2018
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49. ADH1B promotes mesothelial clearance and ovarian cancer infiltration.
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Gharpure KM, Lara OD, Wen Y, Pradeep S, LaFargue C, Ivan C, Rupaimoole R, Hu W, Mangala LS, Wu SY, Nagaraja AS, Baggerly K, and Sood AK
- Abstract
Primary debulking surgery followed by adjuvant chemotherapy is the standard treatment for ovarian cancer. Residual disease after primary surgery is associated with poor patient outcome. Previously, we discovered ADH1B to be a molecular biomarker of residual disease. In the current study, we investigated the functional role of ADH1B in promoting ovarian cancer cell invasiveness and contributing to residual disease. We discovered that ADH1B overexpression leads to a more infiltrative cancer cell phenotype, promotes metastasis, increases the adhesion of cancer cells to mesothelial cells, and increases extracellular matrix degradation. Live cell imaging revealed that ADH1B-overexpressing cancer cells efficiently cleared the mesothelial cell layer compared to control cells. Moreover, gene array analysis revealed that ADH1B affects several pathways related to the migration and invasion of cancer cells. We also discovered that hypoxia increases ADH1B expression in ovarian cancer cells. Collectively, these findings indicate that ADH1B plays an important role in the pathways that promote ovarian cancer cell infiltration and may increase the likelihood of residual disease following surgery., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interests.
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- 2018
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50. RNA interference-based therapy and its delivery systems.
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Chen X, Mangala LS, Rodriguez-Aguayo C, Kong X, Lopez-Berestein G, and Sood AK
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- Animals, Cell- and Tissue-Based Therapy, Drug Resistance, Neoplasm genetics, Genes, MDR, Humans, Molecular Targeted Therapy, Nanoparticles, Neoplasms immunology, Stem Cells metabolism, Gene Transfer Techniques, Genetic Therapy, Neoplasms genetics, Neoplasms therapy, RNA Interference, RNA, Small Interfering genetics
- Abstract
RNA interference (RNAi) is considered a highly specific approach for gene silencing and holds tremendous potential for treatment of various pathologic conditions such as cardiovascular diseases, viral infections, and cancer. Although gene silencing approaches such as RNAi are widely used in preclinical models, the clinical application of RNAi is challenging primarily because of the difficulty in achieving successful systemic delivery. Effective delivery systems are essential to enable the full therapeutic potential of RNAi. An ideal nanocarrier not only addresses the challenges of delivering naked siRNA/miRNA, including its chemically unstable features, extracellular and intracellular barriers, and innate immune stimulation, but also offers "smart" targeted delivery. Over the past decade, great efforts have been undertaken to develop RNAi delivery systems that overcome these obstacles. This review presents an update on current progress in the therapeutic application of RNAi with a focus on cancer therapy and strategies for optimizing delivery systems, such as lipid-based nanoparticles.
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- 2018
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