44 results on '"Paola Amero"'
Search Results
2. Aptamers as Insights for Targeting SARS-CoV-2
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Suna Karadeniz Saygılı, Anna Szymanowska, Gabriel Lopez-Berestein, Cristian Rodriguez-Aguayo, and Paola Amero
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aptamers ,artificial intelligence ,SARS-CoV-2 ,spike receptor ,AXL ,therapeutics ,Biology (General) ,QH301-705.5 - Abstract
The Severe Acute Respiratory Syndrome coronavirus (SARS-CoV-2) continues to be a major cause of high mortality in the world. Despite many therapeutic approaches having been successfully developed, there is still the need to find novel and more effective therapeutic strategies to face the upcoming variants. Here, we will describe the potential use of aptamers, synthetic single-stranded oligonucleotides, as promising tools to target SARS-CoV-2. Since aptamers have been successfully developed against viruses, this review will focus on the latest selection approach method using artificial intelligence, the state-of-the-art in bioinformatics, and we will also summarize the latest discoveries in terms of aptamers against spike protein and other novel receptor proteins involved in SARS-CoV-2 entry and the use of single-cell transcriptomics to define novel promising targets for SARS-CoV-2.
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- 2023
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3. Overcoming adaptive resistance to anti-VEGF therapy by targeting CD5L
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Christopher J. LaFargue, Paola Amero, Kyunghee Noh, Lingegowda S. Mangala, Yunfei Wen, Emine Bayraktar, Sujanitha Umamaheswaran, Elaine Stur, Santosh K. Dasari, Cristina Ivan, Sunila Pradeep, Wonbeak Yoo, Chunhua Lu, Nicholas B. Jennings, Vinod Vathipadiekal, Wei Hu, Anca Chelariu-Raicu, Zhiqiang Ku, Hui Deng, Wei Xiong, Hyun-Jin Choi, Min Hu, Takae Kiyama, Chai-An Mao, Rouba Ali-Fehmi, Michael J. Birrer, Jinsong Liu, Ningyan Zhang, Gabriel Lopez-Berestein, Vittorio de Franciscis, Zhiqiang An, and Anil K. Sood
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Science - Abstract
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.
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- 2023
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4. EphA2- and HDAC-Targeted Combination Therapy in Endometrial Cancer
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Robiya Joseph, Santosh K. Dasari, Sujanitha Umamaheswaran, Lingegowda S. Mangala, Emine Bayraktar, Cristian Rodriguez-Aguayo, Yutuan Wu, Nghi Nguyen, Reid T. Powell, Mary Sobieski, Yuan Liu, Mark Seungwook Kim, Sara Corvigno, Katherine Foster, Pahul Hanjra, Thanh Chung Vu, Mamur A. Chowdhury, Paola Amero, Clifford Stephan, Gabriel Lopez-Berestein, Shannon N. Westin, and Anil K. Sood
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endometrial cancer ,EphA2 ,histone deacetylase ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - 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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5. Aptamers as Potential Therapeutic Tools for Ovarian Cancer: Advancements and Challenges
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Wojciech Szymanowski, Anna Szymanowska, Anna Bielawska, Gabriel Lopez-Berestein, Cristian Rodriguez-Aguayo, and Paola Amero
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aptamers ,ovarian cancer ,tumor microenvironment ,targeted delivery system ,therapeutics ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Ovarian cancer (OC) is the most common lethal gynecologic cause of death in women worldwide, with a high mortality rate and increasing incidence. Despite advancements in the treatment, most OC patients still die from their disease due to late-stage diagnosis, the lack of effective diagnostic methods, and relapses. Aptamers, synthetic, short single-stranded oligonucleotides, have emerged as promising anticancer therapeutics. Their ability to selectively bind to target molecules, including cancer-related proteins and receptors, has revolutionized drug discovery and biomarker identification. Aptamers offer unique insights into the molecular pathways involved in cancer development and progression. Moreover, they show immense potential as drug delivery systems, enabling targeted delivery of therapeutic agents to cancer cells while minimizing off-target effects and reducing systemic toxicity. In the context of OC, the integration of aptamers with non-coding RNAs (ncRNAs) presents an opportunity for precise and efficient gene targeting. Additionally, the conjugation of aptamers with nanoparticles allows for accurate and targeted delivery of ncRNAs to specific cells, tissues, or organs. In this review, we will summarize the potential use and challenges associated with the use of aptamers alone or aptamer–ncRNA conjugates, nanoparticles, and multivalent aptamer-based therapeutics for the treatment of OC.
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- 2023
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6. An Overview of the Immune Modulatory Properties of Long Non-Coding RNAs and Their Potential Use as Therapeutic Targets in Cancer
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Moises Martinez-Castillo, Abdelrahman M. Elsayed, Gabriel López-Berestein, Paola Amero, and Cristian Rodríguez-Aguayo
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lncRNA ,ncRNA ,cancer ,immune response ,biomarkers ,immunotherapy ,Genetics ,QH426-470 - Abstract
Long non-coding RNAs (lncRNAs) play pivotal roles in regulating immune responses, immune cell differentiation, activation, and inflammatory processes. In cancer, they are gaining prominence as potential therapeutic targets due to their ability to regulate immune checkpoint molecules and immune-related factors, suggesting avenues for bolstering anti-tumor immune responses. Here, we explore the mechanistic insights into lncRNA-mediated immune modulation, highlighting their impact on immunity. Additionally, we discuss their potential to enhance cancer immunotherapy, augmenting the effectiveness of immune checkpoint inhibitors and adoptive T cell therapies. LncRNAs as therapeutic targets hold the promise of revolutionizing cancer treatments, inspiring further research in this field with substantial clinical implications.
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- 2023
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7. Non-Coding RNAs: Foes or Friends for Targeting Tumor Microenvironment
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Anna Szymanowska, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, and Paola Amero
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non-coding RNAs ,cancer ,tumor microenvironment ,immune response ,anticancer therapy ,Genetics ,QH426-470 - Abstract
Non-coding RNAs (ncRNAs) are a group of molecules critical for cell development and growth regulation. They are key regulators of important cellular pathways in the tumor microenvironment. To analyze ncRNAs in the tumor microenvironment, the use of RNA sequencing technology has revolutionized the field. The advancement of this technique has broadened our understanding of the molecular biology of cancer, presenting abundant possibilities for the exploration of novel biomarkers for cancer treatment. In this review, we will summarize recent achievements in understanding the complex role of ncRNA in the tumor microenvironment, we will report the latest studies on the tumor microenvironment using RNA sequencing, and we will discuss the potential use of ncRNAs as therapeutics for the treatment of cancer.
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- 2023
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8. Understanding the role of the gut microbiome in gastrointestinal cancer: A review
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Duygu Ağagündüz, Ermelinda Cocozza, Özge Cemali, Ayşe Derya Bayazıt, Maria Francesca Nanì, Ida Cerqua, Floriana Morgillo, Suna Karadeniz Saygılı, Roberto Berni Canani, Paola Amero, and Raffaele Capasso
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microbiome ,gastrointestinal cancer ,non-coding RNAs ,therapeutics ,diagnosis ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Gastrointestinal cancer represents one of the most diagnosed types of cancer. Cancer is a genetic and multifactorial disease, influenced by the host and environmental factors. It has been stated that 20% of cancer is caused by microorganisms such as Helicobacter pylori, hepatitis B and C virus, and human papillomavirus. In addition to these well-known microorganisms associated with cancer, it has been shown differences in the composition of the microbiota between healthy individuals and cancer patients. Some studies have suggested the existence of the selected microorganisms and their metabolites that can promote or inhibit tumorigenesis via some mechanisms. Recent findings have shown that gut microbiome and their metabolites can act as cancer promotors or inhibitors. It has been shown that gastrointestinal cancer can be caused by a dysregulation of the expression of non-coding RNA (ncRNA) through the gut microbiome. This review will summarize the latest reports regarding the relationship among gut microbiome, ncRNAs, and gastrointestinal cancer. The potential applications of diagnosing and cancer treatments will be discussed.
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- 2023
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9. Targeting miRNAs and Other Non-Coding RNAs as a Therapeutic Approach: An Update
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Emine Bayraktar, Recep Bayraktar, Hulya Oztatlici, Gabriel Lopez-Berestein, Paola Amero, and Cristian Rodriguez-Aguayo
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microRNA ,miRNA ,cancer ,drug delivery ,resistance ,therapeutics ,Genetics ,QH426-470 - Abstract
Since the discovery of the first microRNAs (miRNAs, miRs), the understanding of miRNA biology has expanded substantially. miRNAs are involved and described as master regulators of the major hallmarks of cancer, including cell differentiation, proliferation, survival, the cell cycle, invasion, and metastasis. Experimental data indicate that cancer phenotypes can be modified by targeting miRNA expression, and because miRNAs act as tumor suppressors or oncogenes (oncomiRs), they have emerged as attractive tools and, more importantly, as a new class of targets for drug development in cancer therapeutics. With the use of miRNA mimics or molecules targeting miRNAs (i.e., small-molecule inhibitors such as anti-miRS), these therapeutics have shown promise in preclinical settings. Some miRNA-targeted therapeutics have been extended to clinical development, such as the mimic of miRNA-34 for treating cancer. Here, we discuss insights into the role of miRNAs and other non-coding RNAs in tumorigenesis and resistance and summarize some recent successful systemic delivery approaches and recent developments in miRNAs as targets for anticancer drug development. Furthermore, we provide a comprehensive overview of mimics and inhibitors that are in clinical trials and finally a list of clinical trials based on miRNAs.
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- 2023
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10. Combination of EphA2- and Wee1-Targeted Therapies in Endometrial Cancer
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Santosh K. Dasari, Robiya Joseph, Sujanitha Umamaheswaran, Lingegowda S. Mangala, Emine Bayraktar, Cristian Rodriguez-Aguayo, Yutuan Wu, Nghi Nguyen, Reid T. Powell, Mary Sobieski, Yuan Liu, Mamur A. Chowdhury, Paola Amero, Clifford Stephan, Gabriel Lopez-Berestein, Shannon N. Westin, and Anil K. Sood
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endometrial cancer ,EphA2 ,Wee1 ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - 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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11. Therapeutic Targeting of AXL Receptor Tyrosine Kinase Inhibits Tumor Growth and Intraperitoneal Metastasis in Ovarian Cancer Models
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Pinar Kanlikilicer, Bulent Ozpolat, Burcu Aslan, Recep Bayraktar, Nilgun Gurbuz, Cristian Rodriguez-Aguayo, Emine Bayraktar, Merve Denizli, Vianey Gonzalez-Villasana, Cristina Ivan, Ganesh L.R. Lokesh, Paola Amero, Silvia Catuogno, Monika Haemmerle, Sherry Yen-Yao Wu, Rahul Mitra, David G. Gorenstein, David E. Volk, Vittorio de Franciscis, Anil K. Sood, and Gabriel Lopez-Berestein
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AXL ,aptamer ,metastasis ,ovarian cancer ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Despite substantial improvements in the treatment strategies, ovarian cancer is still the most lethal gynecological malignancy. Identification of drug treatable therapeutic targets and their safe and effective targeting is critical to improve patient survival in ovarian cancer. AXL receptor tyrosine kinase (RTK) has been proposed to be an important therapeutic target for metastatic and advanced-stage human ovarian cancer. We found that AXL-RTK expression is associated with significantly shorter patient survival based on the The Cancer Genome Atlas patient database. To target AXL-RTK, we developed a chemically modified serum nuclease-stable AXL aptamer (AXL-APTAMER), and we evaluated its in vitro and in vivo antitumor activity using in vitro assays as well as two intraperitoneal animal models. AXL-aptamer treatment inhibited the phosphorylation and the activity of AXL, impaired the migration and invasion ability of ovarian cancer cells, and led to the inhibition of tumor growth and number of intraperitoneal metastatic nodules, which was associated with the inhibition of AXL activity and angiogenesis in tumors. When combined with paclitaxel, in vivo systemic (intravenous [i.v.]) administration of AXL-aptamer treatment markedly enhanced the antitumor efficacy of paclitaxel in mice. Taken together, our data indicate that AXL-aptamers successfully target in vivo AXL-RTK and inhibit its AXL activity and tumor growth and progression, representing a promising strategy for the treatment of ovarian cancer.
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- 2017
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12. Explainable Artificial Intelligence Reveals Novel Insight into Tumor Microenvironment Conditions Linked with Better Prognosis in Patients with Breast Cancer
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Debaditya Chakraborty, Cristina Ivan, Paola Amero, Maliha Khan, Cristian Rodriguez-Aguayo, Hakan Başağaoğlu, and Gabriel Lopez-Berestein
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explainable artificial intelligence (XAI) ,machine learning ,breast cancer ,tumor microenvironment ,survival analysis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
We investigated the data-driven relationship between immune cell composition in the tumor microenvironment (TME) and the ≥5-year survival rates of breast cancer patients using explainable artificial intelligence (XAI) models. We acquired TCGA breast invasive carcinoma data from the cbioPortal and retrieved immune cell composition estimates from bulk RNA sequencing data from TIMER2.0 based on EPIC, CIBERSORT, TIMER, and xCell computational methods. Novel insights derived from our XAI model showed that B cells, CD8+ T cells, M0 macrophages, and NK T cells are the most critical TME features for enhanced prognosis of breast cancer patients. Our XAI model also revealed the inflection points of these critical TME features, above or below which ≥5-year survival rates improve. Subsequently, we ascertained the conditional probabilities of ≥5-year survival under specific conditions inferred from the inflection points. In particular, the XAI models revealed that the B cell fraction (relative to all cells in a sample) exceeding 0.025, M0 macrophage fraction (relative to the total immune cell content) below 0.05, and NK T cell and CD8+ T cell fractions (based on cancer type-specific arbitrary units) above 0.075 and 0.25, respectively, in the TME could enhance the ≥5-year survival in breast cancer patients. The findings could lead to accurate clinical predictions and enhanced immunotherapies, and to the design of innovative strategies to reprogram the breast TME.
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- 2021
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13. Inactivating Mutations of the IK Gene Weaken Ku80/Ku70-Mediated DNA Repair and Sensitize Endometrial Cancer to Chemotherapy
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Chao Gao, Guangxu Jin, Elizabeth Forbes, Lingegowda S. Mangala, Yingmei Wang, Cristian Rodriguez-Aguayo, Paola Amero, Emine Bayraktar, Ye Yan, Gabriel Lopez-Berestein, Russell R. Broaddus, Anil K. Sood, Fengxia Xue, and Wei Zhang
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IK ,somatic mutation ,DNA repair ,endometrial cancer ,Ku80 ,cisplatin ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - 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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14. PRKAR1B-AS2 Long Noncoding RNA Promotes Tumorigenesis, Survival, and Chemoresistance via the PI3K/AKT/mTOR Pathway
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Abdelrahman M. Elsayed, Emine Bayraktar, Paola Amero, Salama A. Salama, Abdelaziz H. Abdelaziz, Raed S. Ismail, Xinna Zhang, Cristina Ivan, Anil K. Sood, Gabriel Lopez-Berestein, and Cristian Rodriguez-Aguayo
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lncRNA ,PRKAR1B-AS2 ,AC147651.5 ,cisplatin resistance ,PI3K/AKT/mTOR ,ovarian cancer ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Many long noncoding RNAs have been implicated in tumorigenesis and chemoresistance; however, the underlying mechanisms are not well understood. We investigated the role of PRKAR1B-AS2 long noncoding RNA in ovarian cancer (OC) and chemoresistance and identified potential downstream molecular circuitry underlying its action. Analysis of The Cancer Genome Atlas OC dataset, in vitro experiments, proteomic analysis, and a xenograft OC mouse model were implemented. Our findings indicated that overexpression of PRKAR1B-AS2 is negatively correlated with overall survival in OC patients. Furthermore, PRKAR1B-AS2 knockdown-attenuated proliferation, migration, and invasion of OC cells and ameliorated cisplatin and alpelisib resistance in vitro. In proteomic analysis, silencing PRKAR1B-AS2 markedly inhibited protein expression of PI3K-110α and abrogated the phosphorylation of PDK1, AKT, and mTOR, with no significant effect on PTEN. The RNA immunoprecipitation detected a physical interaction between PRKAR1B-AS2 and PI3K-110α. Moreover, PRKAR1B-AS2 knockdown by systemic administration of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine nanoparticles loaded with PRKAR1B-AS2–specific small interfering RNA enhanced cisplatin sensitivity in a xenograft OC mouse model. In conclusion, PRKAR1B-AS2 promotes tumor growth and confers chemoresistance by modulating the PI3K/AKT/mTOR pathway. Thus, targeting PRKAR1B-AS2 may represent a novel therapeutic approach for the treatment of OC patients.
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- 2021
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15. Back to the Future: Rethinking the Great Potential of lncRNAS for Optimizing Chemotherapeutic Response in Ovarian Cancer
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Abdelrahman M. Elsayed, Paola Amero, Salama A. Salama, Abdelaziz H. Abdelaziz, Gabriel Lopez-Berestein, and Cristian Rodriguez-Aguayo
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long non-coding RNAs ,mechanisms of resistance ,chemotherapy ,dysregulated expression ,ovarian cancer ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Ovarian cancer (OC) is one of the most fatal cancers in women worldwide. Currently, platinum- and taxane-based chemotherapy is the mainstay for the treatment of OC. Yet, the emergence of chemoresistance results in therapeutic failure and significant relapse despite a consistent rate of primary response. Emerging evidence substantiates the potential role of lncRNAs in determining the response to standard chemotherapy in OC. The objective of this narrative review is to provide an integrated, synthesized overview of the current state of knowledge regarding the role of lncRNAs in the emergence of resistance to platinum- and taxane-based chemotherapy in OC. In addition, we sought to develop conceptual frameworks for harnessing the therapeutic potential of lncRNAs in strategies aimed at enhancing the chemotherapy response of OC. Furthermore, we offered significant new perspectives and insights on the interplay between lncRNAs and the molecular circuitries implicated in chemoresistance to determine their impacts on therapeutic response. Although this review summarizes robust data concerning the involvement of lncRNAs in the emergence of acquired resistance to platinum- and taxane-based chemotherapy in OC, effective approaches for translating these lncRNAs into clinical practice warrant further investigation.
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- 2020
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16. Blockade of CDK7 Reverses Endocrine Therapy Resistance in Breast Cancer
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Yasmin M. Attia, Samia A. Shouman, Salama A. Salama, Cristina Ivan, Abdelrahman M. Elsayed, Paola Amero, Cristian Rodriguez-Aguayo, and Gabriel Lopez-Berestein
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breast cancer ,estrogen receptor ,resistance ,tamoxifen ,cyclin-dependent kinase 7 ,c-Myc ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Cyclin-dependent kinase (CDK)-7 inhibitors are emerging as promising drugs for the treatment of different types of cancer that show chemotherapy resistance. Evaluation of the effects of CDK7 inhibitor, THZ1, alone and combined with tamoxifen is of paramount importance. Thus, in the current work, we assessed the effects of THZ1 and/or tamoxifen in two estrogen receptor-positive (ER+) breast cancer cell lines (MCF7) and its tamoxifen resistant counterpart (LCC2) in vitro and in xenograft mouse models of breast cancer. Furthermore, we evaluated the expression of CDK7 in clinical samples from breast cancer patients. Cell viability, apoptosis, and genes involved in cell cycle regulation and tamoxifen resistance were determined. Tumor volume and weight, proliferation marker (Ki67), angiogenic marker (CD31), and apoptotic markers were assayed. Bioinformatic data indicated CDK7 expression was associated with negative prognosis, enhanced pro-oncogenic pathways, and decreased response to tamoxifen. Treatment with THZ1 enhanced tamoxifen-induced cytotoxicity, while it inhibited genes involved in tumor progression in MCF-7 and LCC2 cells. In vivo, THZ1 boosted the effect of tamoxifen on tumor weight and tumor volume, reduced Ki67 and CD31 expression, and increased apoptotic cell death. Our findings identify CDK7 as a possible therapeutic target for breast cancer whether it is sensitive or resistant to tamoxifen therapy.
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- 2020
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17. Exosomes: From Garbage Bins to Promising Therapeutic Targets
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Mohammed H. Rashed, Emine Bayraktar, Gouda K. Helal, Mohamed F. Abd-Ellah, Paola Amero, Arturo Chavez-Reyes, and Cristian Rodriguez-Aguayo
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tumor-derived exosomes ,non-coding RNAs ,intercellular communication ,biomarkers ,exosome-based therapeutics ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Intercellular communication via cell-released vesicles is a very important process for both normal and tumor cells. Cell communication may involve exosomes, small vesicles of endocytic origin that are released by all types of cells and are found in abundance in body fluids, including blood, saliva, urine, and breast milk. Exosomes have been shown to carry lipids, proteins, mRNAs, non-coding RNAs, and even DNA out of cells. They are more than simply molecular garbage bins, however, in that the molecules they carry can be taken up by other cells. Thus, exosomes transfer biological information to neighboring cells and through this cell-to-cell communication are involved not only in physiological functions such as cell-to-cell communication, but also in the pathogenesis of some diseases, including tumors and neurodegenerative conditions. Our increasing understanding of why cells release exosomes and their role in intercellular communication has revealed the very complex and sophisticated contribution of exosomes to health and disease. The aim of this review is to reveal the emerging roles of exosomes in normal and pathological conditions and describe the controversial biological role of exosomes, as it is now understood, in carcinogenesis. We also summarize what is known about exosome biogenesis, composition, functions, and pathways and discuss the potential clinical applications of exosomes, especially as biomarkers and novel therapeutic agents.
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- 2017
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18. Data from Rational Combination of CRM1 Inhibitor Selinexor and Olaparib Shows Synergy in Ovarian Cancer Cell Lines and Mouse Models
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Anil K. Sood, Prahlad T. Ram, Shannon N. Westin, Yosef Landesman, Robert L. Coleman, Clifford Stephan, Paola Amero, Yunfei Wen, Deanna Glassman, Sujanitha Umamaheswaran, Mark Kim, Cristina Ivan, Mary Sobieski, Reid T. Powell, Nghi Nguyen, Santosh K. Dasari, Emine Bayraktar, Robiya Joseph, Elaine Stur, Shaolin Ma, Cristian Rodriguez-Aguayo, and Katelyn F. Handley
- Abstract
CRM1 inhibitors have demonstrated antitumor effects in ovarian and other cancers; however, rational combinations are largely unexplored. We performed a high-throughput drug library screen to identify drugs that might combine well with selinexor in ovarian cancer. Next, we tested the combination of selinexor with the top hit from the drug screen in vitro and in vivo. Finally, we assessed for mechanisms underlying the identified synergy using reverse phase protein arrays (RPPA). The drug library screen assessing 688 drugs identified olaparib (a PARP inhibitor) as the most synergistic combination with selinexor. Synergy was further demonstrated by MTT assays. In the A2780luc ip1 mouse model, the combination of selinexor and olaparib yielded significantly lower tumor weight and fewer tumor nodules compared with the control group (P < 0.04 and P < 0.03). In the OVCAR5 mouse model, the combination yielded significantly fewer nodules (P = 0.006) and markedly lower tumor weight compared with the control group (P = 0.059). RPPA analysis indicated decreased expression of DNA damage repair proteins and increased expression of tumor suppressor proteins in the combination treatment group. Collectively, our preclinical findings indicate that combination with selinexor to expand the utility and efficacy of PARP inhibitors in ovarian cancer warrants further exploration.
- Published
- 2023
19. Supplementary Data from Rational Combination of CRM1 Inhibitor Selinexor and Olaparib Shows Synergy in Ovarian Cancer Cell Lines and Mouse Models
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Anil K. Sood, Prahlad T. Ram, Shannon N. Westin, Yosef Landesman, Robert L. Coleman, Clifford Stephan, Paola Amero, Yunfei Wen, Deanna Glassman, Sujanitha Umamaheswaran, Mark Kim, Cristina Ivan, Mary Sobieski, Reid T. Powell, Nghi Nguyen, Santosh K. Dasari, Emine Bayraktar, Robiya Joseph, Elaine Stur, Shaolin Ma, Cristian Rodriguez-Aguayo, and Katelyn F. Handley
- Abstract
Revised Supplementary Data Demonstrating All Supplementary Figures 1-6 and Supplementary Table 1
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- 2023
20. Targeting CDK7 reverses tamoxifen resistance through regulating stemness in ER+ breast cancer
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Yasmin M. Attia, Salama A. Salama, Samia A. Shouman, Cristina Ivan, Abdelrahman M. Elsayed, Paola Amero, Cristian Rodriguez-Aguayo, and Gabriel Lopez-Berestein
- Subjects
Pharmacology ,General Medicine - Published
- 2022
21. Rational Combination of CRM1 Inhibitor Selinexor and Olaparib Shows Synergy in Ovarian Cancer Cell Lines and Mouse Models
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Robert L. Coleman, Emine Bayraktar, Paola Amero, Cristina Ivan, Katelyn F. Handley, Cristian Rodriguez-Aguayo, Prahlad T. Ram, Deanna Glassman, Clifford Stephan, Anil K. Sood, Mark Seungwook Kim, Mary Sobieski, Elaine Stur, Nghi Nguyen, Shaolin Ma, Sujanitha Umamaheswaran, Yunfei Wen, Santosh K. Dasari, Reid T. Powell, Robiya Joseph, Yosef Landesman, and Shannon N. Westin
- Subjects
Drug ,Cancer Research ,media_common.quotation_subject ,Poly ADP ribose polymerase ,Mice, Nude ,Article ,Piperazines ,Olaparib ,Mice ,chemistry.chemical_compound ,In vivo ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Animals ,Humans ,media_common ,Ovarian Neoplasms ,business.industry ,Triazoles ,medicine.disease ,In vitro ,High-Throughput Screening Assays ,Disease Models, Animal ,Hydrazines ,Oncology ,chemistry ,Cell culture ,PARP inhibitor ,Cancer research ,Phthalazines ,Female ,Ovarian cancer ,business - Abstract
CRM1 inhibitors have demonstrated antitumor effects in ovarian and other cancers; however, rational combinations are largely unexplored. We performed a high-throughput drug library screen to identify drugs that might combine well with selinexor in ovarian cancer. Next, we tested the combination of selinexor with the top hit from the drug screen in vitro and in vivo. Finally, we assessed for mechanisms underlying the identified synergy using reverse phase protein arrays (RPPA). The drug library screen assessing 688 drugs identified olaparib (a PARP inhibitor) as the most synergistic combination with selinexor. Synergy was further demonstrated by MTT assays. In the A2780luc ip1 mouse model, the combination of selinexor and olaparib yielded significantly lower tumor weight and fewer tumor nodules compared with the control group (P < 0.04 and P < 0.03). In the OVCAR5 mouse model, the combination yielded significantly fewer nodules (P = 0.006) and markedly lower tumor weight compared with the control group (P = 0.059). RPPA analysis indicated decreased expression of DNA damage repair proteins and increased expression of tumor suppressor proteins in the combination treatment group. Collectively, our preclinical findings indicate that combination with selinexor to expand the utility and efficacy of PARP inhibitors in ovarian cancer warrants further exploration.
- Published
- 2021
22. Therapeutic efficacy of liposomal Grb2 antisense oligodeoxynucleotide (L-Grb2) in preclinical models of ovarian and uterine cancer
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Olivia D. Lara, Cristina Ivan, Anil K. Sood, Lingegowda S. Mangala, Gabriel Lopez-Berestein, Paola Amero, Wei Hu, Ana Tari Ashizawa, Shaolin Ma, Emine Bayraktar, Prasanta Dutta, Cristian Rodriguez-Aguayo, Ying Wang, and Pratip K. Bhattacharya
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0301 basic medicine ,Angiogenesis ,therapeutic approaches ,nucleic-acid based therapeutics ,uterine cancer ,Metastasis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Uterine cancer ,medicine ,Viability assay ,business.industry ,Cancer ,medicine.disease ,030104 developmental biology ,ovarian cancer ,Oncology ,Paclitaxel ,chemistry ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,biological phenomena, cell phenomena, and immunity ,Ovarian cancer ,business ,Research Paper - 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.
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- 2020
23. RNA delivery for cancer gene therapy
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Selin Oncul, Paola Amero, Cristian Rodriguez-Aguayo, Anil K. Sood, George A. Calin, and Gabriel Lopez-Berestein
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- 2022
24. Contributors
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Mohamad-Gabriel Alameh, Marice Alcantara, Jessica Alluin, Paola Amero, Virginia Arechavala-Gomeza, George A. Calin, David R. Corey, Hagen Cramer, Niels Dammes, Daniel W. Drolet, James Frederiksen, Amy D. Gelinas, Nagy A. Habib, Inbal Hazan-Halevy, Kevin Holm, Nebojsa Janjic, Krystal C. Johnson, Samantha T. Johnson, Edo Kon, Marcin Kortylewski, Dalit Landesman-Milo, Marc M. Lemaitre, Christopher Lincoln, Gabriel Lopez-Berestein, Sean A. Lynch, Selin Oncul, Rachel M. Ostroff, Dan Peer, Cristian Rodriguez-Aguayo, John C. Rohloff, Daniel Rossi, John J. Rossi, Thomas M. Rupp, Daniel J. Schneider, Patricia Soblechero-Martín, Min-Sun Song, Anil K. Sood, Yu-Lin Su, Bruce A. Sullenger, Jon Voutila, Drew Weissman, Preston Williams, Chunsong Yu, Haixiang Yu, Zhuoran Zhang, and Jiehua Zhou
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- 2022
25. Long non-coding RNAs in ovarian cancer: expression profile and functional spectrum
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Anil K. Sood, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Paola Amero, Selin Öncül, and George A. Calin
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Transcription, Genetic ,Review ,Biology ,Immunomodulation ,03 medical and health sciences ,0302 clinical medicine ,Transcription (biology) ,Biomarkers, Tumor ,medicine ,Animals ,Humans ,Molecular Biology ,030304 developmental biology ,Ovarian Neoplasms ,0303 health sciences ,Neovascularization, Pathologic ,Oncogene ,Gene Expression Profiling ,Disease Management ,Cell Biology ,Prognosis ,medicine.disease ,Long non-coding RNA ,Cell biology ,Gene Expression Regulation, Neoplastic ,030220 oncology & carcinogenesis ,Disease Progression ,Female ,RNA Interference ,RNA, Long Noncoding ,Disease Susceptibility ,Transcriptome ,Ovarian cancer ,Homeostasis - Abstract
Long non-coding RNAs (lncRNAs), initially recognized as byproducts of the transcription process, have been proven to play crucial modulatory roles in preserving overall homoeostasis of cells and tissues. Furthermore, aberrant levels of these transcripts have been shown to contribute many diseases, including cancer. Among these, many aspects of ovarian cancer biology have been found to be regulated by lncRNAs, including cancer initiation, progression and dissemination. In this review, we summarize recent studies to highlight the various roles of lncRNAs in ovary in normal and pathological conditions, immune system, diagnosis, prognosis, and therapy. We address lncRNAs that have been extensively studied in ovarian cancer and their contribution to cellular dynamics.
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- 2019
26. Explainable Artificial Intelligence Reveals Novel Insight into Tumor Microenvironment Conditions Linked with Better Prognosis in Patients with Breast Cancer
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Paola Amero, Gabriel Lopez-Berestein, Maliha Khan, Cristina Ivan, Hakan Başağaoğlu, Debaditya Chakraborty, and Cristian Rodriguez-Aguayo
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0301 basic medicine ,FOS: Computer and information sciences ,explainable artificial intelligence (XAI) ,Cancer Research ,Computer Science - Machine Learning ,Computer Science - Artificial Intelligence ,T cell ,Biology ,Article ,Machine Learning (cs.LG) ,survival analysis ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Immune system ,breast cancer ,medicine ,tumor microenvironment ,Quantitative Biology - Genomics ,B cell ,Survival analysis ,RC254-282 ,Genomics (q-bio.GN) ,Tumor microenvironment ,business.industry ,Cancer ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Artificial Intelligence (cs.AI) ,machine learning ,Oncology ,030220 oncology & carcinogenesis ,FOS: Biological sciences ,Artificial intelligence ,business ,CD8 - Abstract
We investigated the data-driven relationship between features in the tumor microenvironment (TME) and the overall and 5-year survival in triple-negative breast cancer (TNBC) and non-TNBC (NTNBC) patients by using Explainable Artificial Intelligence (XAI) models. We used clinical information from patients with invasive breast carcinoma from The Cancer Genome Atlas and from two studies from the cbioPortal, the PanCanAtlas project and the GDAC Firehose study. In this study, we used a normalized RNA sequencing data-driven cohort from 1,015 breast cancer patients, alive or deceased, from the UCSC Xena data set and performed integrated deconvolution with the EPIC method to estimate the percentage of seven different immune and stromal cells from RNA sequencing data. Novel insights derived from our XAI model showed that CD4+ T cells and B cells are more critical than other TME features for enhanced prognosis for both TNBC and NTNBC patients. Our XAI model revealed the critical inflection points (i.e., threshold fractions) of CD4+ T cells and B cells above or below which 5-year survival rates improve. Subsequently, we ascertained the conditional probabilities of $\geq$ 5-year survival in both TNBC and NTNBC patients under specific conditions inferred from the inflection points. In particular, the XAI models revealed that a B-cell fraction exceeding 0.018 in the TME could ensure 100% 5-year survival for NTNBC patients. The findings from this research could lead to more accurate clinical predictions and enhanced immunotherapies and to the design of innovative strategies to reprogram the TME of breast cancer patients., 14 pages, 5 figures, preprint
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- 2021
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27. Conversion of RNA Aptamer into Modified DNA Aptamers Provides for Prolonged Stability and Enhanced Antitumor Activity
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Cristian Rodriguez-Aguayo, Yasmin M. Attia, Ganesh L.R. Lokesh, Shuxing Zhang, Vittorio Cristini, Anil K. Sood, Rahul Mitra, Gabriel Lopez-Berestein, Abdelrahman M. Elsayed, Vittorio de Franciscis, David E. Volk, Paola Amero, Cristina Ivan, Rajan Chaudhari, Roberto Cardenas-Zuniga, Thomas J. S. Schubert, Efigenia Montalvo-González, and Zhihui Wang
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Nuclease ,biology ,Oligonucleotide ,Chemistry ,Aptamer ,RNA ,General Chemistry ,Aptamers, Nucleotide ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Catalysis ,In vitro ,Antibodies ,0104 chemical sciences ,Bioavailability ,Colloid and Surface Chemistry ,In vivo ,Neoplasms ,biology.protein ,Gene silencing ,Humans - Abstract
Aptamers, synthetic single-strand oligonucleotides that are similar in function to antibodies, are promising as therapeutics because of their minimal side effects. However, the stability and bioavailability of the aptamers pose a challenge. We developed aptamers converted from RNA aptamer to modified DNA aptamers that target phospho-AXL with improved stability and bioavailability. On the basis of the comparative analysis of a library of 17 converted modified DNA aptamers, we selected aptamer candidates, GLB-G25 and GLB-A04, that exhibited the highest bioavailability, stability, and robust antitumor effect in in vitro experiments. Backbone modifications such as thiophosphate or dithiophosphate and a covalent modification of the 5'-end of the aptamer with polyethylene glycol optimized the pharmacokinetic properties, improved the stability of the aptamers in vivo by reducing nuclease hydrolysis and renal clearance, and achieved high and sustained inhibition of AXL at a very low dose. Treatment with these modified aptamers in ovarian cancer orthotopic mouse models significantly reduced tumor growth and the number of metastases. This effective silencing of the phospho-AXL target thus demonstrated that aptamer specificity and bioavailability can be improved by the chemical modification of existing aptamers for phospho-AXL. These results lay the foundation for the translation of these aptamer candidates and companion biomarkers to the clinic.
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- 2021
28. Inactivating Mutations of the IK Gene Weaken Ku80/Ku70-Mediated DNA Repair and Sensitize Endometrial Cancer to Chemotherapy
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Cristian Rodriguez-Aguayo, Emine Bayraktar, Anil K. Sood, Wei Zhang, Elizabeth Forbes, Ye Yan, Fengxia Xue, Lingegowda S. Mangala, Russell Broaddus, Guangxu Jin, Yingmei Wang, Gabriel Lopez-Berestein, Chao Gao, and Paola Amero
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Cancer Research ,Gene knockdown ,Mutation ,Mutation rate ,Ku70 ,Ku80 ,DNA repair ,cisplatin ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Biology ,medicine.disease_cause ,IK ,Frameshift mutation ,Germline mutation ,Oncology ,endometrial cancer ,medicine ,Cancer research ,somatic mutation ,RC254-282 - 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
29. PRKAR1B-AS2 Long Noncoding RNA Promotes Tumorigenesis, Survival, and Chemoresistance via the PI3K/AKT/mTOR Pathway
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Raed S. Ismail, Cristina Ivan, Gabriel Lopez-Berestein, Cristian Rodriguez-Aguayo, Emine Bayraktar, Abdelrahman M. Elsayed, Salama A. Salama, Xinna Zhang, Paola Amero, Abdel-Aziz H. Abdel-Aziz, and Anil K. Sood
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Small interfering RNA ,Carcinogenesis ,Cell Survival ,AC147651.5 ,medicine.disease_cause ,Catalysis ,Article ,lcsh:Chemistry ,Inorganic Chemistry ,Phosphatidylinositol 3-Kinases ,lncRNA ,Cell Line, Tumor ,medicine ,PTEN ,Gene silencing ,Humans ,PI3K/AKT/mTOR ,RNA, Neoplasm ,Physical and Theoretical Chemistry ,lcsh:QH301-705.5 ,Molecular Biology ,Protein kinase B ,Spectroscopy ,PI3K/AKT/mTOR pathway ,Ovarian Neoplasms ,Gene knockdown ,biology ,Chemistry ,TOR Serine-Threonine Kinases ,Organic Chemistry ,General Medicine ,Long non-coding RNA ,Computer Science Applications ,ovarian cancer ,lcsh:Biology (General) ,lcsh:QD1-999 ,Drug Resistance, Neoplasm ,PRKAR1B-AS2 ,biology.protein ,Cancer research ,Female ,RNA, Long Noncoding ,cisplatin resistance ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Many long noncoding RNAs have been implicated in tumorigenesis and chemoresistance, however, the underlying mechanisms are not well understood. We investigated the role of PRKAR1B-AS2 long noncoding RNA in ovarian cancer (OC) and chemoresistance and identified potential downstream molecular circuitry underlying its action. Analysis of The Cancer Genome Atlas OC dataset, in vitro experiments, proteomic analysis, and a xenograft OC mouse model were implemented. Our findings indicated that overexpression of PRKAR1B-AS2 is negatively correlated with overall survival in OC patients. Furthermore, PRKAR1B-AS2 knockdown-attenuated proliferation, migration, and invasion of OC cells and ameliorated cisplatin and alpelisib resistance in vitro. In proteomic analysis, silencing PRKAR1B-AS2 markedly inhibited protein expression of PI3K-110α and abrogated the phosphorylation of PDK1, AKT, and mTOR, with no significant effect on PTEN. The RNA immunoprecipitation detected a physical interaction between PRKAR1B-AS2 and PI3K-110α. Moreover, PRKAR1B-AS2 knockdown by systemic administration of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine nanoparticles loaded with PRKAR1B-AS2–specific small interfering RNA enhanced cisplatin sensitivity in a xenograft OC mouse model. In conclusion, PRKAR1B-AS2 promotes tumor growth and confers chemoresistance by modulating the PI3K/AKT/mTOR pathway. Thus, targeting PRKAR1B-AS2 may represent a novel therapeutic approach for the treatment of OC patients.
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- 2021
30. Back to the Future: Rethinking the Great Potential of lncRNAS for Optimizing Chemotherapeutic Response in Ovarian Cancer
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Salama A. Salama, Cristian Rodriguez-Aguayo, Abdelrahman M. Elsayed, Gabriel Lopez-Berestein, Abdel-Aziz H. Abdel-Aziz, and Paola Amero
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Primary response ,medicine.disease ,chemotherapy ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,lcsh:RC254-282 ,Clinical Practice ,Chemotherapeutic response ,long non-coding RNAs ,Acquired resistance ,ovarian cancer ,dysregulated expression ,mechanisms of resistance ,Internal medicine ,medicine ,Therapeutic failure ,Narrative review ,Ovarian cancer ,business ,Chemotherapy response - Abstract
Ovarian cancer (OC) is one of the most fatal cancers in women worldwide. Currently, platinum- and taxane-based chemotherapy is the mainstay for the treatment of OC. Yet, the emergence of chemoresistance results in therapeutic failure and significant relapse despite a consistent rate of primary response. Emerging evidence substantiates the potential role of lncRNAs in determining the response to standard chemotherapy in OC. The objective of this narrative review is to provide an integrated, synthesized overview of the current state of knowledge regarding the role of lncRNAs in the emergence of resistance to platinum- and taxane-based chemotherapy in OC. In addition, we sought to develop conceptual frameworks for harnessing the therapeutic potential of lncRNAs in strategies aimed at enhancing the chemotherapy response of OC. Furthermore, we offered significant new perspectives and insights on the interplay between lncRNAs and the molecular circuitries implicated in chemoresistance to determine their impacts on therapeutic response. Although this review summarizes robust data concerning the involvement of lncRNAs in the emergence of acquired resistance to platinum- and taxane-based chemotherapy in OC, effective approaches for translating these lncRNAs into clinical practice warrant further investigation.
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- 2020
31. Therapeutic potential of FLANC, a novel primate-specific long non-coding RNA in colorectal cancer
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Mihnea P. Dragomir, Menashe Bar-Eli, Enrique Fuentes-Mattei, Cristian Rodriguez-Aguayo, Ayumu Taguchi, Tina Catela Ivkovic, Diana L. Bonilla, Zhihui Wang, Xinna Zhang, Isidore Rigoutsos, Giovanni Lanza, Erik Knutsen, Hiroyuki Katayama, Cristina Ivan, Sanja Kapitanović, Emine Bayraktar, Martin Pichler, Anh M. Tran, Li Huang, Recep Bayraktar, Rajat Bhattacharya, Ondrej Slaby, Yoshinaga Okugawa, Bozo Loncar, George A. Calin, Simone Anfossi, Ajay Goel, Paola Amero, William Ruixian He, Samir M. Hanash, Sang Kil Lee, Guoliang Huang, Roberta Gafà, Su Youn Nam, Gabriel Lopez-Berestein, Vittorio Cristini, Hui Ling, Christiane Klec, and Petra Vychytilova-Faltejskova
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0301 basic medicine ,Genetic Markers ,STAT3 Transcription Factor ,Vascular Endothelial Growth Factor A ,Small interfering RNA ,Colorectal cancer ,Angiogenesis ,Carcinogenesis ,oncogenes ,Genetic enhancement ,colorectal cancer ,Biology ,Article ,NO ,angiogenesis ,gene therapy ,molecular genetics ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Downregulation and upregulation ,Drug Discovery ,medicine ,Biomarkers, Tumor ,Animals ,Humans ,Cell Proliferation ,Neovascularization, Pathologic ,Gastroenterology ,Genetic Therapy ,medicine.disease ,Long non-coding RNA ,3. Good health ,Pharmacogenomic Testing ,Gene Expression Regulation, Neoplastic ,Vascular endothelial growth factor A ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,RNA, Long Noncoding ,Colorectal Neoplasms ,angiogenesis, colorectal cancer, gene therapy, molecular genetics, oncogenes - Abstract
ObjectiveTo investigate the function of a novel primate-specific long non-coding RNA (lncRNA), named FLANC, based on its genomic location (co-localised with a pyknon motif), and to characterise its potential as a biomarker and therapeutic target.DesignFLANC expression was analysed in 349 tumours from four cohorts and correlated to clinical data. In a series of multiple in vitro and in vivo models and molecular analyses, we characterised the fundamental biological roles of this lncRNA. We further explored the therapeutic potential of targeting FLANC in a mouse model of colorectal cancer (CRC) metastases.ResultsFLANC, a primate-specific lncRNA feebly expressed in normal colon cells, was significantly upregulated in cancer cells compared with normal colon samples in two independent cohorts. High levels of FLANC were associated with poor survival in two additional independent CRC patient cohorts. Both in vitro and in vivo experiments demonstrated that the modulation of FLANC expression influenced cellular growth, apoptosis, migration, angiogenesis and metastases formation ability of CRC cells. In vivo pharmacological targeting of FLANC by administration of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine nanoparticles loaded with a specific small interfering RNA, induced significant decrease in metastases, without evident tissue toxicity or pro-inflammatory effects. Mechanistically, FLANC upregulated and prolonged the half-life of phosphorylated STAT3, inducing the overexpression of VEGFA, a key regulator of angiogenesis.ConclusionsBased on our findings, we discovered, FLANC as a novel primate-specific lncRNA that is highly upregulated in CRC cells and regulates metastases formation. Targeting primate-specific transcripts such as FLANC may represent a novel and low toxic therapeutic strategy for the treatment of patients.
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- 2020
32. Therapeutic Targeting of AXL Receptor Tyrosine Kinase Inhibits Tumor Growth and Intraperitoneal Metastasis in Ovarian Cancer Models
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Cristina Ivan, Gabriel Lopez-Berestein, Nilgun Gurbuz, Silvia Catuogno, Sherry Yen Yao Wu, Vianey Gonzalez-Villasana, Vittorio de Franciscis, Cristian Rodriguez-Aguayo, David G. Gorenstein, Monika Haemmerle, Pinar Kanlikilicer, Anil K. Sood, Bulent Ozpolat, Burcu Aslan, Emine Bayraktar, Rahul Mitra, David E. Volk, Merve Denizli, Paola Amero, Recep Bayraktar, and Ganesh L.R. Lokesh
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0301 basic medicine ,Oncology ,Drug ,medicine.medical_specialty ,Angiogenesis ,media_common.quotation_subject ,Article ,Metastasis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Drug Discovery ,medicine ,metastasis ,Tumor growth ,media_common ,AXL receptor tyrosine kinase ,business.industry ,lcsh:RM1-950 ,AXL ,aptamer ,medicine.disease ,3. Good health ,030104 developmental biology ,ovarian cancer ,lcsh:Therapeutics. Pharmacology ,Paclitaxel ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,Molecular Medicine ,Phosphorylation ,business ,Ovarian cancer - Abstract
Despite substantial improvements in the treatment strategies, ovarian cancer is still the most lethal gynecological malignancy. Identification of drug treatable therapeutic targets and their safe and effective targeting is critical to improve patient survival in ovarian cancer. AXL receptor tyrosine kinase (RTK) has been proposed to be an important therapeutic target for metastatic and advanced-stage human ovarian cancer. We found that AXL-RTK expression is associated with significantly shorter patient survival based on the The Cancer Genome Atlas patient database. To target AXL-RTK, we developed a chemically modified serum nuclease-stable AXL aptamer (AXL-APTAMER), and we evaluated its in vitro and in vivo antitumor activity using in vitro assays as well as two intraperitoneal animal models. AXL-aptamer treatment inhibited the phosphorylation and the activity of AXL, impaired the migration and invasion ability of ovarian cancer cells, and led to the inhibition of tumor growth and number of intraperitoneal metastatic nodules, which was associated with the inhibition of AXL activity and angiogenesis in tumors. When combined with paclitaxel, in vivo systemic (intravenous [i.v.]) administration of AXL-aptamer treatment markedly enhanced the antitumor efficacy of paclitaxel in mice. Taken together, our data indicate that AXL-aptamers successfully target in vivo AXL-RTK and inhibit its AXL activity and tumor growth and progression, representing a promising strategy for the treatment of ovarian cancer.
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- 2017
33. Aptamers: Novel Therapeutics and Potential Role in Neuro-Oncology
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Cristian Rodriguez-Aguayo, Soumen Khatua, Gabriel Lopez-Berestein, and Paola Amero
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0301 basic medicine ,Drug ,Cancer Research ,media_common.quotation_subject ,Neuro oncology ,Aptamer ,aptamers ,diagnostic ,Review ,Cell Surface Proteins ,blood–brain barrier ,Bioinformatics ,Adult glioblastoma ,03 medical and health sciences ,Preclinical research ,0302 clinical medicine ,Medicine ,media_common ,Clinical Oncology ,business.industry ,Cancer ,medicine.disease ,therapeutic ,pediatric ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,business ,neuro-oncology - Abstract
Simple Summary Despite the remarkable effort of researchers to find more effective treatments for pediatric brain tumors, the prognosis continues to be poor. Forty percent of pediatric patients develop treatment resistance and relapse, and the morbidities and long-term side effects of systemic therapy remain concerning. Significant advances have been made by next-generation genomic profiling. Novel oncogenic drivers have been identified as potential targets for the treatment of pediatric brain tumors. Aptamers, which are synthetic single-strand oligonucleotides, specifically target, bind with high affinity, internalize, and deliver a wide range of therapeutic moieties inside the cells. Although several aptamers have been tested in preclinical and clinical studies for adult glioblastoma, the use of aptamers in pediatric neuro-oncology remains unexplored. Increased knowledge regarding the molecular mechanisms of the pathogenesis of pediatric brain tumors, as well as selection of novel aptamers and/or adaptation of aptamers currently used in adult glioblastoma, might open a novel research field. Abstract A relatively new paradigm in cancer therapeutics is the use of cancer cell–specific aptamers, both as therapeutic agents and for targeted delivery of anticancer drugs. After the first therapeutic aptamer was described nearly 25 years ago, and the subsequent first aptamer drug approved, many efforts have been made to translate preclinical research into clinical oncology settings. Studies of aptamer-based technology have unveiled the vast potential of aptamers in therapeutic and diagnostic applications. Among pediatric solid cancers, brain tumors are the leading cause of death. Although a few aptamer-related translational studies have been performed in adult glioblastoma, the use of aptamers in pediatric neuro-oncology remains unexplored. This review will discuss the biology of aptamers, including mechanisms of targeting cell surface proteins, various modifications of aptamer structure to enhance therapeutic efficacy, the current state and challenges of aptamer use in neuro-oncology, and the potential therapeutic role of aptamers in pediatric brain tumors.
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- 2020
34. Exosomes: From Garbage Bins to Promising Therapeutic Targets
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Mohamed F. Abd-Ellah, Gouda K. Helal, Emine Bayraktar, Paola Amero, Arturo Chavez-Reyes, Mohammed H. Rashed, and Cristian Rodriguez-Aguayo
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0301 basic medicine ,Cell signaling ,Exosome biogenesis ,Endocytic cycle ,Tumor cells ,Review ,Cell Communication ,Exosomes ,Bioinformatics ,medicine.disease_cause ,Catalysis ,Inorganic Chemistry ,Pathogenesis ,lcsh:Chemistry ,03 medical and health sciences ,Drug Delivery Systems ,Neoplasms ,Humans ,Medicine ,Physical and Theoretical Chemistry ,Molecular Biology ,lcsh:QH301-705.5 ,Spectroscopy ,exosome-based therapeutics ,tumor-derived exosomes ,business.industry ,Organic Chemistry ,biomarkers ,Biological Transport ,Neurodegenerative Diseases ,General Medicine ,Microvesicles ,Computer Science Applications ,Cell biology ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,intercellular communication ,non-coding RNAs ,business ,Carcinogenesis ,Intracellular - Abstract
Intercellular communication via cell-released vesicles is a very important process for both normal and tumor cells. Cell communication may involve exosomes, small vesicles of endocytic origin that are released by all types of cells and are found in abundance in body fluids, including blood, saliva, urine, and breast milk. Exosomes have been shown to carry lipids, proteins, mRNAs, non-coding RNAs, and even DNA out of cells. They are more than simply molecular garbage bins, however, in that the molecules they carry can be taken up by other cells. Thus, exosomes transfer biological information to neighboring cells and through this cell-to-cell communication are involved not only in physiological functions such as cell-to-cell communication, but also in the pathogenesis of some diseases, including tumors and neurodegenerative conditions. Our increasing understanding of why cells release exosomes and their role in intercellular communication has revealed the very complex and sophisticated contribution of exosomes to health and disease. The aim of this review is to reveal the emerging roles of exosomes in normal and pathological conditions and describe the controversial biological role of exosomes, as it is now understood, in carcinogenesis. We also summarize what is known about exosome biogenesis, composition, functions, and pathways and discuss the potential clinical applications of exosomes, especially as biomarkers and novel therapeutic agents.
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- 2017
35. Abstract 368: Next generation DNA aptamers with prolonged stability and antitumor activity
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Gabriel Lopez-Berestein, Anil K. Sood, Shuxing Zhang, Rajan Chaudhari, Paola Amero, and Cristian Rodriguez-Aguayo
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Cancer Research ,Chemistry ,Oligonucleotide ,GAS6 ,Aptamer ,Nucleic acid sequence ,Cancer ,medicine.disease ,In vitro ,chemistry.chemical_compound ,Oncology ,medicine ,Cancer research ,Ovarian cancer ,DNA - Abstract
Aberrations in Gas6/AXL signaling is associated with many human diseases including ovarian cancer, where in patients expressing high levels of AXL have shorter overall survival than patients expressing low levels. Aptamers are short synthetic oligonucleotides (DNA or RNA) that can bind with highest specificity to various other macromolecules such as peptides, proteins and carbohydrates, based on their tertiary structures. Aptamers are similar in their functionality to antibodies in their specificity; easier to manufacture than antibodies; have minimal side effects; and thus hold a high promise as therapeutics. The typical issues with the use of aptamers as therapeutic agents are their selectivity, stability, and bioavailability. We present the development of the next generation DNA aptamers, targeting p-AXL specifically to as a therapeutic in ovarian cancer (OC) by chemical modifications to their primary sequence. Improved bioavailability and stability, based on the comparative analysis the library of 17 DNA aptamers that differed in the position and number of fluoro- and thio- modifications on their nucleotide sequence, were used as the criteria for the selection and characterization of the best aptamer candidates to target p-AXL. Two of the best candidates, GLB-G25 and GLB-A04 thus chosen with the highest bioavailability and stability, when tested in ovarian cancer cell lines, decreased the migration and invasion of cells in vitro. Treatment of ovarian cancer orthotopic murine model animals with modified DNA aptamer candidates chosen above significantly reduced tumor growth and the number of metastases. The candidates, GLB-G25 and GLB-A04 show highest potential to be developed into therapeutics to target p-AXL that is elevated in several cancers including ovarian cancer. Note: This abstract was not presented at the meeting. Citation Format: Paola AMERO, Cristian Rodriguez-Aguayo, Rajan R. Chaudhari, Shuxing Zhang, Anil K. Sood, Gabriel Lopez-Berestein. Next generation DNA aptamers with prolonged stability and antitumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 368.
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- 2019
36. Abstract 194: Overcoming adaptive resistance to anti-VEGF therapy by targeting CD5L
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Vittorio de Franciscis, Minsoon Cho, Zhiqiang An, Yihong Wan, Wei Hu, Kyunghee Noh, Paola Amero, Christopher J. LaFargue, Rajesha Rupaimoole, Robert L. Coleman, Chunhua Lu, Sunila Pradeep, Selanare Mangala, Ningyan Zhang, Anil K. Sood, and Gabriel Lopez-Bernstein
- Subjects
Tube formation ,Cancer Research ,Cell growth ,Chemistry ,Growth factor ,medicine.medical_treatment ,Cell migration ,Transfection ,Oncology ,Downregulation and upregulation ,Cancer research ,medicine ,Ectopic expression ,PI3K/AKT/mTOR pathway - Abstract
Purpose: To identify mechanisms responsible for the development of adaptive resistance to anti-vascular endothelial growth factor (VEGF) therapy, and to develop novel agents to reverse its occurrence. Methods: Gene expression profiling was performed on endothelial cells isolated from tumors sensitive or resistant to anti-VEGF therapy in a syngeneic ovarian cancer mouse model. A series of in vitro (lentiviral transfection, tube formation, siRNA knockdown, luciferase promoter assays) and in vivo (including Tie2; PPARγ KO mice) experiments were then used to elucidate the upstream and downstream effectors of CD5L, as well as the efficacy of CD5L inhibition in pre-clinical orthotopic mouse models. Results: We identified substantially increased CD5L expression in endothelial cells isolated from anti-VEGF therapy resistant vs. sensitive tumors. Ectopic expression of CD5L in RF24 endothelial cells resulted in increased tube formation, cell migration, and cell proliferation, whereas siCD5L treatment resulted in an overall decrease. Observing that a PPARγ binding site was present in the CD5L promoter, we found that ectopic expression of PPARγ into RF24 cells results in increased CD5L expression, whereas siPPARγ treatment decreased it. Ectopic PPARγ expression increased luciferase activity but decreased activity with siPPARγ treatment when using a reporter assay for CD5L promoter. Conversely, mutation of the PPARγ binding site in the promoter construct lacked any increase in activity after ectopic PPARγ expression. IPA analysis identified HIF1α as playing an integral role in the PPARγ /CD5L activation pathway. Indeed, hypoxic conditions resulted in an increase of both PPARγ and CD5L in RF24 cells. HIF1α stabilizers (cobalt chloride) and inhibitors (YC-1 and topotecan) also showed an increase and decrease in PPARγ and CD5L expression, respectively. RPPA analysis of anti-VEGF resistant tumor endothelial cells implicated an upregulation of the PI3K pathway. While exogenous CD5L treatment led to increased p-AKT, the addition of the PI3K inhibitor LY294002 negated this effect and also decreased tube formation and cell migration. Next, we injected both WT B6 and Tie2:PPARγ KO mice with the ID8 mouse ovarian cancer cell line and treated with B20 until moribund. Mice harboring the PPARγ KO had significantly increased survival as well as decreased tumor weight, number of nodules, Ki67 expression, and blood vessel density. Our non-syngeneic model was then treated with B20 and either CD5L RNA aptamer or vehicle. The aptamer group treated with CD5L aptamer displayed significantly decreased tumor weight, number of nodules, Ki67 expression, and blood vessel density. Conclusions: This study identifies a pathway centered on CD5L as an important driver of adaptive resistance to anti-angiogenic therapy. Citation Format: Christopher J. LaFargue, Paola Amero, Kyunghee Noh, Selanare Mangala, Chunhua Lu, Minsoon Cho, Sunila Pradeep, Yihong Wan, Wei Hu, Rajesha Rupaimoole, Robert L. Coleman, Ningyan Zhang, Zhiqiang An, Gabriel Lopez-Bernstein, Vittorio de Franciscis, Anil K. Sood. Overcoming adaptive resistance to anti-VEGF therapy by targeting CD5L [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 194.
- Published
- 2019
37. Effects of a Lactobacillus paracasei B21060 based synbiotic on steatosis, insulin signaling and toll-like receptor expression in rats fed a high-fat diet
- Author
-
MATTACE RASO, GIUSEPPINA, Raffaele Simeoli, Anna Iacono, Anna Santoro, Paola Amero, PACIELLO, ORLANDO, RUSSO, ROBERTO, Giuseppe D'Agostino, Margherita Di Costanzo, BERNI CANANI, ROBERTO, CALIGNANO, ANTONIO, MELI, ROSARIA, MATTACE RASO, Giuseppina, Raffaele, Simeoli, Anna, Iacono, Anna, Santoro, Paola, Amero, Paciello, Orlando, Russo, Roberto, Giuseppe, D'Agostino, Margherita Di, Costanzo, BERNI CANANI, Roberto, Calignano, Antonio, and Meli, Rosaria
- Subjects
Inflammation ,Toll-like receptor ,Glucose tolerance ,Insulin resistance ,Gut permeability ,Non-alcoholic fatty liver disease - Abstract
Insulin resistance (IR) has been identified as crucial pathophysiological factor in the development and progression of non-alcoholic fatty liver disease (NAFLD). Although mounting evidence suggests that perturbation of gut microflora exacerbates the severity of chronic liver diseases, therapeutic approaches using synbiotic has remained overlooked. Here, we show that a synbiotic composed by Lactobacillus paracasei B21060 plus arabinogalactan and fructo-oligosaccharides lessens NAFLD progression in a rat model of high fat feeding. IR and steatosis were induced by administration of high fat diet (HFD) for 6 weeks. Steatosis and hepatic inflammation, Toll-like receptor (TLR) pattern, glucose tolerance, insulin signaling and gut permeability were studied. Liver inflammatory markers were down-regulated in rats receiving the synbiotic, along with an increased expression of nuclear peroxisome proliferator-activated receptors and expression of downstream target genes. The synbiotic improved many aspects of IR, such as fasting response, hormonal homeostasis and glycemic control. Indeed it prevented the impairment of hepatic insulin signaling, reducing the phosphorylation of insulin receptor substrate-1 in Ser 307 and down-regulating suppressor of cytokine signaling 3. Gene expression analysis revealed that in the liver the synbiotic reduced cytokines synthesis and restored the HFD-dysregulated TLR 2, 4 and 9 mRNAs toward a physiological level of expression. The synbiotic preserved gut barrier integrity and reduced the relative amount of Gram-negative Enterobacteriales and Escherichia coli in colonic mucosa. Overall, our data indicate that the L. paracasei B21060 based synbiotic is effective in reducing the severity of liver injury and IR associated with high fat intake, suggesting its possible therapeutic/preventive clinical utilization.
- Published
- 2014
38. Abstract 5786: Grabbing GRB2: The use of liposome-incorporated Grb2 antisense oligonucleotides as a novel therapy in gynecologic malignancies
- Author
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Cristian Rodriquez-Aguayo, Olivia D. Lara, Selanere Mangala, Emine Bayrakter, Anil K. Sood, Paola Amero, Christopher J. LaFargue, Ana Tari-Ashizawa, and Gabriel Lopez-Berestein
- Subjects
Cancer Research ,business.industry ,Cancer ,medicine.disease ,Blot ,chemistry.chemical_compound ,Leukemia ,Serous fluid ,Oncology ,Paclitaxel ,chemistry ,In vivo ,Cancer research ,medicine ,Carcinoma ,Clinical significance ,biological phenomena, cell phenomena, and immunity ,business - Abstract
Prexigebersen (liposome-incorporated nuclease resistant antisense oligonucleotides specific for GRB2, L-GRB2) has proven highly effective in the treatment of leukemia, however its application in solid malignancies including gynecologic cancer has yet to be investigated. Given the biological significance of GRB2, we aim to assess the effect of prexigebersen in pre-clinical models. We tested the clinical significance of GRB2 using publicly available high-throughput data. We investigated the expression of GRB2 in a series of in vitro (Western Blotting) experiments in high-grade serous (HGSC) and uterine (UC) carcinoma models. We also tested in vivo (orthotopic mouse model) the biological effects of prexigebersen in HGSC models (OVCAR 5), first in a dose-defining experiment then in combination with standard dose paclitaxel. We first examined GRB2 using TCGA and GISTIC data and found alterations (amplifications, deletions and mutations) in 6% (33 of 594) of HGSC cases and 5% (25 of 547) of UC cases. Amplifications of GRB2 are associated with a decreased patient survival (p Citation Format: Olivia D. Lara, Cristian Rodriquez-Aguayo, Emine Bayrakter, Paola Amero, Selanere Mangala, Chris LaFargue, Ana Tari-Ashizawa, Gabriel Lopez-Berestein, Anil Sood. Grabbing GRB2: The use of liposome-incorporated Grb2 antisense oligonucleotides as a novel therapy in gynecologic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5786.
- Published
- 2018
39. Grabbing the Grb2/GAB2 complex in ovarian cancer
- Author
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Cristian Rodriguez-Aguayo, Selanere Mangala, Emine Bayraktar, Christopher J. LaFargue, Olivia D. Lara, Paola Amero, and Anil K. Sood
- Subjects
0301 basic medicine ,03 medical and health sciences ,030104 developmental biology ,Oncology ,business.industry ,medicine ,Cancer research ,Obstetrics and Gynecology ,Ovarian cancer ,medicine.disease ,business - Published
- 2018
40. Development of novel modified aptamers to target Axl receptor in ovarian cancer
- Author
-
Shu Zhang, Paola Amero, Cristina Ivan, Gabriel Lopez-Berestein, Cristian Rodriguez-Aguayo, Emine Bayraktar, David E. Volk, Anil K. Sood, Rajan Chaudhari, and Ganesh L.R. Lokesh
- Subjects
Oncology ,business.industry ,Aptamer ,medicine ,Cancer research ,Hematology ,Ovarian cancer ,medicine.disease ,Receptor ,business - Published
- 2018
41. Polychlorinated biphenyls (PCB 101, PCB 153 and PCB 180) alter leptin signaling and lipid metabolism in differentiated 3T3-L1 adipocytes
- Author
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Francesca Guida, Raffaele Simeoli, Maria Carmela Ferrante, Rosaria Meli, Anna Santoro, Anna Monnolo, Paola Amero, Giuseppina Mattace Raso, Ferrante, MARIA CARMELA, Amero, P., Santoro, A., Monnolo, Anna, Simeoli, R., Di Guida, F., MATTACE RASO, Giuseppina, and Meli, Rosaria
- Subjects
Leptin ,STAT3 Transcription Factor ,medicine.medical_specialty ,Blotting, Western ,Adipose tissue ,Peroxisome proliferator-activated receptor ,Suppressor of Cytokine Signaling Proteins ,Biology ,Toxicology ,Real-Time Polymerase Chain Reaction ,Proinflammatory cytokine ,Mice ,Internal medicine ,3T3-L1 Cells ,medicine ,Adipocytes ,Animals ,SOCS3 ,Coloring Agents ,Pharmacology ,chemistry.chemical_classification ,Protein Tyrosine Phosphatase, Non-Receptor Type 1 ,Adipocyte ,Leptin receptor ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,digestive, oral, and skin physiology ,3T3-L1 ,Lipid metabolism ,Cell Differentiation ,Lipid Metabolism ,Polychlorinated Biphenyls ,Endocrinology ,chemistry ,Suppressor of Cytokine Signaling 3 Protein ,Receptors, Leptin ,Environmental Pollutants ,Mitogen-Activated Protein Kinases ,Azo Compounds ,polychlorinated biphenyl ,hormones, hormone substitutes, and hormone antagonists ,Signal Transduction - Abstract
Non-dioxin-like polychlorinated biphenyls (NDL-PCBs) are highly lipophilic environmental contaminants that accumulate in lipid-rich tissues, such as adipose tissue. Here, we reported the effects induced by PCBs 101, 153 and 180, three of the six NDL-PCBs defined as indicators, on mature 3T3-L1 adipocytes. We observed an increase in lipid content, in leptin gene expression and a reduction of leptin receptor expression and signaling, when cells were exposed to PCBs, alone or in combination. These modifications were consistent with the occurrence of "leptin-resistance" in adipose tissue, a typical metabolic alteration related to obesity. Therefore, we investigated how PCBs affect the expression of pivotal proteins involved in the signaling of leptin receptor. We evaluated the PCB effect on the intracellular pathway JAK/STAT, determining the phosphorylation of STAT3, a downstream activator of the transcription of leptin gene targets, and the expression of SOCS3 and PTP1B, two important regulators of leptin resistance. In particular, PCBs 153 and 180 or all PCB combinations induced a significant reduction in pSTAT3/STAT3 ratio and an increase in PTP1B and SOCS3, evidencing an additive effect. The impairment of leptin signaling was associated with the reduction of AMPK/ACC pathway activation, leading to the increase in lipid content. These pollutants were also able to increase the transcription of inflammatory cytokines (IL-6 and TNFα). It is worthy to note that the PCB concentrations used are comparable to levels detectable in human adipose tissue. Our data strongly support the hypothesis that NDL-PCBs may interfere with the lipid metabolism contributing to the development of obesity and related diseases.
- Published
- 2014
42. Effects of a Lactobacillus paracasei B21060 based synbiotic on steatosis, insulin signaling and toll-like receptor expression in rats fed a high-fat diet
- Author
-
Roberto Russo, Rosaria Meli, Raffaele Simeoli, Antonio Calignano, Giuseppe D'Agostino, Paola Amero, Roberto Berni Canani, Giuseppina Mattace Raso, Anna Santoro, Anna Iacono, Margherita Di Costanzo, and Orlando Paciello
- Subjects
Male ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Peroxisome proliferator-activated receptor ,Oligosaccharides ,Suppressor of Cytokine Signaling Proteins ,Synbiotics ,Biochemistry ,Galactans ,Rats, Sprague-Dawley ,SOCS3 ,Intestinal Mucosa ,chemistry.chemical_classification ,Liver injury ,Nutrition and Dietetics ,Glucose Transporter Type 4 ,biology ,Fatty liver ,Adipose Tissue ,Liver ,Adiponectin ,Signal Transduction ,medicine.medical_specialty ,Down-Regulation ,Diet, High-Fat ,Insulin resistance ,Enterobacteriaceae ,Internal medicine ,medicine ,Animals ,RNA, Messenger ,Molecular Biology ,medicine.disease ,Toll-Like Receptor 2 ,Rats ,Fatty Liver ,PPAR gamma ,Toll-Like Receptor 4 ,Insulin receptor ,Lactobacillus ,Endocrinology ,chemistry ,Suppressor of Cytokine Signaling 3 Protein ,Toll-Like Receptor 9 ,Immunology ,biology.protein ,Insulin Receptor Substrate Proteins ,Steatosis ,Insulin Resistance - Abstract
Insulin resistance (IR) has been identified as crucial pathophysiological factor in the development and progression of non-alcoholic fatty liver disease (NAFLD). Although mounting evidence suggests that perturbation of gut microflora exacerbates the severity of chronic liver diseases, therapeutic approaches using synbiotic has remained overlooked. Here, we show that a synbiotic composed by Lactobacillus paracasei B21060 plus arabinogalactan and fructo-oligosaccharides lessens NAFLD progression in a rat model of high fat feeding. IR and steatosis were induced by administration of high fat diet (HFD) for 6 weeks. Steatosis and hepatic inflammation, Toll-like receptor (TLR) pattern, glucose tolerance, insulin signaling and gut permeability were studied. Liver inflammatory markers were down-regulated in rats receiving the synbiotic, along with an increased expression of nuclear peroxisome proliferator-activated receptors and expression of downstream target genes. The synbiotic improved many aspects of IR, such as fasting response, hormonal homeostasis and glycemic control. Indeed it prevented the impairment of hepatic insulin signaling, reducing the phosphorylation of insulin receptor substrate-1 in Ser 307 and down-regulating suppressor of cytokine signaling 3. Gene expression analysis revealed that in the liver the synbiotic reduced cytokines synthesis and restored the HFD-dysregulated TLR 2, 4 and 9 mRNAs toward a physiological level of expression. The synbiotic preserved gut barrier integrity and reduced the relative amount of Gram–negative Enterobacteriales and Escherichia coli in colonic mucosa. Overall, our data indicate that the L. paracasei B21060 based synbiotic is effective in reducing the severity of liver injury and IR associated with high fat intake, suggesting its possible therapeutic/preventive clinical utilization.
- Published
- 2013
43. Effects of non-dioxin-like polychlorinated biphenyl congeners (PCB 101, PCB 153 and PCB 180) alone or mixed on J774A.1 macrophage cell line: modification of apoptotic pathway
- Author
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Rosaria Meli, Raffaele Simeoli, Paola Amero, Anna Santoro, Maria Teresa Clausi, Maria Carmela Ferrante, G. Mattace Raso, Giuseppina Autore, Giuseppe Bianco, Anna Iacono, Emanuela Esposito, Ferrante, MARIA CARMELA, MATTACE RASO, Giuseppina, Esposito, E., Bianco, G., Iacono, A., Clausi, M. T., Amero, Paola, Santoro, Anna, Simeoli, Raffaele, Autore, G., and Meli, Rosaria
- Subjects
Programmed cell death ,Macrophage ,Cell Survival ,Apoptosis ,DNA Fragmentation ,Toxicology ,Cell Line ,Polychlorinated biphenyl ,chemistry.chemical_compound ,Mice ,Animals ,Viability assay ,Glyceraldehyde 3-phosphate dehydrogenase ,bcl-2-Associated X Protein ,biology ,Caspase 3 ,Macrophages ,food and beverages ,General Medicine ,Polychlorinated Biphenyls ,Cell biology ,chemistry ,Proto-Oncogene Proteins c-bcl-2 ,Cell culture ,Toxicity ,Immunology ,biology.protein ,DNA fragmentation ,Environmental Pollutants - Abstract
Non-dioxin-like polychlorinated biphenyls (PCBs) are stable and lipophilic chemicals that persist in the environment and tend to bioaccumulate in the food chains. In the present study, we have investigated the effect of PCBs 101, 153, and 180 on macrophage J774A.1 by assessing cell viability and apoptotic cell death. We have combined morphological techniques and biochemical ones to establish the relevance of apoptosis in macrophage cell death induced by PCBs, alone or in combination. Treatment with the examined PCBs caused the loss of cell viability and accelerated apoptosis in a concentration-dependent manner. Moreover, a synergistic effect on cell death and apoptosis was evidenced for all PCBs at concentrations which were inactive alone. The apoptosis induced by PCBs involved the increase of caspase-3 activity. Also, Bcl-2 and Bax proteins were assessed to elucidate the apoptosis machinery induced in macrophage cultures by PCBs. Our results indicate that the increase in PCB-induced apoptosis correlates with a reduction in the expression of antiapoptotic Bcl-2 and an increase in the expression of proapoptotic Bax. Interestingly, concentrations of PCBs inactive by themselves induce apoptosis when PCBs are combined. In conclusion, our findings suggest that, although less toxic than dioxin like congeners, the examined non-dioxin-like PCBs are equally dangerous as immunotoxic pollutants, also considering their presence as mixtures at higher levels than dioxin-like PCBs in biotic and abiotic matrices. © 2011 Elsevier Ireland Ltd.
- Published
- 2011
44. Abstract 4196: An RNA aptamer-based approach for human glioma treatment
- Author
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Gerolama Condorelli, Vittorio de Franciscis, Gennaro De Vita, Silvia Catuogno, Anna Rienzo, Paola Amero, Laura Cerchia, Carla Lucia Esposito, and Simona Camorani
- Subjects
Cancer Research ,biology ,Aptamer ,RNA ,Cancer ,medicine.disease ,Bioinformatics ,Receptor tyrosine kinase ,Oncology ,In vivo ,Glioma ,Cancer cell ,Gene expression ,medicine ,biology.protein ,Cancer research - Abstract
Gliomas are the most common primary central nervous system tumors with a dismal prognosis. Despite recent advances in surgery, radiotherapy, and chemotherapy, current treatment regimens have a modest survival benefit. Due to a combination of its complex phenotype and organ-specific clinical manifestations, efforts to refine glioma treatment with targeted therapies have largely been frustrated. Hence, finding specific ligands capable of detecting and measuring the altered pattern of gene expression and to discriminate between different tumor phenotypes, is a strategic and plausible objective for the diagnosis and therapy of glioma. To date, antibody-based approaches have been developed for in vivo applications but, in most cases, they show toxicity in vivo and do not reach adequate sensitivity. Thanks to their unique characteristics (low size, good affinity for the target, no immunogenicity, chemical structures that can be easily modified to improve their in vivo applications), single-stranded nucleic acid ligand molecules, named aptamers, represent a valid alternative to antibodies for in vivo targeted recognition as therapeutics or delivery agents for nanoparticles, small interfering RNAs, chemotherapeutic cargos and molecular imaging probes. By applying cell-SELEX on cancer cells we have generated and characterized different nuclease resistant 2′fluoro-pyrimidines RNA aptamers as high affinity ligands and inhibitors of human receptor tyrosine kinases (RTKs) with a crucial role in glioma, including EGFR, EGFRVIII, EphB3, Axl and PDGFRβ. All the aptamers are able to efficiently and specifically inhibit tumor growth in cell based assays and in animal models of human glioma. Further, some of these aptamers strongly cooperates in inducing inhibition of tumor growth thus providing the basis for further development of antitumor combination therapies. Citation Format: Simona Camorani, Carla L. Esposito, Silvia Catuogno, Paola Amero, Anna Rienzo, Gennaro De Vita, Gerolama Condorelli, Vittorio de Franciscis, Laura Cerchia. An RNA aptamer-based approach for human glioma treatment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4196. doi:10.1158/1538-7445.AM2014-4196
- Published
- 2014
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