Epigenetic Reprogramming for Targeting IDH-Mutant Malignant Gliomas

Targeting the epigenome has been considered a compelling treatment modality for several cancers, including gliomas. Nearly 80% of the lower-grade gliomas and secondary glioblastomas harbor recurrent mutations in isocitrate dehydrogenase (IDH). Mutant IDH generates high levels of 2-hydroxyglutarate (2-HG) that inhibit various components of the epigenetic machinery, including histone and DNA demethylases. The encouraging results from current epigenetic therapies in hematological malignancies have reinvigorated the interest in solid tumors and gliomas, both preclinically and clinically. Here, we summarize the recent advancements in epigenetic therapy for lower-grade gliomas and discuss the challenges associated with current treatment options. A particular focus is placed on therapeutic mechanisms underlying favorable outcome with epigenetic-based drugs in basic and translational research of gliomas. This review also highlights emerging bridges to combination treatment with respect to epigenetic drugs. Given that epigenetic therapies, particularly DNA methylation inhibitors, increase tumor immunogenicity and antitumor immune responses, appropriate drug combinations with immune checkpoint inhibitors may lead to improvement of treatment effectiveness of immunotherapy, ultimately leading to tumor cell eradication.

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The Evolutionary Landscape of Treatment for BRAFV600E Mutant Metastatic Colorectal Cancer

Cancers ◽

10.3390/cancers13010137 ◽

2021 ◽

Vol 13 (1) ◽

pp. 137

Author(s):

Gianluca Mauri ◽

Erica Bonazzina ◽

Alessio Amatu ◽

Federica Tosi ◽

Katia Bencardino ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Checkpoint Inhibitors ◽

Mapk Pathway ◽

Treatment Options ◽

Braf Inhibitor ◽

Current Treatment ◽

Cytotoxic Chemotherapy ◽

Cytotoxic Agents ◽

Poor Prognostic Factor

The BRAFV600E mutation is found in 8–10% of metastatic colorectal cancer (mCRC) patients and it is recognized as a poor prognostic factor with a median overall survival inferior to 20 months. At present, besides immune checkpoint inhibitors (CPIs) for those tumors with concomitant MSI-H status, recommended treatment options include cytotoxic chemotherapy + anti-VEGF in the first line setting, and a combination of EGFR and a BRAF inhibitor (cetuximab plus encorafenib) in second line. However, even with the latter targeted approach, acquired resistance limits the possibility of more than an incremental benefit and survival is still dismal. In this review, we discuss current treatment options for this subset of patients and perform a systematic review of ongoing clinical trials. Overall, we identified six emerging strategies: targeting MAPK pathway (monotherapy or combinations), targeting MAPK pathway combined with cytotoxic agents, intensive cytotoxic regimen combinations, targeted agents combined with CPIs, oxidative stress induction, and cytotoxic agents combined with antiangiogenic drugs and CPIs. In the future, the integration of new therapeutic strategies targeting key players in the BRAFV600E oncogenic pathways with current treatment approach based on cytotoxic chemotherapy and surgery is likely to redefine the treatment landscape of these CRC patients.

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Malignant Melanoma of the Gastrointestinal Tract: Symptoms, Diagnosis, and Current Treatment Options

Cells ◽

10.3390/cells10020327 ◽

2021 ◽

Vol 10 (2) ◽

pp. 327

Author(s):

Darina Kohoutova ◽

Dominic Worku ◽

Hala Aziz ◽

Julian Teare ◽

Justin Weir ◽

...

Keyword(s):

Overall Survival ◽

Malignant Melanoma ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Symptom Control ◽

Current Treatment ◽

Gi Tract ◽

Systemic Treatments ◽

Precise Diagnosis ◽

The Uk

Malignant melanoma (MM) has become the fifth most frequent cancer in the UK. It is the most common carcinoma to metastasize to the gastrointestinal (GI) tract. MM particularly has an affinity to spread to the small bowel, which is followed by the involvement of the stomach and large intestine. Excellent endoscopic options including video capsule endoscopy and enteroscopy are available for a precise diagnosis of GI involvement by a metastatic MM. The complete surgical resection of GI metastatic MM in carefully selected patients not only provides symptom control, but has also been associated with an increase in overall survival. The approval of BRAF-targeted therapies and immune checkpoint inhibitors has transformed therapeutic approaches for patients with metastatic MM over the past decade. Currently, the overall survival of patients with advanced metastatic MM who have been treated with a combination of immunotherapeutic agents reaches 52% at five years. The role of surgery for patients with the metastatic involvement of the GI tract with MM is evolving in the era of effective systemic treatments.

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Checkpoint Inhibitor-Induced Colitis—A Clinical Overview of Incidence, Prognostic Implications and Extension of Current Treatment Options

Pharmaceuticals ◽

10.3390/ph14040367 ◽

2021 ◽

Vol 14 (4) ◽

pp. 367

Author(s):

Carmen Portenkirchner ◽

Peter Kienle ◽

Karoline Horisberger

Keyword(s):

Checkpoint Inhibitors ◽

Treatment Options ◽

Prognostic Significance ◽

Oncological Outcome ◽

Underlying Disease ◽

Current Treatment ◽

Current Therapy ◽

Fecal Transplantation ◽

Vulnerable Patient ◽

Patient Groups

In recent years, anti-tumor immunotherapies have witnessed a major breakthrough with the emergence of immune checkpoint inhibitors (ICIs). However, the use of ICIs has also brought an era of a certain class of adverse events that differ from those of classical chemotherapies and are more reminiscent of autoimmune diseases. This article focuses exclusively on colitis as an irAE with emphasis on vulnerable patient groups, the prognostic significance of colitis, treatment, and new therapeutic approaches that may be applicable. Colitis itself is associated with a favorable oncological outcome of the underlying disease but is as well the most common irAE leading to discontinuation of therapy. Especially in vulnerable patient groups such as IBD patients and elderly patients, colitis occurs more frequently as a side effect. It is precisely in these two patient groups that side effects more often lead to discontinuation of therapy. Therefore, in addition to the current therapy of colitis through immunosuppression, the focus should also be on new forms of therapy of severe colitis, such as fecal transplantation or ileostomy creation.

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Current Systemic Treatment Options in Metastatic Urothelial Carcinoma after Progression on Checkpoint Inhibition Therapy—A Systemic Review Combined with Single-Group Meta-Analysis of Three Studies Testing Enfortumab Vedotin

Cancers ◽

10.3390/cancers13133206 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3206

Author(s):

Susanne Deininger ◽

Peter Törzsök ◽

David Oswald ◽

Lukas Lusuardi

Keyword(s):

Urothelial Carcinoma ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Treatment Options ◽

Objective Response ◽

Progression Free Survival ◽

Current Treatment ◽

Systemic Review ◽

Single Group ◽

Metastatic Urothelial Carcinoma

Background: In the first and second-line therapy of metastatic urothelial carcinoma (mUC), checkpoint inhibitors (CPI) such as Pembrolizumab and Atezolizumab have been widely implemented. Little is currently known about what therapeutic options are effective after therapy with CPI. This article presents a systemic review of current treatment options in this setting. Methods: From August 2020 to 15 April 2021, a literature search was performed through the PubMed/Medline. Subsequently, a single-group meta-analysis of three studies testing Enfortumab vedotin (EV) was conducted. Results: Five therapy regimens tested in the post-CPI setting with adequate data were identified: Chemotherapy (CT), Ramucirumab plus Docetaxel, Erdafitinib (Erd), EV, and Sacituzumab govitecan (SG). In n = 74 + 125 + 288 patients, the single-group meta-analysis showed an objective response rate of 42.1% for EV compared to 17.9% for CT in a similar setting. EV was also ahead in progression free survival (5.9 months with EV vs. 3.7 months with CT) and overall survival (12.8 months with EV vs. 9.0 months with CT). Conclusion: Most data are currently available for EV. Further research is needed on the question of which patients’ subcollectives particularly benefit from which therapeutic approach.

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Management of Acute Myeloid Leukemia: Current Treatment Options and Future Perspectives

Cancers ◽

10.3390/cancers13225722 ◽

2021 ◽

Vol 13 (22) ◽

pp. 5722

Author(s):

Maximilian Fleischmann ◽

Ulf Schnetzke ◽

Andreas Hochhaus ◽

Sebastian Scholl

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Treatment Options ◽

Treatment Strategies ◽

Current Treatment ◽

Current Status ◽

Epigenetic Therapy ◽

Comprehensive Overview ◽

Secondary Resistance ◽

Acute Myeloid

Treatment of acute myeloid leukemia (AML) has improved in recent years and several new therapeutic options have been approved. Most of them include mutation-specific approaches (e.g., gilteritinib for AML patients with activating FLT3 mutations), or are restricted to such defined AML subgroups, such as AML-MRC (AML with myeloid-related changes) or therapy-related AML (CPX-351). With this review, we aim to present a comprehensive overview of current AML therapy according to the evolved spectrum of recently approved treatment strategies. We address several aspects of combined epigenetic therapy with the BCL-2 inhibitor venetoclax and provide insight into mechanisms of resistance towards venetoclax-based regimens, and how primary or secondary resistance might be circumvented. Furthermore, a detailed overview on the current status of AML immunotherapy, describing promising concepts, is provided. This review focuses on clinically important aspects of current and future concepts of AML treatment, but will also present the molecular background of distinct targeted therapies, to understand the development and challenges of clinical trials ongoing in AML patients.

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Current Treatment Options for HCC: From Pharmacokinetics to Efficacy and Adverse Events in Liver Cirrhosis

Current Drug Metabolism ◽

10.2174/1389200221999200918141239 ◽

2020 ◽

Vol 21 (11) ◽

pp. 866-884

Author(s):

Giovanni Galati ◽

Antonio Fabio Massimo Vainieri ◽

Claudia Angela Maria Fulgenzi ◽

Stefano Di Donato ◽

Marianna Silletta ◽

...

Keyword(s):

Adverse Events ◽

Metabolic Pathways ◽

Current Knowledge ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Growth Factor Receptor ◽

Current Treatment ◽

European Medicines Agency ◽

Multikinase Inhibitor ◽

Endothelial Growth Factor

Background: Hepatocellular carcinoma (HCC) is among the world’s most common cancers. For over ten years, the only medical treatment for it has been the multikinase inhibitor Sorafenib. Currently, however, other first or second-line therapeutic options have also shown efficacy against HCC, such as multikinase inhibitors (Regorafenib, Lenvatinib, and Cabozantinib), a monoclonal antibody against the vascular endothelial growth factor receptor 2 (Ramucirumab), and immune-checkpoint inhibitors (Nivolumab, Pembrolizumab, Ipilimumab). Aim: The aim of this paper is to review the metabolic pathways of drugs that have been tested for the treatment of HCC and the potential influence of liver failure over those pathways. Methods: The Food and Drug Administration (FDA)’s and European Medicines Agency (EMA)’s datasheets, results from clinical trials and observational studies have been reviewed. Results: This review summarizes the current knowledge regarding targets, metabolic pathways, drug interactions, and adverse events of medical treatments for HCC in cirrhotic patients. Conclusions: The new scenario of systemic HCC therapy includes more active drugs with different metabolic pathways and different liver adverse events. Clinical and pharmacological studies providing more data on the safety of these molecules are urgently needed.

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Exploring the Clinical Impact of Predictive Biomarkers in Serous Ovarian Carcinomas

Current Drug Targets ◽

10.2174/1389450120666191016143836 ◽

2020 ◽

Vol 21 (10) ◽

pp. 974-995

Author(s):

Cécile Le Page ◽

Jacqueline Chung ◽

Kurosh Rahimi ◽

Martin Köbel ◽

Diane Provencher ◽

...

Keyword(s):

Treatment Effectiveness ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Survival Rates ◽

Predictive Biomarkers ◽

Molecular Characteristics ◽

Low Grade ◽

Clinical Markers ◽

Ovarian Carcinomas ◽

Kras Mutations

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Although initial response rates to standard platinum-based treatment are at 70–80%, long-term response in advanced EOC disease is rarely achieved with the development of chemoresistance and recurrence, contributing to overall survival rates below 45%. Additional challenges stem from EOC heterogeneity, reflecting at least five histological subtypes, each with different underlying molecular characteristics and clinicopathology that have significant implications in treatment effectiveness and management. Since the last decade, technologies in genomics, proteomics and pathology have been deployed to find reliable clinical markers that can identify patients sensitive to standard chemotherapy treatments and stratify patients for more suitable targeted therapies. These efforts have identified several molecular markers of prognostic value that have been validated as biomarkers, such as BRCA and KRAS mutations, or are currently under investigation in clinical trials, such as CD8 T cells, immune checkpoint inhibitors and progesterone receptor. Recent advancements in biomarker research have also revealed new targets that have expanded treatment options, introducing poly (ADP-ribose) polymerase (PARP) inhibitors, anti-angiogenic agents, inhibitors targeting signaling pathways, and immunotherapy to improve maintenance therapies or enhance first-line therapy. This review presents a summary of current biomarkers, in clinical use or under evaluation, demonstrating a potential to inform on patient selection for treatment efficacy and predict response to EOC therapies, with particular focus on the serous subtypes, including high-grade and low-grade serous carcinomas.

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An Overview of Dementias

Perspectives on Swallowing and Swallowing Disorders (Dysphagia) ◽

10.1044/sasd21.3.75 ◽

2012 ◽

Vol 21 (3) ◽

pp. 75-84

Author(s):

Venkata Vijaya K. Dalai ◽

Jason E. Childress ◽

Paul E Schulz

Keyword(s):

Clinical Presentation ◽

Treatment Options ◽

Current Treatment ◽

Great Variability ◽

Health Concern ◽

Public Health Concern ◽

Life Threatening ◽

The Common ◽

Neurodegenerative Dementias ◽

Made In

Dementia is a major public health concern that afflicts an estimated 24.3 million people worldwide. Great strides are being made in order to better diagnose, prevent, and treat these disorders. Dementia is associated with multiple complications, some of which can be life-threatening, such as dysphagia. There is great variability between dementias in terms of when dysphagia and other swallowing disorders occur. In order to prepare the reader for the other articles in this publication discussing swallowing issues in depth, the authors of this article will provide a brief overview of the prevalence, risk factors, pathogenesis, clinical presentation, diagnosis, current treatment options, and implications for eating for the common forms of neurodegenerative dementias.

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