101 results on '"Rupaimoole R"'
Search Results
2. Hypoxia-upregulated microRNA-630 targets Dicer, leading to increased tumor progression
- Author
-
Rupaimoole, R, Ivan, C, Yang, D, Gharpure, K M, Wu, S Y, Pecot, C V, Previs, R A, Nagaraja, A S, Armaiz-Pena, G N, McGuire, M, Pradeep, S, Mangala, L S, Rodriguez-Aguayo, C, Huang, L, Bar-Eli, M, Zhang, W, Lopez-Berestein, G, Calin, G A, and Sood, A K
- Published
- 2016
- Full Text
- View/download PDF
3. Sustained adrenergic signaling leads to increased metastasis in ovarian cancer via increased PGE2 synthesis
- Author
-
Nagaraja, A S, Dorniak, P L, Sadaoui, N C, Kang, Y, Lin, T, Armaiz-Pena, G, Wu, S Y, Rupaimoole, R, Allen, J K, Gharpure, K M, Pradeep, S, Zand, B, Previs, R A, Hansen, J M, Ivan, C, Rodriguez-Aguayo, C, Yang, P, Lopez-Berestein, G, Lutgendorf, S K, Cole, S W, and Sood, A K
- Published
- 2016
- Full Text
- View/download PDF
4. Identification of miR-34 Synergistic Small Molecule Inhibitor for Therapy Against NSCLC
- Author
-
Rupaimoole, R., primary and Slack, F., additional
- Published
- 2017
- Full Text
- View/download PDF
5. Metronomic Docetaxel in PRINT Nanoparticles and EZH2 Silencing Have Synergistic Antitumor Effect in Ovarian Cancer
- Author
-
Mangala, S. L., Armaiz-Pena, G. N., Lopez-Berestein, G., Gharpure, K. M., Rupaimoole, R., Luft, J. C., Wu, S. Y., Chu, K. S., Bowerman, C. J., Rahhal, T. B., DeSimone, J. M., Pradeep, S., Han, H.-D., Napier, M. E., Miyake, T., and Sood, A. K.
- Abstract
The purpose of this study was to investigate the antitumor effects of a combination of metronomic doses of a novel delivery vehicle, PLGA-PRINT nanoparticles containing docetaxel, and anti-angiogenic mEZH2 siRNA incorporated into chitosan nanoparticles. In vivo dose-finding studies and therapeutic experiments were conducted in well-established orthotopic mouse models of epithelial ovarian cancer. Antitumor effects were determined on the basis of reduction in mean tumor weight and number of metastatic tumor nodules in the animals. The tumor tissues from these in vivo studies were stained to evaluate the proliferation index (Ki67), apoptosis index (cleaved caspase 3), and microvessel density (CD31). The lowest dose of metronomic regimen (0.5 mg/kg) resulted in significant reduction in tumor growth. The combination of PLGA-PRINT-docetaxel and CH-mEZH2 siRNA showed significant antitumor effects in the HeyA8 and SKOV3ip1 tumor models (p
- Published
- 2014
- Full Text
- View/download PDF
6. Targeting KRas-dependent tumour growth, circulating tumour cells and metastasis in vivo by clinically significant miR-193a-3p
- Author
-
Seviour, E G, primary, Sehgal, V, additional, Mishra, D, additional, Rupaimoole, R, additional, Rodriguez-Aguayo, C, additional, Lopez-Berestein, G, additional, Lee, J-S, additional, Sood, A K, additional, Kim, M P, additional, Mills, G B, additional, and Ram, P T, additional
- Published
- 2016
- Full Text
- View/download PDF
7. Modeling bad behavior: Overcoming anti-VEGF resistance in vivo
- Author
-
Dalton, H.J., primary, Pradeep, S., additional, Previs, R.A., additional, Hansen, J.M., additional, Rupaimoole, R., additional, Zand, B., additional, Nick, A.M., additional, Hu, W., additional, Coleman, R.L., additional, and Sood, A.K., additional
- Published
- 2016
- Full Text
- View/download PDF
8. Sustained adrenergic signaling leads to increased metastasis in ovarian cancer via increased PGE2 synthesis
- Author
-
Nagaraja, A S, primary, Dorniak, P L, additional, Sadaoui, N C, additional, Kang, Y, additional, Lin, T, additional, Armaiz-Pena, G, additional, Wu, S Y, additional, Rupaimoole, R, additional, Allen, J K, additional, Gharpure, K M, additional, Pradeep, S, additional, Zand, B, additional, Previs, R A, additional, Hansen, J M, additional, Ivan, C, additional, Rodriguez-Aguayo, C, additional, Yang, P, additional, Lopez-Berestein, G, additional, Lutgendorf, S K, additional, Cole, S W, additional, and Sood, A K, additional
- Published
- 2015
- Full Text
- View/download PDF
9. The FAK of uterine cancer: PTEN expression predicts response of uterine cancer to focal adhesion kinase inhibition
- Author
-
Previs, R.A., primary, Thanapprapasr, D., additional, Hu, W., additional, Rupaimoole, R., additional, Huang, J., additional, Dalton, H.J., additional, Ali, R., additional, Armaiz-Pena, G.N., additional, Hansen, J.M., additional, Zand, B., additional, Coleman, R.L., additional, and Sood, A.K., additional
- Published
- 2015
- Full Text
- View/download PDF
10. Fuel for the fire: Connecting genomics with metabolomics in ovarian cancer
- Author
-
Previs, R.A., primary, Moss, T.J., additional, Zand, B., additional, Rupaimoole, R., additional, Dalton, H.J., additional, Hansen, J.M., additional, Armaiz-Pena, G.N., additional, Lutgendorf, S., additional, Coleman, R.L., additional, Bhattacharya, P., additional, Ram, P., additional, and Sood, A.K., additional
- Published
- 2015
- Full Text
- View/download PDF
11. Role of increased n-acetylaspartate levels in epithelial ovarian cancer
- Author
-
Zand, B., primary, Previs, R.A., additional, Zacharias, N.M., additional, Rupaimoole, R., additional, Dalton, H.J., additional, Hansen, J.M., additional, Rodriguez-Aguayo, C., additional, Guindani, M., additional, Lopez-Berestein, G., additional, Bhattacharya, P., additional, and Sood, A.K., additional
- Published
- 2015
- Full Text
- View/download PDF
12. Antagonism of Tumoral Prolactin Receptor Promotes Autophagy-Related Cell Death
- Author
-
Wen, Y, Zand, B, Ozpolat, B, Szczepanski, MJ, Lu, C, Yuca, E, Carroll, AR, Alpay, N, Bartholomeusz, C, Tekedereli, I, Kang, Y, Rupaimoole, R, Pecot, CV, Dalton, HJ, Hernandez, A, Lokshin, A, Lutgendorf, SK, Liu, J, Hittelman, WN, Chen, WY, Lopez-Berestein, G, Szajnik, M, Ueno, NT, Coleman, RL, Sood, AK, Wen, Y, Zand, B, Ozpolat, B, Szczepanski, MJ, Lu, C, Yuca, E, Carroll, AR, Alpay, N, Bartholomeusz, C, Tekedereli, I, Kang, Y, Rupaimoole, R, Pecot, CV, Dalton, HJ, Hernandez, A, Lokshin, A, Lutgendorf, SK, Liu, J, Hittelman, WN, Chen, WY, Lopez-Berestein, G, Szajnik, M, Ueno, NT, Coleman, RL, and Sood, AK
- Abstract
Therapeutic upregulation of macroautophagy in cancer cells provides an alternative mechanism forcell death. Prolactin (PRL) and its receptor (PRLR) are considered attractive therapeutic targets because of their roles as growth factors in tumor growth and progression. We utilized G129R, an antagonist peptide of PRL, to block activity of the tumoral PRL/PRLR axis, which resulted in inhibition of tumor growth in orthotopic models of human ovarian cancer. Prolonged treatment with G129R induced the accumulation of redundant autolysosomes in 3D cancer spheroids, leading to a type II programmed cell death. This inducible autophagy was a noncanonical beclin-1-independent pathway and was sustained by an astrocytic phosphoprotein (PEA-15) and protein kinase C zeta interactome. Lower levels of tumoral PRL/PRLR inclinical samples were associated with longer patient survival. Our findings provide an understanding of the mechanisms of tumor growth inhibition through targeting PRL/PRLR and may have clinical implications. © 2014 The Authors.
- Published
- 2014
13. Not your mother's bisphosphonate: Targeting angiogenesis in ovarian cancer
- Author
-
Dalton, H.J., primary, Reusser, N.M., additional, Zien, A., additional, Previs, R.A., additional, Rupaimoole, R., additional, Zand, B., additional, Bottsford-Miller, J.N., additional, Nick, A.M., additional, Coleman, R.L., additional, and Sood, A.K., additional
- Published
- 2014
- Full Text
- View/download PDF
14. The Eph Family: Not playing nice in uterine cancer
- Author
-
Dalton, H., primary, Ivan, C., additional, Pecot, C., additional, Rupaimoole, R., additional, Zand, B., additional, Bottsford-Miller, J., additional, Hu, W., additional, Nick, A., additional, Coleman, R., additional, and Sood, A., additional
- Published
- 2013
- Full Text
- View/download PDF
15. Separating the good, the bad, and the ugly: New directions in genomic prediction of outcome in ovarian cancer
- Author
-
Zand, B., primary, Ivan, C., additional, Pecot, C., additional, Rupaimoole, R., additional, Dalton, H., additional, Bottsford-Miller, J., additional, Hu, W., additional, Nick, A., additional, and Sood, A., additional
- Published
- 2013
- Full Text
- View/download PDF
16. Deception of suppression: Unexpected effects of tristetraprolin in ovarian cancer
- Author
-
Zand, B., primary, Ivan, C., additional, Pecot, C., additional, Rupaimoole, R., additional, Dalton, H., additional, Bottsford-Miller, J., additional, Hu, W., additional, Nick, A., additional, and Sood, A., additional
- Published
- 2013
- Full Text
- View/download PDF
17. Targeting KRas-dependent tumour growth, circulating tumour cells and metastasis in vivoby clinically significant miR-193a-3p
- Author
-
Seviour, E G, Sehgal, V, Mishra, D, Rupaimoole, R, Rodriguez-Aguayo, C, Lopez-Berestein, G, Lee, J-S, Sood, A K, Kim, M P, Mills, G B, and Ram, P T
- Abstract
KRas is mutated in a significant number of human cancers and so there is an urgent therapeutic need to target KRas signalling. To target KRas in lung cancers we used a systems approach of integrating a genome-wide miRNA screen with patient-derived phospho-proteomic signatures of the KRas downstream pathway, and identified miR-193a-3p, which directly targets KRas. Unique aspects of miR-193a-3p biology include two functionally independent target sites in the KRas 3′UTR and clinically significant correlation between miR-193a-3p and KRas expression in patients. Rescue experiments with mutated KRas 3’UTR showed very significantly that the anti-tumour effect of miR-193a-3p is via specific direct targeting of KRas and not due to other targets. Ex vivoand in vivostudies utilizing nanoliposome packaged miR-193a-3p demonstrated significant inhibition of tumour growth, circulating tumour cell viability and decreased metastasis. These studies show the broader applicability of using miR-193a-3p as a therapeutic agent to target KRas-mutant cancer.
- Published
- 2017
- Full Text
- View/download PDF
18. Role of increased n-acetylaspartate levels in epithelial ovarian cancer
- Author
-
Previs, R.A., Zacharias, N.M., Rupaimoole, R., Dalton, H.J., Hansen, J.M., Rodriguez-Aguayo, C., Guindani, M., Lopez-Berestein, G., Bhattacharya, P., and Sood, A.K.
- Published
- 2015
- Full Text
- View/download PDF
19. Fuel for the fire: Connecting genomics with metabolomics in ovarian cancer
- Author
-
Moss, T.J., Zand, B., Rupaimoole, R., Dalton, H.J., Hansen, J.M., Armaiz-Pena, G.N., Lutgendorf, S., Coleman, R.L., Bhattacharya, P., Ram, P., and Sood, A.K.
- Published
- 2015
- Full Text
- View/download PDF
20. The FAK of uterine cancer: PTEN expression predicts response of uterine cancer to focal adhesion kinase inhibition
- Author
-
Thanapprapasr, D., Hu, W., Rupaimoole, R., Huang, J., Dalton, H.J., Ali, R., Armaiz-Pena, G.N., Hansen, J.M., Zand, B., Coleman, R.L., and Sood, A.K.
- Published
- 2015
- Full Text
- View/download PDF
21. Not your mother's bisphosphonate: Targeting angiogenesis in ovarian cancer
- Author
-
Reusser, N.M., Zien, A., Previs, R.A., Rupaimoole, R., Zand, B., Bottsford-Miller, J.N., Nick, A.M., Coleman, R.L., and Sood, A.K.
- Published
- 2014
- Full Text
- View/download PDF
22. Deception of suppression: Unexpected effects of tristetraprolin in ovarian cancer
- Author
-
Ivan, C., Pecot, C., Rupaimoole, R., Dalton, H., Bottsford-Miller, J., Hu, W., Nick, A., and Sood, A.
- Published
- 2013
- Full Text
- View/download PDF
23. The Eph Family: Not playing nice in uterine cancer
- Author
-
Ivan, C., Pecot, C., Rupaimoole, R., Zand, B., Bottsford-Miller, J., Hu, W., Nick, A., Coleman, R., and Sood, A.
- Published
- 2013
- Full Text
- View/download PDF
24. Separating the good, the bad, and the ugly: New directions in genomic prediction of outcome in ovarian cancer
- Author
-
Ivan, C., Pecot, C., Rupaimoole, R., Dalton, H., Bottsford-Miller, J., Hu, W., Nick, A., and Sood, A.
- Published
- 2013
- Full Text
- View/download PDF
25. Improving vascular maturation using noncoding RNAs increases antitumor effect of chemotherapy.
- Author
-
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
- Published
- 2021
- Full Text
- View/download PDF
26. ATP11B mediates platinum resistance in ovarian cancer.
- Author
-
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
- Published
- 2021
- Full Text
- View/download PDF
27. Author Correction: Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression.
- Author
-
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.
- Published
- 2020
- Full Text
- View/download PDF
28. A High-Throughput Small Molecule Screen Identifies Ouabain as Synergistic with miR-34a in Killing Lung Cancer Cells.
- Author
-
Rupaimoole R, Yoon B, Zhang WC, Adams BD, and Slack FJ
- Abstract
MicroRNA-34 (miR-34) is one of the major families of tumor suppressor miRNAs often lost in cancers. Delivery of miR-34a mimics to affected tumors as a therapeutic strategy has been tried in pre-clinical studies and in a phase I clinical trial. One approach to increase efficacy and reduce toxicity is to rationally identify drug combinations with small molecules that synergize with miR-34a. In this study we performed a high-throughput screen of a large panel of small molecules with known biological activity and identified ouabain as a candidate small molecule that synergized with miR-34a in killing lung cancer cells. We elucidated autophagy activation as a key mechanism by which miR-34a and ouabain causes increased cytotoxicity in cells. We posit that this combinatorial approach could reduce the active dose of miR-34a needed in vivo to observe tumor shrinkage and potentiate the development of miR-34a combination therapies in the future., Competing Interests: Declaration of Interests F.J.S. discloses financial interests and SAB roles with Mira DX and MiRNA Therapeutics. The other authors declare no competing interests., (Copyright © 2020. Published by Elsevier Inc.)
- Published
- 2020
- Full Text
- View/download PDF
29. Pan-cancer genomic analysis links 3'UTR DNA methylation with increased gene expression in T cells.
- Author
-
McGuire MH, Herbrich SM, Dasari SK, Wu SY, Wang Y, Rupaimoole R, Lopez-Berestein G, Baggerly KA, and Sood AK
- Subjects
- Animals, Biomarkers, Tumor, Computational Biology methods, DNA (Cytosine-5-)-Methyltransferases genetics, DNA Methyltransferase 3A, Databases, Genetic, Epigenesis, Genetic, Female, Flow Cytometry, Gene Expression, Gene Expression Profiling, Gene Knockdown Techniques, Hepatitis A Virus Cellular Receptor 2 genetics, Humans, Lymphocyte Activation immunology, Mice, Neoplasms immunology, Neoplasms mortality, Prognosis, T-Lymphocytes immunology, 3' Untranslated Regions, DNA Methylation, Gene Expression Regulation, Neoplastic, Genomics methods, Neoplasms genetics, T-Lymphocytes metabolism
- Abstract
Background: Investigations into the function of non-promoter DNA methylation have yielded new insights into the epigenetic regulation of gene expression. However, integrated genome-wide non-promoter DNA methylation and gene expression analyses across a wide number of tumour types and corresponding normal tissues have not been performed., Methods: To investigate the impact of non-promoter DNA methylation on cancer pathogenesis, we performed a large-scale analysis of gene expression and DNA methylation profiles, finding enrichment in the 3'UTR DNA methylation positively correlated with gene expression. Filtering for genes in which 3'UTR DNA methylation strongly correlated with gene expression yielded a list of genes enriched for functions involving T cell activation., Findings: The important immune checkpoint gene Havcr2 showed a substantial increase in 3'UTR DNA methylation upon T cell activation and subsequent upregulation of gene expression in mice. Furthermore, this increase in Havcr2 gene expression was abrogated by treatment with decitabine., Interpretation: These findings indicate that the 3'UTR is a functionally relevant DNA methylation site. Additionally, we show a potential novel mechanism of HAVCR2 regulation in T cells, providing new insights for modulating immune checkpoint blockade., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
30. PRKRA /PACT Expression Promotes Chemoresistance of Mucinous Ovarian Cancer.
- Author
-
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.)
- Published
- 2019
- Full Text
- View/download PDF
31. FABP4 as a key determinant of metastatic potential of ovarian cancer.
- Author
-
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.
- Published
- 2018
- Full Text
- View/download PDF
32. ATP11B mediates platinum resistance in ovarian cancer.
- Author
-
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
- Published
- 2018
- Full Text
- View/download PDF
33. Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction.
- Author
-
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.)
- Published
- 2018
- Full Text
- View/download PDF
34. Improving vascular maturation using noncoding RNAs increases antitumor effect of chemotherapy.
- Author
-
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
- Published
- 2018
- Full Text
- View/download PDF
35. ADH1B promotes mesothelial clearance and ovarian cancer infiltration.
- Author
-
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.
- Published
- 2018
- Full Text
- View/download PDF
36. Personalized RNA Medicine for Pancreatic Cancer.
- Author
-
Gilles ME, Hao L, Huang L, Rupaimoole R, Lopez-Casas PP, Pulver E, Jeong JC, Muthuswamy SK, Hidalgo M, Bhatia SN, and Slack FJ
- Subjects
- Animals, Carcinoma, Pancreatic Ductal genetics, Cell Line, Tumor, Cell Proliferation genetics, Disease Models, Animal, Gene Expression Profiling methods, Humans, Mice, Mice, Nude, Oncogenes genetics, Precision Medicine methods, Xenograft Model Antitumor Assays methods, Pancreatic Neoplasms, MicroRNAs genetics, Pancreatic Neoplasms genetics
- Abstract
Purpose: Since drug responses vary between patients, it is crucial to develop pre-clinical or co-clinical strategies that forecast patient response. In this study, we tested whether RNA-based therapeutics were suitable for personalized medicine by using patient-derived-organoid (PDO) and patient-derived-xenograft (PDX) models. Experimental Design: We performed microRNA (miRNA) profiling of PDX samples to determine the status of miRNA deregulation in individual pancreatic ductal adenocarcinoma (PDAC) patients. To deliver personalized RNA-based-therapy targeting oncogenic miRNAs that form part of this common PDAC miRNA over-expression signature, we packaged antimiR oligonucleotides against one of these miRNAs in tumor-penetrating nanocomplexes (TPN) targeting cell surface proteins on PDAC tumors. Results: As a validation for our pre-clinical strategy, the therapeutic potential of one of our nano-drugs, TPN-21, was first shown to decrease tumor cell growth and survival in PDO avatars for individual patients, then in their PDX avatars. Conclusions: This general approach appears suitable for co-clinical validation of personalized RNA medicine and paves the way to prospectively identify patients with eligible miRNA profiles for personalized RNA-based therapy. Clin Cancer Res; 24(7); 1734-47. ©2018 AACR ., (©2018 American Association for Cancer Research.)
- Published
- 2018
- Full Text
- View/download PDF
37. Differential Effects of EGFL6 on Tumor versus Wound Angiogenesis.
- Author
-
Noh K, Mangala LS, Han HD, Zhang N, Pradeep S, Wu SY, Ma S, Mora E, Rupaimoole R, Jiang D, Wen Y, Shahzad MMK, Lyons Y, Cho M, Hu W, Nagaraja AS, Haemmerle M, Mak CSL, Chen X, Gharpure KM, Deng H, Xiong W, Kingsley CV, Liu J, Jennings N, Birrer MJ, Bouchard RR, Lopez-Berestein G, Coleman RL, An Z, and Sood AK
- Subjects
- Animals, Blotting, Western, Calcium-Binding Proteins, Cell Adhesion Molecules, Cell Line, Tumor, Cell Movement genetics, Cell Movement physiology, Chitosan metabolism, Female, Glycoproteins genetics, Humans, In Vitro Techniques, Integrins genetics, Integrins metabolism, Mice, Mice, Knockout, Nanoparticles chemistry, Neoplasm Proteins genetics, Neovascularization, Pathologic genetics, Neovascularization, Pathologic metabolism, Peptides genetics, Phosphatidylinositol 3-Kinases metabolism, Phosphorylation genetics, Phosphorylation physiology, Proto-Oncogene Proteins c-akt metabolism, Receptor, TIE-2 genetics, Receptor, TIE-2 metabolism, Twist-Related Protein 1 genetics, Twist-Related Protein 1 metabolism, Wound Healing genetics, Wound Healing physiology, Glycoproteins metabolism, Neoplasm Proteins metabolism, Peptides metabolism
- Abstract
Angiogenesis inhibitors are important for cancer therapy, but clinically approved anti-angiogenic agents have shown only modest efficacy and can compromise wound healing. This necessitates the development of novel anti-angiogenesis therapies. Here, we show significantly increased EGFL6 expression in tumor versus wound or normal endothelial cells. Using a series of in vitro and in vivo studies with orthotopic and genetically engineered mouse models, we demonstrate the mechanisms by which EGFL6 stimulates tumor angiogenesis. In contrast to its antagonistic effects on tumor angiogenesis, EGFL6 blockage did not affect normal wound healing. These findings have significant implications for development of anti-angiogenesis therapies., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
38. Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression.
- Author
-
Dalton HJ, Pradeep S, McGuire M, Hailemichael Y, Ma S, Lyons Y, Armaiz-Pena GN, Previs RA, Hansen JM, Rupaimoole R, Gonzalez-Villasana V, Cho MS, Wu SY, Mangala LS, Jennings NB, Hu W, Langley R, Mu H, Andreeff M, Bar-Eli M, Overwijk W, Ram P, Lopez-Berestein G, Coleman RL, and Sood AK
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Cell Survival genetics, Disease Models, Animal, Female, Humans, Macrophages immunology, Mice, Neoplasms drug therapy, Neoplasms genetics, Neoplasms metabolism, Neoplasms pathology, Neovascularization, Pathologic drug therapy, Promoter Regions, Genetic, Tumor Microenvironment drug effects, Tumor Microenvironment immunology, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic drug effects, Macrophages metabolism, Receptors, Vascular Endothelial Growth Factor antagonists & inhibitors, Receptors, Vascular Endothelial Growth Factor genetics
- Abstract
Purpose: VEGF-targeted therapies have modest efficacy in cancer patients, but acquired resistance is common. The mechanisms underlying such resistance are poorly understood. Experimental Design: To evaluate the potential role of immune cells in the development of resistance to VEGF blockade, we first established a preclinical model of adaptive resistance to anti-VEGF therapy. Additional in vitro and in vivo studies were carried out to characterize the role of macrophages in such resistance. Results: Using murine cancer models of adaptive resistance to anti-VEGF antibody (AVA), we found a previously unrecognized role of macrophages in such resistance. Macrophages were actively recruited to the tumor microenvironment and were responsible for the emergence of AVA resistance. Depletion of macrophages following emergence of resistance halted tumor growth and prolonged survival of tumor-bearing mice. In a macrophage-deficient mouse model, resistance to AVA failed to develop, but could be induced by injection of macrophages. Downregulation of macrophage VEGFR-1 and VEGFR-3 expression accompanied upregulation of alternative angiogenic pathways, facilitating escape from anti-VEGF therapy. Conclusions: These findings provide a new understanding of the mechanisms underlying the modest efficacy of current antiangiogenesis therapies and identify new opportunities for combination approaches for ovarian and other cancers. Clin Cancer Res; 23(22); 7034-46. ©2017 AACR ., (©2017 American Association for Cancer Research.)
- Published
- 2017
- Full Text
- View/download PDF
39. Role of Platelet-Derived Tgfβ1 in the Progression of Ovarian Cancer.
- Author
-
Hu Q, Hisamatsu T, Haemmerle M, Cho MS, Pradeep S, Rupaimoole R, Rodriguez-Aguayo C, Lopez-Berestein G, Wong STC, Sood AK, and Afshar-Kharghan V
- Subjects
- Animals, Blood Platelets metabolism, Cell Line, Tumor, Cell Proliferation, Disease Models, Animal, Disease Progression, Female, Heterografts, Humans, Immunohistochemistry, Mice, Mice, Transgenic, Neovascularization, Pathologic genetics, Neovascularization, Pathologic metabolism, Ovarian Neoplasms metabolism, RNA, Small Interfering genetics, Time Factors, Transforming Growth Factor beta1 metabolism, Tumor Burden, Gene Expression, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology, Transforming Growth Factor beta1 genetics
- Abstract
Purpose: Transforming growth factor β1 (Tgfβ1) plays an important role in cancer. Most of Tgfβ1 in plasma is from platelets; thus, we studied whether platelet Tgfβ1 has any role in the progression of ovarian cancer, and whether this role is limited to metastasis or also involves the growth of primary tumors. Experimental Design: We compared the growth of murine ovarian cancer cell-induced tumors in platelet-specific Tgfβ1-deficient mice and wild-type mice. Using resected tumor nodules, we studied the effect of platelet Tgfβ1 on neoangiogenesis and on platelet extravasation into tumors. To investigate the effect of Tgfβ1 at different stages of ovarian cancer, we reduced expression of Tgfβ1 receptor (its TgfβR1 component) in tumors at different time points after injection of cancer cells, and compared the final tumor size. Results: Lack of platelet Tgfβ1 in mice reduced tumor growth, neoangiogenesis, and platelet extravasation. Ovarian cancer tumors in platelet-specific Tgfβ1-deficient mice reached less than half of their size in wild-type littermates. Knockdown of TgfβR1 on cancer cells in the first 2 weeks after their injection reduced tumor growth, but was less effective if initiated after 3 weeks. Conclusions: We showed that platelet Tgfβ1 increased the growth of primary tumors in murine models of ovarian cancer. We also showed that inhibition of TgfβR1 is more effective in reducing the growth of ovarian cancer if initiated earlier. Our results supported a therapeutic benefit in preventing platelet activation, degranulation, and release of Tgfβ1 in ovarian cancer. Clin Cancer Res; 23(18); 5611-21. ©2017 AACR ., (©2017 American Association for Cancer Research.)
- Published
- 2017
- Full Text
- View/download PDF
40. Platelets reduce anoikis and promote metastasis by activating YAP1 signaling.
- Author
-
Haemmerle M, Taylor ML, Gutschner T, Pradeep S, Cho MS, Sheng J, Lyons YM, Nagaraja AS, Dood RL, Wen Y, Mangala LS, Hansen JM, Rupaimoole R, Gharpure KM, Rodriguez-Aguayo C, Yim SY, Lee JS, Ivan C, Hu W, Lopez-Berestein G, Wong ST, Karlan BY, Levine DA, Liu J, Afshar-Kharghan V, and Sood AK
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Animals, Blood Platelets cytology, Cell Line, Tumor, Coculture Techniques, Female, Gene Expression Profiling methods, Humans, Mice, Inbred C57BL, Mice, Nude, Neoplasm Metastasis, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology, Phosphoproteins genetics, RNA Interference, Transcription Factors, Transplantation, Heterologous, YAP-Signaling Proteins, Adaptor Proteins, Signal Transducing metabolism, Anoikis, Blood Platelets metabolism, Ovarian Neoplasms metabolism, Phosphoproteins metabolism, Signal Transduction
- Abstract
Thrombocytosis is present in more than 30% of patients with solid malignancies and correlates with worsened patient survival. Tumor cell interaction with various cellular components of the tumor microenvironment including platelets is crucial for tumor growth and metastasis. Although it is known that platelets can infiltrate into tumor tissue, secrete pro-angiogenic and pro-tumorigenic factors and thereby increase tumor growth, the precise molecular interactions between platelets and metastatic cancer cells are not well understood. Here we demonstrate that platelets induce resistance to anoikis in vitro and are critical for metastasis in vivo. We further show that platelets activate RhoA-MYPT1-PP1-mediated YAP1 dephosphorylation and promote its nuclear translocation which induces a pro-survival gene expression signature and inhibits apoptosis. Reduction of YAP1 in cancer cells in vivo protects against thrombocytosis-induced increase in metastasis. Collectively, our results indicate that cancer cells depend on platelets to avoid anoikis and succeed in the metastatic process.Platelets have been associated with increased tumor growth and metastasis but the mechanistic details of this interaction are still unclear. Here the authors show that platelets improve anoikis resistance of cancer cells and increase metastasis by activating Yap through a RhoA/MYPT-PP1 pathway.
- Published
- 2017
- Full Text
- View/download PDF
41. Role of YAP1 as a Marker of Sensitivity to Dual AKT and P70S6K Inhibition in Ovarian and Uterine Malignancies.
- Author
-
Previs RA, Armaiz-Pena GN, Ivan C, Dalton HJ, Rupaimoole R, Hansen JM, Lyons Y, Huang J, Haemmerle M, Wagner MJ, Gharpure KM, Nagaraja AS, Filant J, McGuire MH, Noh K, Dorniak PL, Linesch SL, Mangala LS, Pradeep S, Wu SY, and Sood AK
- Subjects
- Angiogenesis Inhibitors administration & dosage, Angiogenesis Inhibitors pharmacology, Animals, Antineoplastic Agents, Phytogenic administration & dosage, Antineoplastic Agents, Phytogenic pharmacology, Antineoplastic Combined Chemotherapy Protocols pharmacology, Apoptosis drug effects, Bevacizumab administration & dosage, Bevacizumab pharmacology, Cell Line, Tumor, Cell Proliferation drug effects, Female, Humans, Inhibitory Concentration 50, Kaplan-Meier Estimate, Mice, Nude, Ovarian Neoplasms drug therapy, Paclitaxel administration & dosage, Paclitaxel pharmacology, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Ribosomal Protein S6 Kinases, 70-kDa antagonists & inhibitors, Transcription Factors, Tumor Burden drug effects, Uterine Neoplasms drug therapy, Xenograft Model Antitumor Assays, YAP-Signaling Proteins, Adaptor Proteins, Signal Transducing metabolism, Biomarkers, Tumor metabolism, Ovarian Neoplasms metabolism, Phosphoproteins metabolism, Proto-Oncogene Proteins c-akt metabolism, Ribosomal Protein S6 Kinases, 70-kDa metabolism, Uterine Neoplasms metabolism
- Abstract
Background: The PI3K/AKT/P70S6K pathway is an attractive therapeutic target in ovarian and uterine malignancies because of its high rate of deregulation and key roles in tumor growth. Here, we examined the biological effects of MSC2363318A, which is a novel inhibitor of AKT1, AKT3, and P70S6K., Methods: Orthotopic murine models of ovarian and uterine cancer were utilized to study the effect of MSC2363318A on survival and regression. For each cell line, 10 mice were treated in each of the experimental arms tested. Moreover, in vitro experiments in 21 cell lines (MTT, immunoblot analysis, plasmid transfection, reverse phase protein array [RPPA]) were carried out to characterize underlying mechanisms and potential biomarkers of response. All statistical tests were two-sided., Results: MSC2363318A decreased tumor growth and metastases in multiple murine orthotopic models of ovarian (SKOV3ip1, HeyA8, and Igrov1) and uterine (Hec1a) cancer by reducing proliferation and angiogenesis and increasing cell death. Statistically significant prolonged overall survival was achieved with combination MSC2363318A and paclitaxel in the SKUT2 (endometrioid) uterine cancer mouse model ( P < .001). Mice treated with combination MSC2363318A and paclitaxel had the longest overall survival (mean = 104.2 days, 95% confidence interval [CI] = 97.0 to 111.4) compared with those treated with vehicle (mean = 61.9 days, 95% CI = 46.3 to 77.5), MSC2363318A alone (mean = 89.7 days, 95% CI = 83.0 to 96.4), and paclitaxel alone (mean = 73.6 days, 95% CI = 53.4 to 93.8). Regression and stabilization of established tumors in the Ishikawa (endometrioid) uterine cancer model was observed in mice treated with combination MSC2363318A and paclitaxel. Synergy between MSC2363318A and paclitaxel was observed in vitro in cell lines that had an IC50 of 5 µM or greater. RPPA results identified YAP1 as a candidate marker to predict cell lines that were most sensitive to MSC2363318A (R = 0.54, P = .02). After establishment of a murine ovarian cancer model of adaptive anti-angiogenic resistance (SKOV3ip1-luciferase), we demonstrate that resensitization to bevacizumab occurs with the addition of MSC2363318A, resulting in improved overall survival ( P = .01) using the Kaplan-Meier method. Mice treated with bevacizumab induction followed by MSC2363318A had the longest overall survival (mean = 66.0 days, 95% CI = 53.9 to 78.1) compared with mice treated with control (mean = 42.0 days, 95% CI = 31.4 to 52.6) and bevacizumab-sensitive mice (mean = 47.2 days; 95% CI = 37.5 to 56.9)., Conclusions: MSC2363318A has therapeutic efficacy in multiple preclinical models of ovarian and uterine cancer. These findings support clinical development of a dual AKT/P70S6K inhibitor., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2017
- Full Text
- View/download PDF
42. Combining Anti-Mir-155 with Chemotherapy for the Treatment of Lung Cancers.
- Author
-
Van Roosbroeck K, Fanini F, Setoyama T, Ivan C, Rodriguez-Aguayo C, Fuentes-Mattei E, Xiao L, Vannini I, Redis RS, D'Abundo L, Zhang X, Nicoloso MS, Rossi S, Gonzalez-Villasana V, Rupaimoole R, Ferracin M, Morabito F, Neri A, Ruvolo PP, Ruvolo VR, Pecot CV, Amadori D, Abruzzo L, Calin S, Wang X, You MJ, Ferrajoli A, Orlowski R, Plunkett W, Lichtenberg TM, Davuluri RV, Berindan-Neagoe I, Negrini M, Wistuba II, Kantarjian HM, Sood AK, Lopez-Berestein G, Keating MJ, Fabbri M, and Calin GA
- Subjects
- Animals, Cell Line, Tumor, Cisplatin administration & dosage, Gene Expression Regulation, Neoplastic drug effects, Gene Expression Regulation, Neoplastic genetics, Humans, Lung Neoplasms genetics, Lung Neoplasms pathology, Mice, MicroRNAs antagonists & inhibitors, Tumor Suppressor Protein p53 genetics, Antagomirs administration & dosage, Drug Resistance, Neoplasm genetics, Lung Neoplasms drug therapy, MicroRNAs genetics
- Abstract
Purpose: The oncogenic miR-155 is upregulated in many human cancers, and its expression is increased in more aggressive and therapy-resistant tumors, but the molecular mechanisms underlying miR-155-induced therapy resistance are not fully understood. The main objectives of this study were to determine the role of miR-155 in resistance to chemotherapy and to evaluate anti-miR-155 treatment to chemosensitize tumors. Experimental Design: We performed in vitro studies on cell lines to investigate the role of miR-155 in therapy resistance. To assess the effects of miR-155 inhibition on chemoresistance, we used an in vivo orthotopic lung cancer model of athymic nude mice, which we treated with anti-miR-155 alone or in combination with chemotherapy. To analyze the association of miR-155 expression and the combination of miR-155 and TP53 expression with cancer survival, we studied 956 patients with lung cancer, chronic lymphocytic leukemia, and acute lymphoblastic leukemia. Results: We demonstrate that miR-155 induces resistance to multiple chemotherapeutic agents in vitro , and that downregulation of miR-155 successfully resensitizes tumors to chemotherapy in vivo We show that anti-miR-155-DOPC can be considered non-toxic in vivo We further demonstrate that miR-155 and TP53 are linked in a negative feedback mechanism and that a combination of high expression of miR-155 and low expression of TP53 is significantly associated with shorter survival in lung cancer. Conclusions: Our findings support the existence of an miR-155/TP53 feedback loop, which is involved in resistance to chemotherapy and which can be specifically targeted to overcome drug resistance, an important cause of cancer-related death. Clin Cancer Res; 23(11); 2891-904. ©2016 AACR ., (©2016 American Association for Cancer Research.)
- Published
- 2017
- Full Text
- View/download PDF
43. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases.
- Author
-
Rupaimoole R and Slack FJ
- Subjects
- Animals, Clinical Trials as Topic methods, Genetic Therapy methods, Genetic Therapy trends, Humans, MicroRNAs metabolism, Neoplasms metabolism, Disease Management, MicroRNAs administration & dosage, MicroRNAs genetics, Neoplasms genetics, Neoplasms therapy
- Abstract
In just over two decades since the discovery of the first microRNA (miRNA), the field of miRNA biology has expanded considerably. Insights into the roles of miRNAs in development and disease, particularly in cancer, have made miRNAs attractive tools and targets for novel therapeutic approaches. Functional studies have confirmed that miRNA dysregulation is causal in many cases of cancer, with miRNAs acting as tumour suppressors or oncogenes (oncomiRs), and miRNA mimics and molecules targeted at miRNAs (antimiRs) have shown promise in preclinical development. Several miRNA-targeted therapeutics have reached clinical development, including a mimic of the tumour suppressor miRNA miR-34, which reached phase I clinical trials for treating cancer, and antimiRs targeted at miR-122, which reached phase II trials for treating hepatitis. In this article, we describe recent advances in our understanding of miRNAs in cancer and in other diseases and provide an overview of current miRNA therapeutics in the clinic. We also discuss the challenge of identifying the most efficacious therapeutic candidates and provide a perspective on achieving safe and targeted delivery of miRNA therapeutics.
- Published
- 2017
- Full Text
- View/download PDF
44. Improving vascular maturation using noncoding RNAs increases antitumor effect of chemotherapy.
- Author
-
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
- Subjects
- Cell Line, Tumor, Humans, Nanoparticles, Neoplasms blood supply, Neoplasms therapy, Transfection, Antineoplastic Agents pharmacology, Aptamers, Nucleotide, Endothelial Cells cytology, MicroRNAs administration & dosage, Neovascularization, Pathologic prevention & control
- Abstract
Current antiangiogenesis therapy relies on inhibiting newly developed immature tumor blood vessels and starving tumor cells. This strategy has shown transient and modest efficacy. Here, we report a better approach to target cancer-associated endothelial cells (ECs), reverse permeability and leakiness of tumor blood vessels, and improve delivery of chemotherapeutic agents to the tumor. First, we identified deregulated microRNAs (miRs) from patient-derived cancer-associated ECs. Silencing these miRs led to decreased vascular permeability and increased maturation of blood vessels. Next, we screened a thioaptamer (TA) library to identify TAs selective for tumor-associated ECs. An annexin A2-targeted TA was identified and used for delivery of miR106b-5p and miR30c-5p inhibitors, resulting in vascular maturation and antitumor effects without inducing hypoxia. These findings could have implications for improving vascular-targeted therapy.
- Published
- 2016
- Full Text
- View/download PDF
45. A role for miR-34 in colon cancer stem cell homeostasis.
- Author
-
Rupaimoole R and Slack FJ
- Abstract
Competing Interests: The authors have no conflicts of interest to declare.
- Published
- 2016
- Full Text
- View/download PDF
46. Macrophage TGF- β 1 and the Proapoptotic Extracellular Matrix Protein BIGH3 Induce Renal Cell Apoptosis in Prediabetic and Diabetic Conditions.
- Author
-
Moritz RJ, LeBaron RG, Phelix CF, Rupaimoole R, Kim HS, Tsin A, and Asmis R
- Abstract
Metabolically stressed kidney is in part characterized by infiltrating macrophages and macrophage-derived TGF- β 1 that promote the synthesis of various ECM molecules. TGF- β 1 strongly enhances the expression of the gene TGFBI that encodes a cell-adhesion class, proapoptotic ECM protein called BIGH3. We hypothesized that in a diabetic environment a relationship between infiltrating macrophages, macrophage-derived TGF- β 1, and BIGH3 protein promotes renal cell death. To investigate this hypothesis, we used our mouse model of diabetic complications. Mice on a high-fat diet developed hypercholesterolemia, and exposure to streptozotocin rendered hypercholesterolemic mice diabetic. Immunohistochemical images show increased macrophage infiltration and BIGH3 protein in the kidney cortices of hypercholesterolemic and diabetic mice. Macrophages induced a two-fold increase in BIGH3 expression and an 86% increase in renal proximal tubule epithelial cell apoptosis. TGF- β 1 antibody and TGF- β 1 receptor chemical antagonist blocked macrophage-induced apoptosis. BIGH3 antibody completely blocked apoptosis that was induced by TGF- β 1, and blocked apoptosis induced by exogenous recombinant BIGH3. These results uncover a distinctive interplay of macrophage-derived TGF- β 1, BIGH3 protein, and apoptosis, and indicate that BIGH3 is central in a novel pathway that promotes diabetic nephropathy. Macrophage TGF- β 1 and BIGH3 are identified as prediabetic biomarkers, and potential therapeutic targets for intervention in prediabetic and diabetic individuals., Competing Interests: Conflict of Interests The authors declare that there is no conflict of interest regarding the publication of this paper.
- Published
- 2016
- Full Text
- View/download PDF
47. Developing hyperpolarized silicon particles for in vivo MRI targeting of ovarian cancer.
- Author
-
Whiting N, Hu J, Zacharias NM, Lokesh GL, Volk DE, Menter DG, Rupaimoole R, Previs R, Sood AK, and Bhattacharya P
- Abstract
Silicon-based nanoparticles are ideally suited for use as biomedical imaging agents due to their biocompatibility, biodegradability, and simple surface chemistry that facilitates drug loading and targeting. A method of hyperpolarizing silicon particles using dynamic nuclear polarization, which increases magnetic resonance imaging signals by several orders-of-magnitude through enhanced nuclear spin alignment, has recently been developed to allow silicon particles to function as contrast agents for in vivo magnetic resonance imaging. The enhanced spin polarization of silicon lasts significantly longer than other hyperpolarized agents (tens of minutes, whereas [Formula: see text] for other species at room temperature), allowing a wide range of potential applications. We report our recent characterizations of hyperpolarized silicon particles, with the ultimate goal of targeted, noninvasive, and nonradioactive molecular imaging of various cancer systems. A variety of particle sizes (20 nm to [Formula: see text]) were found to have hyperpolarized relaxation times ranging from [Formula: see text] to 50 min. The addition of various functional groups to the particle surface had no effect on the hyperpolarization buildup or decay rates and allowed in vivo imaging over long time scales. Additional in vivo studies examined a variety of particle administration routes in mice, including intraperitoneal injection, rectal enema, and oral gavage.
- Published
- 2016
- Full Text
- View/download PDF
48. Dll4 Inhibition plus Aflibercept Markedly Reduces Ovarian Tumor Growth.
- Author
-
Huang J, Hu W, Hu L, Previs RA, Dalton HJ, Yang XY, Sun Y, McGuire M, Rupaimoole R, Nagaraja AS, Kang Y, Liu T, Nick AM, Jennings NB, Coleman RL, Jaffe RB, and Sood AK
- Subjects
- Animals, Antibodies, Monoclonal pharmacology, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols pharmacology, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Female, GATA3 Transcription Factor metabolism, Gene Expression Regulation, Neoplastic drug effects, Humans, Mice, Neoplasm Transplantation, Ovarian Neoplasms metabolism, Recombinant Fusion Proteins pharmacology, Up-Regulation drug effects, Xenograft Model Antitumor Assays, Antibodies, Monoclonal administration & dosage, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Intracellular Signaling Peptides and Proteins metabolism, Membrane Proteins metabolism, Ovarian Neoplasms drug therapy, Receptors, Vascular Endothelial Growth Factor administration & dosage, Recombinant Fusion Proteins administration & dosage
- Abstract
Delta-like ligand 4 (Dll4), one of the Notch ligands, is overexpressed in ovarian cancer, especially in tumors resistant to anti-VEGF therapy. Here, we examined the biologic effects of dual anti-Dll4 and anti-VEGF therapy in ovarian cancer models. Using Dll4-Fc blockade and anti-Dll4 antibodies (murine REGN1035 and human REGN421), we evaluated the biologic effects of Dll4 inhibition combined with aflibercept or chemotherapy in orthotopic mouse models of ovarian cancer. We also examined potential mechanisms by which dual Dll4 and VEGF targeting inhibit tumor growth using immunohistochemical staining for apoptosis and proliferation markers. Reverse-phase protein arrays were used to identify potential downstream targets of Dll4 blockade. Dual targeting of VEGF and Dll4 with murine REGN1035 showed superior antitumor effects in ovarian cancer models compared with either monotherapy. In the A2780 model, REGN1035 (targets murine Dll4) or REGN421 (targets human Dll4) reduced tumor weights by 62% and 82%, respectively; aflibercept alone reduced tumor weights by 90%. Greater therapeutic effects were observed for Dll4 blockade (REGN1035) combined with either aflibercept or docetaxel (P < 0.05 for the combination vs. aflibercept). The superior antitumor effects of REGN1035 and aflibercept were related to increased apoptosis in tumor cells compared with the monotherapy. We also found that GATA3 expression was significantly increased in tumor stroma from the mice treated with REGN1035 combined with docetaxel or aflibercept, suggesting an indirect effect of these combination treatments on the tumor stroma. These findings identify that dual targeting of Dll4 and VEGF is an attractive therapeutic approach. Mol Cancer Ther; 15(6); 1344-52. ©2016 AACR., (©2016 American Association for Cancer Research.)
- Published
- 2016
- Full Text
- View/download PDF
49. FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal.
- Author
-
Haemmerle M, Bottsford-Miller J, Pradeep S, Taylor ML, Choi HJ, Hansen JM, Dalton HJ, Stone RL, Cho MS, Nick AM, Nagaraja AS, Gutschner T, Gharpure KM, Mangala LS, Rupaimoole R, Han HD, Zand B, Armaiz-Pena GN, Wu SY, Pecot CV, Burns AR, Lopez-Berestein G, Afshar-Kharghan V, and Sood AK
- Subjects
- Adenosine Diphosphate metabolism, Animals, Antibodies, Neoplasm pharmacology, Bevacizumab pharmacology, Blood Platelets pathology, Cell Hypoxia drug effects, Cell Hypoxia genetics, Cell Line, Tumor, Female, Focal Adhesion Kinase 1 antagonists & inhibitors, Focal Adhesion Kinase 1 genetics, Humans, Indazoles, Mice, Mice, Knockout, Neoplasm Proteins antagonists & inhibitors, Neoplasm Proteins genetics, Neovascularization, Pathologic enzymology, Neovascularization, Pathologic genetics, Neovascularization, Pathologic pathology, Ovarian Neoplasms enzymology, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology, Pyrimidines pharmacology, Sulfonamides pharmacology, Tumor Microenvironment genetics, Xenograft Model Antitumor Assays, Antineoplastic Combined Chemotherapy Protocols pharmacology, Focal Adhesion Kinase 1 metabolism, Neoplasm Proteins metabolism, Neovascularization, Pathologic drug therapy, Ovarian Neoplasms drug therapy, Tumor Microenvironment drug effects
- Abstract
Recent studies in patients with ovarian cancer suggest that tumor growth may be accelerated following cessation of antiangiogenesis therapy; however, the underlying mechanisms are not well understood. In this study, we aimed to compare the effects of therapy withdrawal to those of continuous treatment with various antiangiogenic agents. Cessation of therapy with pazopanib, bevacizumab, and the human and murine anti-VEGF antibody B20 was associated with substantial tumor growth in mouse models of ovarian cancer. Increased tumor growth was accompanied by tumor hypoxia, increased tumor angiogenesis, and vascular leakage. Moreover, we found hypoxia-induced ADP production and platelet infiltration into tumors after withdrawal of antiangiogenic therapy, and lowering platelet counts markedly inhibited tumor rebound after withdrawal of antiangiogenic therapy. Focal adhesion kinase (FAK) in platelets regulated their migration into the tumor microenvironment, and FAK-deficient platelets completely prevented the rebound tumor growth. Additionally, combined therapy with a FAK inhibitor and the antiangiogenic agents pazopanib and bevacizumab reduced tumor growth and inhibited negative effects following withdrawal of antiangiogenic therapy. In summary, these results suggest that FAK may be a unique target in situations in which antiangiogenic agents are withdrawn, and dual targeting of FAK and VEGF could have therapeutic implications for ovarian cancer management.
- Published
- 2016
- Full Text
- View/download PDF
50. A miR-192-EGR1-HOXB9 regulatory network controls the angiogenic switch in cancer.
- Author
-
Wu SY, Rupaimoole R, Shen F, Pradeep S, Pecot CV, Ivan C, Nagaraja AS, Gharpure KM, Pham E, Hatakeyama H, McGuire MH, Haemmerle M, Vidal-Anaya V, Olsen C, Rodriguez-Aguayo C, Filant J, Ehsanipour EA, Herbrich SM, Maiti SN, Huang L, Kim JH, Zhang X, Han HD, Armaiz-Pena GN, Seviour EG, Tucker S, Zhang M, Yang D, Cooper LJ, Ali-Fehmi R, Bar-Eli M, Lee JS, Ram PT, Baggerly KA, Lopez-Berestein G, Hung MC, and Sood AK
- Subjects
- Animals, Cell Line, Tumor, Down-Regulation, Early Growth Response Protein 1 genetics, Early Growth Response Protein 1 metabolism, Female, Genetic Therapy, Homeodomain Proteins genetics, Homeodomain Proteins metabolism, Humans, Kidney Neoplasms blood supply, Kidney Neoplasms therapy, Mice, MicroRNAs genetics, MicroRNAs metabolism, Ovarian Neoplasms blood supply, Ovarian Neoplasms therapy, Phosphatidylcholines, Tumor Burden, Early Growth Response Protein 1 physiology, Gene Regulatory Networks, Homeodomain Proteins physiology, Kidney Neoplasms genetics, MicroRNAs physiology, Neovascularization, Pathologic genetics, Ovarian Neoplasms genetics
- Abstract
A deeper mechanistic understanding of tumour angiogenesis regulation is needed to improve current anti-angiogenic therapies. Here we present evidence from systems-based miRNA analyses of large-scale patient data sets along with in vitro and in vivo experiments that miR-192 is a key regulator of angiogenesis. The potent anti-angiogenic effect of miR-192 stems from its ability to globally downregulate angiogenic pathways in cancer cells through regulation of EGR1 and HOXB9. Low miR-192 expression in human tumours is predictive of poor clinical outcome in several cancer types. Using 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) nanoliposomes, we show that miR-192 delivery leads to inhibition of tumour angiogenesis in multiple ovarian and renal tumour models, resulting in tumour regression and growth inhibition. This anti-angiogenic and anti-tumour effect is more robust than that observed with an anti-VEGF antibody. Collectively, these data identify miR-192 as a central node in tumour angiogenesis and support the use of miR-192 in an anti-angiogenesis therapy.
- Published
- 2016
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.