scholarly journals Efficacy of a Three Drug-Based Therapy for Neuroblastoma in Mice

2021 ◽  
Vol 22 (13) ◽  
pp. 6753
Author(s):  
Patrizia Garbati ◽  
Raffaella Barbieri ◽  
Matilde Calderoni ◽  
Francesca Baldini ◽  
Mario Nizzari ◽  
...  
Keyword(s):  
Early Childhood ◽  
Multidrug Resistance ◽  
High Risk ◽  
Therapeutic Approaches ◽  
Pharmacological Approach ◽  
New Therapeutic Approaches ◽  
Cancer Types ◽  
Approved Drugs ◽  
Chemotherapy Efficacy ◽  
Fda Approved Drugs

High-risk neuroblastoma (HR-NB) still remains the most dangerous tumor in early childhood. For this reason, the identification of new therapeutic approaches is of fundamental importance. Recently, we combined the conventional pharmacological approach to NB, represented by cisplatin, with fendiline hydrochloride, an inhibitor of several transporters involved in multidrug resistance of cancer cells, which demonstrated an enhancement of the ability of cisplatin to induce apoptosis. In this work, we co-administrated acetazolamide, a carbonic anhydrase isoform IX (CAIX) inhibitor which was reported to increase chemotherapy efficacy in various cancer types, to the cisplatin/fendiline approach in SKNBE2 xenografts in NOD-SCID mice with the aim of identifying a novel and more effective treatment. We observed that the combination of the three drugs increases more than twelvefold the differences in the cytotoxic activity of cisplatin alone, leading to a remarkable decrease of the expression of malignancy markers. Our conclusion is that this approach, based on three FDA-approved drugs, may constitute an appropriate improvement of the pharmacological approach to HR-NB.

scholarly journals The landscape of long noncoding RNA-involved and tumor-specific fusions across various cancers

2020 ◽  
Vol 48 (22) ◽  
pp. 12618-12631
Author(s):  
Mengbiao Guo ◽  
Zhen-Dong Xiao ◽  
Zhiming Dai ◽  
Ling Zhu ◽  
Hang Lei ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Chimeric Proteins ◽  
Protein Coding ◽  
Cellular Processes ◽  
Cancer Types ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Somatic Copy Number Alterations

Abstract The majority of the human genome encodes long noncoding RNA (lncRNA) genes, critical regulators of various cellular processes, which largely outnumber protein-coding genes. However, lncRNA-involved fusions have not been surveyed and characterized yet. Here, we present a systematic study of the lncRNA fusion landscape across cancer types and identify >30 000 high-confidence tumor-specific lncRNA fusions (using 8284 tumor and 6946 normal samples). Fusions positively correlated with DNA damage and cancer stemness and were specifically low in microsatellite instable (MSI)-High or virus-infected tumors. Moreover, fusions distribute differently among cancer molecular subtypes, but with shared enrichment in tumors that are microsatellite stable (MSS), with high somatic copy number alterations (SCNA), and with poor survival. Importantly, we find a potentially new mechanism, mediated by enhancer RNAs (eRNA), which generates secondary fusions that form densely connected fusion networks with many fusion hubs targeted by FDA-approved drugs. Finally, we experimentally validate functions of two tumor-promoting chimeric proteins derived from mRNA-lncRNA fusions, KDM4B–G039927 and EPS15L1–lncOR7C2–1. The EPS15L1 fusion protein may regulate (Gasdermin E) GSDME, critical in pyroptosis and anti-tumor immunity. Our study completes the fusion landscape in cancers, sheds light on fusion mechanisms, and enriches lncRNA functions in tumorigenesis and cancer progression.

scholarly journals What does a non-response to induction chemotherapy imply in high-risk medulloblastomas?

2021 ◽  
Author(s):  
Jihane Adelon ◽  
Christelle Dufour ◽  
Stéphanie Foulon ◽  
Julien Masliah Planchon ◽  
David Meyronnet ◽  
...  
Keyword(s):  
High Risk ◽  
Induction Chemotherapy ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Therapeutic Approaches ◽  
Post Induction ◽  
New Therapeutic Approaches ◽  
Molecular Group ◽  
Group 3 ◽  
Chemotherapy Patients

Abstract Purpose. Some high-risk medulloblastomas (HR-MB) do not respond to induction chemotherapy, with either post-induction stable (SD) or progressive disease (PD). To date, there is no consensus regarding their optimal management. Methods. A retrospective, multicentre study of non-responder HR-MB patients treated according to the PNET HR+5 protocol (NCT00936156) between 01/01/2009 and 31/12/2018. After two courses of etoposide and carboplatin induction chemotherapy, patients with SD or PD were analyzed. Based on the clinician’s decision, the PNET HR+5 protocol was either pursued with tandem high-dose chemotherapy (HDCT) and craniospinal irradiation (CSI) (continuation group) or it was modified (switched group). Results. Forty-nine patients were identified. After induction, 37 patients had SD and 12 had PD. The outcomes were significantly better for the SD group: the 5-y PFS and OS were 52% (95% confidence interval [95% CI] 35-67) and 70% (95% CI 51-83), respectively, in the SD group and 17% (95% CI 3-41) and 13% (95% CI 1-40), respectively, in the PD group (p < 0.0001). The PNET HR+5 strategy was pursued for 3 patients in the PD group, of whom only one survived. In the SD group, it was pursued for 24 patients. The 5-y PFS and the OS were 78% (95% CI 54-90) in the continuation group and 0% and 56% (95% CI 23-79), respectively, in the switched group. In the SD group, multivariate analysis revealed that MYC amplification, molecular group 3, and a switched strategy were independent prognostic factors for progression. Conclusion. Patients with post-induction SD may benefit from HDCT and CSI, whereas improvement of the way patients with early PD are treated will require new therapeutic approaches.

scholarly journals Epigenetic Regulation in Melanoma: Facts and Hopes

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2048
Author(s):  
Emilio Francesco Giunta ◽  
Gianluca Arrichiello ◽  
Marcello Curvietto ◽  
Annalisa Pappalardo ◽  
Davide Bosso ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Methylation Status ◽  
Survival Rates ◽  
Therapeutic Approaches ◽  
New Therapeutic Approaches ◽  
Cancer Initiation ◽  
Advanced Stages ◽  
Melanoma Patients ◽  
Mapk Inhibitors ◽  
Approved Drugs

Cutaneous melanoma is a lethal disease, even when diagnosed in advanced stages. Although recent progress in biology and treatment has dramatically improved survival rates, new therapeutic approaches are still needed. Deregulation of epigenetics, which mainly controls DNA methylation status and chromatin remodeling, is implied not only in cancer initiation and progression, but also in resistance to antitumor drugs. Epigenetics in melanoma has been studied recently in both melanoma preclinical models and patient samples, highlighting its potential role in different phases of melanomagenesis, as well as in resistance to approved drugs such as immune checkpoint inhibitors and MAPK inhibitors. This review summarizes what is currently known about epigenetics in melanoma and dwells on the recognized and potential new targets for testing epigenetic drugs, alone or together with other agents, in advanced melanoma patients.

scholarly journals Application of the antitussive agents oxelaidin and butamirate as anti-glioma agents

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sook-Ja Lee ◽  
Seon-Yong Yeom ◽  
Jee-Young Lee ◽  
Chaehwa Park
Keyword(s):  
High Throughput Screening ◽  
Intraperitoneal Administration ◽  
Docking Simulation ◽  
Signaling Cascades ◽  
Toxic Agents ◽  
Ras Family ◽  
Cancer Types ◽  
Approved Drugs ◽  
Antitussive Agents ◽  
Fda Approved Drugs

AbstractGlioblastoma (GBM) is an aggressive brain tumor with a strong tendency of relapse and resistance to chemotherapy, but we currently lack non-toxic agents that effectively treat GBM. In this study, high-throughput screening of FDA-approved drugs was performed to identify safe and effective molecules and test their effect on GBM cell lines, LN229, U87 and T98G. Cough suppressants, oxelaidin and butamirate inhibited GBM growth. A Ras family GTPase, Ras-related associated with diabetes (RRAD), contributes to activation of STAT3, which is essential for survival and growth of many cancer types. Interestingly, oxelaidin and butamirate did not affect proliferation in RRAD negative GBM cells. Docking simulation analyses revealed selective interactions between oxelaidin and RRAD. The mechanism by which butamirate and oxelaidin inhibits GBM cell growth involves the suppression of STAT3 transcriptional activity, leading to down-regulation of cyclin D1 and survivin. In addition, components of RRAD-associated signaling cascades, including p-EGFR, p-Akt, and p-STAT3, were inhibited upon oxelaidin treatment. Intraperitoneal administration of oxelaidin or butamirate markedly suppressed tumor growth in a glioblastoma xenograft mouse model without significant adverse effects. Our collective findings indicate that oxelaidin and butamirate exert anti-tumor effects in glioblastoma, supporting its utility as a novel therapeutic candidate for glioblastoma.

scholarly journals Glycan Mimetics from Natural Products: New Therapeutic Opportunities for Neurodegenerative Disease

Molecules ◽  
2019 ◽  
Vol 24 (24) ◽  
pp. 4604
Author(s):  
Wenyue Wang ◽  
Sandeep Gopal ◽  
Roger Pocock ◽  
Zhicheng Xiao
Keyword(s):  
Multiple Sclerosis ◽  
Natural Products ◽  
Therapeutic Approaches ◽  
Daily Lives ◽  
New Therapeutic Approaches ◽  
Prevention And Treatment ◽  
Cellular Recognition ◽  
Approved Drugs ◽  
Lateral Sclerosis ◽  
Carbohydrate Chains

Neurodegenerative diseases (NDs) affect millions of people worldwide. Characterized by the functional loss and death of neurons, NDs lead to symptoms (dementia and seizures) that affect the daily lives of patients. In spite of extensive research into NDs, the number of approved drugs for their treatment remains limited. There is therefore an urgent need to develop new approaches for the prevention and treatment of NDs. Glycans (carbohydrate chains) are ubiquitous, abundant, and structural complex natural biopolymers. Glycans often covalently attach to proteins and lipids to regulate cellular recognition, adhesion, and signaling. The importance of glycans in both the developing and mature nervous system is well characterized. Moreover, glycan dysregulation has been observed in NDs such as Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). Therefore, glycans are promising but underexploited therapeutic targets. In this review, we summarize the current understanding of glycans in NDs. We also discuss a number of natural products that functionally mimic glycans to protect neurons, which therefore represent promising new therapeutic approaches for patients with NDs.

scholarly journals Repurposing dextromethorphan and metformin for treating nicotine-induced cancer by directly targeting CHRNA7 to inhibit JAK2/STAT3/SOX2 signaling

Oncogene ◽  
2021 ◽  
Author(s):  
Lu Wang ◽  
Du Liang ◽  
Xiao Xiong ◽  
Yusheng Lin ◽  
Jianlin Zhu ◽  
...  
Keyword(s):  
Cholinergic Receptor ◽  
Dna Hypomethylation ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Related Risk ◽  
Cancer Types ◽  
Alpha 7 ◽  
Promoter Dna ◽  
Approved Drugs ◽  
Fda Approved Drugs

AbstractSmoking is one of the most impactful lifestyle-related risk factors in many cancer types including esophageal squamous cell carcinoma (ESCC). As the major component of tobacco and e-cigarettes, nicotine is not only responsible for addiction to smoking but also a carcinogen. Here we report that nicotine enhances ESCC cancer malignancy and tumor-initiating capacity by interacting with cholinergic receptor nicotinic alpha 7 subunit (CHRNA7) and subsequently activating the JAK2/STAT3 signaling pathway. We found that aberrant CHRNA7 expression can serve as an independent prognostic factor for ESCC patients. In multiple ESCC mouse models, dextromethorphan and metformin synergistically repressed nicotine-enhanced cancer-initiating cells (CIC) properties and inhibited ESCC progression. Mechanistically, dextromethorphan non-competitively inhibited nicotine binding to CHRNA7 while metformin downregulated CHRNA7 expression by antagonizing nicotine-induced promoter DNA hypomethylation of CHRNA7. Since dextromethorphan and metformin are two safe FDA-approved drugs with minimal undesirable side-effects, the combination of these drugs has a high potential as either a preventive and/or a therapeutic strategy against nicotine-promoted ESCC and perhaps other nicotine-sensitive cancer types as well.

scholarly journals The controversial role of ABC transporters in clinical oncology

2011 ◽  
Vol 50 ◽  
pp. 209-232 ◽  
Author(s):  
Akina Tamaki ◽  
Caterina Ierano ◽  
Gergely Szakacs ◽  
Robert W. Robey ◽  
Susan E. Bates
Keyword(s):  
Multidrug Resistance ◽  
Abc Transporters ◽  
Clinical Intervention ◽  
Cancer Resistance ◽  
P Glycoprotein ◽  
Cancer Types ◽  
Resistance Protein ◽  
Chemotherapy Efficacy ◽  
Transporter Expression

The phenomenon of multidrug resistance in cancer is often associated with the overexpression of the ABC (ATP-binding cassette) transporters Pgp (P-glycoprotein) (ABCB1), MRP1 (multidrug resistance-associated protein 1) (ABCC1) and ABCG2 [BCRP (breast cancer resistance protein)]. Since the discovery of Pgp over 35 years ago, studies have convincingly linked ABC transporter expression to poor outcome in several cancer types, leading to the development of transporter inhibitors. Three generations of inhibitors later, we are still no closer to validating the ‘Pgp hypothesis’, the idea that increased chemotherapy efficacy can be achieved by inhibition of transporter-mediated efflux. In this chapter, we highlight the difficulties and past failures encountered in the development of clinical inhibitors of ABC transporters. We discuss the challenges that remain in our effort to exploit decades of work on ABC transporters in oncology. In learning from past mistakes, it is hoped that ABC transporters can be developed as targets for clinical intervention.

scholarly journals The Macrophages-Microbiota Interplay in Colorectal Cancer (CRC)-Related Inflammation: Prognostic and Therapeutic Significance

2020 ◽  
Vol 21 (18) ◽  
pp. 6866
Author(s):  
Silvia Mola ◽  
Chiara Pandolfo ◽  
Antonio Sica ◽  
Chiara Porta
Keyword(s):  
Colorectal Cancer ◽  
Tumor Development ◽  
Prognostic Indicators ◽  
Functional Heterogeneity ◽  
Therapeutic Approaches ◽  
Effector Cells ◽  
New Therapeutic Approaches ◽  
Cancer Types ◽  
Macrophage Subtypes ◽  
Main Population

Tumor-associated macrophages (TAMs) are the main population of myeloid cells infiltrating solid tumors and the pivotal orchestrators of cancer-promoting inflammation. However, due to their exceptional plasticity, macrophages can be also key effector cells and powerful activators of adaptive anti-tumor immunity. This functional heterogeneity is emerging in human tumors, colorectal cancer (CRC) in particular, where the dynamic co-existence of different macrophage subtypes influences tumor development, outcome, and response to therapies. Intestinal macrophages are in close interaction with enteric microbiota, which contributes to carcinogenesis and affects treatment outcomes. This interplay may be particularly relevant in CRC, one of the most prevalent and lethal cancer types in the world. Therefore, both macrophages and intestinal microbiota are considered promising prognostic indicators and valuable targets for new therapeutic approaches. Here, we discuss the current understanding of the molecular circuits underlying the interplay between macrophages and microbiota in CRC development, progression, and response to both conventional therapies and immunotherapies.

scholarly journals Crosstalk between the Tumor Microenvironment and Immune System in Pancreatic Ductal Adenocarcinoma: Potential Targets for New Therapeutic Approaches

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Paola Parente ◽  
Pietro Parcesepe ◽  
Claudia Covelli ◽  
Nunzio Olivieri ◽  
Andrea Remo ◽  
...  
Keyword(s):  
Immune System ◽  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Pancreatic Tumor ◽  
Ductal Adenocarcinoma ◽  
Tumor Aggressiveness ◽  
Therapeutic Approaches ◽  
New Therapeutic Approaches ◽  
Chemotherapy Efficacy ◽  
Qualitative Literature

Pancreatic ductal adenocarcinoma is a lethal disease for which radical surgery and chemotherapy represent the only curative options for a small proportion of patients. Recently, FOLFIRINOX and nab-paclitaxel plus gemcitabine have improved the survival of metastatic patients but prognosis remains poor. A pancreatic tumor microenvironment is a dynamic milieu of cellular and acellular elements, and it represents one of the major limitations to chemotherapy efficacy. The continued crosstalk between cancer cells and the surrounding microenvironment causes immunosuppression within pancreatic immune infiltrate increasing tumor aggressiveness. Several potential targets have been identified among tumor microenvironment components, and different therapeutic approaches are under investigation. In this article, we provide a qualitative literature review about the crosstalk between the tumor microenvironment components and immune system in pancreatic cancer. Finally, we discuss potential therapeutic strategies targeting the tumor microenvironment and we show the ongoing trials.

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