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 Immune Checkpoint Inhibitors in Epithelial Ovarian Cancer: An Overview on Efficacy and Future Perspectives

Diagnostics ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 146 ◽  
Author(s):  
Fulvio Borella ◽  
Eleonora Ghisoni ◽  
Gaia Giannone ◽  
Stefano Cosma ◽  
Chiara Benedetto ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Therapeutic Approaches ◽  
Medical Treatments ◽  
New Therapeutic Approaches ◽  
Early Phase Trials ◽  
Improve Patient

Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological cancers. Despite improvements in medical treatments, the prognosis for EOC remains poor, and there is an urgent need for new therapeutic strategies. Immune checkpoint inhibitors (CPIs) have dramatically improved survival of several cancers and are under evaluation in OC. Unfortunately, CPIs have shown globally unsatisfactory results. The aim of this manuscript is to critically review the results from early-phase trials with CPIs in terms of safety and activity, discuss the possible reasons for disappointing results and the new therapeutic approaches to improve patient outcomes.

scholarly journals Treatment of Advanced Metastatic Melanoma

2021 ◽  
pp. 2021164S
Author(s):  
Pietro Quaglino ◽  
Paolo Fava ◽  
Luca Tonella ◽  
Marco Rubatto ◽  
Simone Ribero ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Targeted Therapies ◽  
Checkpoint Inhibitors ◽  
Performance Status ◽  
Survival Rates ◽  
National Health System ◽  
Stage Iv ◽  
Daily Practice ◽  
Long Term Results ◽  
Melanoma Patients

The introduction in clinical practice of new drug compounds both targeted therapies anti-BRAF and checkpoint inhibitors have largely improved our potential to manage advanced metastatic melanoma patients. This has led to a significant improvement in terms of response rates and particularly in the overall survival (OS). The long-term results of trials with follow-up data of patients treated with targeted or immunotherapies reported median OS rates around 24 months, with 5-year survival rates around 35-40%. As to the drugs currently available and reimbursed by the Italian National Health System, 3 combinations of anti-BRAF/anti-MEK inhibitors are available (dabrafenib/trametinib, vemurafenib/cobimetinib and the most recently introduced encorafenib/binimetinib). As for checkpoint inhibitors, first line immunotherapy is represented by anti-PD1 blockers (nivolumab and pembrolizumab), whilst the anti-CTLA-4 ipilimumab can be used as second line immunotherapy. The decision-making factors that define the best treatment approach in stage IV patients with metastatic melanoma include the mutation pattern, performance status, high/low tumor load, brain metastases, progression pattern (low/fast), and availability of clinical trials. This review will analyze the current therapeutic tools adopted for the treatment of metastatic melanoma patients. It will then focus on the latest results obtained by novel treatments (checkpoint inhibitors and targeted therapies) which can be used in the clinical daily practice.

scholarly journals Enhancing Therapeutic Approaches for Melanoma Patients Targeting Epigenetic Modifiers

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6180
Author(s):  
Maria Gracia-Hernandez ◽  
Zuleima Munoz ◽  
Alejandro Villagra
Keyword(s):  
Targeted Therapies ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Epigenetic Alterations ◽  
Therapeutic Approaches ◽  
Extrinsic Factors ◽  
Epigenetic Drugs ◽  
Epigenetic Modifiers ◽  
Melanoma Patients

Melanoma is the least common but deadliest type of skin cancer. Melanomagenesis is driven by a series of mutations and epigenetic alterations in oncogenes and tumor suppressor genes that allow melanomas to grow, evolve, and metastasize. Epigenetic alterations can also lead to immune evasion and development of resistance to therapies. Although the standard of care for melanoma patients includes surgery, targeted therapies, and immune checkpoint blockade, other therapeutic approaches like radiation therapy, chemotherapy, and immune cell-based therapies are used for patients with advanced disease or unresponsive to the conventional first-line therapies. Targeted therapies such as the use of BRAF and MEK inhibitors and immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA4 only improve the survival of a small subset of patients. Thus, there is an urgent need to identify alternative standalone or combinatorial therapies. Epigenetic modifiers have gained attention as therapeutic targets as they modulate multiple cellular and immune-related processes. Due to melanoma’s susceptibility to extrinsic factors and reversible nature, epigenetic drugs are investigated as a therapeutic avenue and as adjuvants for targeted therapies and immune checkpoint inhibitors, as they can sensitize and/or reverse resistance to these therapies, thus enhancing their therapeutic efficacy. This review gives an overview of the role of epigenetic changes in melanoma progression and resistance. In addition, we evaluate the latest advances in preclinical and clinical research studying combinatorial therapies and discuss the use of epigenetic drugs such as HDAC and DNMT inhibitors as potential adjuvants for melanoma patients.

scholarly journals Current Therapeutic Strategies in BRAF-Mutant Metastatic Colorectal Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Elisa Grassi ◽  
Jody Corbelli ◽  
Giorgio Papiani ◽  
Maria Aurelia Barbera ◽  
Federica Gazzaneo ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Strong Association ◽  
Standard Of Care ◽  
Therapeutic Approaches ◽  
Treatment Optimization ◽  
New Therapeutic Approaches ◽  
Poorly Differentiated ◽  
Colon Rectal Cancer ◽  
Mutation Braf ◽  
Braf Mutant

Around 8–12% of patients with advanced colon rectal cancer (CRC) present with BRAF alterations, in particular V600E mutation, which is associated with right-side, poorly differentiated and mucinous type tumors. The presence of BRAF mutation (BRAF-mt) has been identified as a hallmark of poor prognosis and treatment optimization in this patient subgroup is an important goal. Currently, the standard of care is an aggressive strategy involving triplet chemotherapy and anti-VEGF agents, but new therapeutic approaches are emerging. Very promising results have been obtained with targeted therapy combinations, such as anti-BRAF agents plus anti-EGFR agents. Furthermore, around 60% of BRAF-mt patients show a strong association with high microsatellite instability (MSI-H) and immune checkpoint inhibitors could represent the new standard of care for this subgroup. The focus of this review is to summarize current strategies for BRAF-mt CRC treatment and highlight new therapeutic options.

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 Combined targeted therapy and immunotherapy in melanoma: a review of the impact on the tumor microenvironment and outcomes of early clinical trials

2019 ◽  
Vol 11 ◽  
pp. 175883591983082 ◽  
Author(s):  
Meredith S. Pelster ◽  
Rodabe N. Amaria
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Tumor Microenvironment ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarker ◽  
Therapeutic Approaches ◽  
T Cell Infiltration ◽  
Melanoma Patients ◽  
The Impact ◽  
Preclinical Work

The development of BRAF and MEK inhibitors (BRAFis and MEKis) and immune checkpoint inhibitors have changed the management of advanced stage melanoma and improved the outcomes of patients with this malignancy. However, both therapeutic approaches have limitations, including a limited duration of benefit in subsets of BRAF-mutant melanoma patients treated with targeted therapy and a lower overall response rate without a clear predictive biomarker in patients treated with checkpoint inhibitors. Preclinical and translational data have shown that BRAFis and MEKis alter the tumor microenvironment to make it more amenable to immunotherapy and have provided the scientific rationale for combing BRAFis and MEKis with immunotherapy. In this review, the initial studies demonstrating the impact of BRAFis and MEKis on the expression of melanoma differentiation antigens, T-cell infiltration, and the balance of immune stimulatory and immune suppressive cells and cytokines are addressed. Preclinical work on the combination of targeted therapy with BRAFis and MEKis with immunotherapy are reviewed, highlighting improved tumor responses in mouse models of BRAF-mutated melanoma treated with combinatorial strategies. Lastly, data from early clinical trials of combined targeted therapy and immunotherapy are discussed, focusing on response rates and toxicities.

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 Major Histocompatibility Complex Class I-Related Chain A (MICA) Allelic Variants Associate With Susceptibility and Prognosis of Gastric Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Karen Toledo-Stuardo ◽  
Carolina H. Ribeiro ◽  
Andrea Canals ◽  
Marcela Morales ◽  
Valentina Gárate ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tandem Repeats ◽  
Protein A ◽  
Survival Rates ◽  
Therapeutic Approaches ◽  
New Therapeutic Approaches ◽  
Histocompatibility Complex ◽  
Increased Risk ◽  
Early Tumor ◽  
Protein Variants

Gastric cancer (GC) is the fifth most prevalent type of cancer worldwide. Gastric tumor cells express MICA protein, a ligand to NKG2D receptor that triggers natural killer (NK) cells effector functions for early tumor elimination. MICA gene is highly polymorphic, thus originating alleles that encode protein variants with a controversial role in cancer. The main goal of this work was to study MICA gene polymorphisms and their relationship with the susceptibility and prognosis of GC. Fifty patients with GC and 50 healthy volunteers were included in this study. MICA alleles were identified using Sanger sequencing methods. The analysis of MICA gene sequence revealed 13 MICA sequences and 5 MICA-short tandem repeats (STR) alleles in the studied cohorts We identified MICA*002 (*A9) as the most frequent allele in both, patients and controls, followed by MICA*008 allele (*A5.1). MICA*009/049 allele was significantly associated with increased risk of GC (OR: 5.11 [95% CI: 1.39–18.74], p = 0.014). The analysis of MICA-STR alleles revealed a higher frequency of MICA*A5 in healthy individuals than GC patients (OR = 0.34 [95% CI: 0.12–0.98], p = 0.046). Survival analysis after gastrectomy showed that patients with MICA*002/002 or MICA*002/004 alleles had significantly higher survival rates than those patients bearing MICA*002/008 (p = 0.014) or MICA*002/009 (MICA*002/049) alleles (p = 0.040). The presence of threonine in the position MICA-181 (MICA*009/049 allele) was more frequent in GC patients than controls (p = 0.023). Molecular analysis of MICA-181 showed that the presence of threonine provides greater mobility to the protein than arginine in the same position (MICA*004), which could explain, at least in part, some immune evasion mechanisms developed by the tumor. In conclusion, our findings suggest that the study of MICA alleles is crucial to search for new therapeutic approaches and may be useful for the evaluation of risk and prognosis of GC and personalized therapy.

New therapeutic approaches for polymyositis and dermatomyositis

2011 ◽  
Vol 152 (39) ◽  
pp. 1552-1559 ◽  
Author(s):  
Katalin Dankó ◽  
Melinda Vincze
Keyword(s):  
Immunosuppressive Agents ◽  
Inflammatory Myopathy ◽  
Proximal Muscle ◽  
Therapeutic Approaches ◽  
First Line ◽  
New Therapeutic Approaches ◽  
Remission Period ◽  
Immune Mediated ◽  
Systemic Manifestations ◽  
Line Of Therapy

Inflammatory myopathies are chronic, immune-mediated diseases characterized with progressive proximal muscle weakness. They encompass a variety of syndromes with protean manifestations. The aims of therapy are to increase muscle strength, prevent the development of contractures, and to manage the systemic manifestations of the disease. This is a complex treatment which requires routine and wide knowledge. The most important task is to recognize the disease and guide the patient to immunologic center. Although the first line of therapy continues to include corticosteroids, there are a multitude of agents available for treating patients with myositis. There are several different immunosuppressive agents which may be applied alone or in combination with each other, as well as an increasing number of novel and exciting biologic agents targeting molecules participating in the pathogenesis of inflammatory myopathy. Physiotherapy and rehabilitation in the remission period may significantly improve the functional outcome of patients with these disorders. Orv. Hetil., 2011, 152, 1552–1559.

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