Browse
Submit Data
Databases
API
Help

Dataset Information

10 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Novel approaches and current challenges with targeting the endocannabinoid system.

ABSTRACT:

Introduction

The pathophysiological relevance of the endocannabinoid system has been widely demonstrated in a variety of diseases including cancer, neurological disorders, and metabolic issues. Therefore, targeting the receptors and the endogenous machinery involved in this system can provide a successful therapeutic outcome. Ligands targeting the canonical cannabinoid receptors, CB₁ and CB₂, along with inhibitors of the endocannabinoid enzymes have been thoroughly studied in diverse disease models. In fact, phytocannabinoids such as cannabidiol or Δ⁹-tetrahydrocannabinol are currently on the market for the management of neuropathic pain due to spasticity in multiple sclerosis or seizures in children epilepsy amongst others.

Areas covered

Challenges in the pharmacology of cannabinoids arise from its pharmacokinetics, off-target effects, and psychoactive effects. In this context, the current review outlines the novel molecular approaches emerging in the field discussing their clinical potential.

Expert opinion

Even if orthosteric CB₁ and CB₂ ligands are on the forefront in cannabinoid clinical research, emerging strategies such as allosteric or biased modulation of these receptors along with controlled off-targets effects may increase the therapeutic potential of cannabinoids.

SUBMITTER: Morales P

PROVIDER: S-EPMC7502221 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Melanoma central nervous system metastases: current approaches, challenges, and opportunities.

Project description:Melanoma central nervous system metastases are increasing, and the challenges presented by this patient population remain complex. In December 2015, the Melanoma Research Foundation and the Wistar Institute hosted the First Summit on Melanoma Central Nervous System (CNS) Metastases in Philadelphia, Pennsylvania. Here, we provide a review of the current status of the field of melanoma brain metastasis research; identify key challenges and opportunities for improving the outcomes in patients with melanoma brain metastases; and set a framework to optimize future research in this critical area.

| S-EPMC5398760 | biostudies-literature

Vaccinomics: current findings, challenges and novel approaches for vaccine development.

Project description:Recent years have witnessed a growing interest in a field of vaccinology that we have named vaccinomics. The overall idea behind vaccinomics is to identify genetic and other mechanisms and pathways that determine immune responses, and thereby provide new candidate vaccine approaches. Considerable data show that host genetic polymorphisms act as important determinants of innate and adaptive immunity to vaccines. This review highlights examples of the role of immunogenetics and immunogenomics in understanding immune responses to vaccination, which are highly variable across the population. The influence of HLA genes, non-HLA, and innate genes in inter-individual variations in immune responses to viral vaccines are examined using population-based gene/SNP association studies. The ability to understand relationships between immune response gene variants and vaccine-specific immunity may assist in designing new vaccines. At the same time, application of state-of-the-art next-generation sequencing technology (and bioinformatics) is desired to provide new genetic information and its relationship to the immune response.

| S-EPMC3160164 | biostudies-literature

Passive Immunotherapies for Central Nervous System Disorders: Current Delivery Challenges and New Approaches.

Project description:Passive immunotherapy, i.e., the administration of exogenous antibodies that recognize a specific target antigen, has gained significant momentum as a potential treatment strategy for several central nervous system (CNS) disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and brain cancer, among others. Advances in antibody engineering to create therapeutic antibody fragments or antibody conjugates have introduced new strategies that may also be applied to treat CNS disorders. However, drug delivery to the CNS for antibodies and other macromolecules has thus far proven challenging, due in large part to the blood-brain barrier and blood-cerebrospinal fluid barriers that greatly restrict transport of peripherally administered molecules from the systemic circulation into the CNS. Here, we summarize the various passive immunotherapy approaches under study for the treatment of CNS disorders, with a primary focus on disease-specific and target site-specific challenges to drug delivery and new, cutting edge methods.

| S-EPMC7234797 | biostudies-literature

The endocannabinoid system - current implications for drug development.

Project description:In this review, the state of the art for compounds affecting the endocannabinoid (eCB) system is described with a focus on the treatment of pain. Amongst directly acting CB receptor ligands, clinical experience with ∆9 -tetrahydracannabinol and medical cannabis in chronic non-cancer pain indicates that there are differences between the benefits perceived by patients and the at best modest effect seen in meta-analyses of randomized controlled trials. The reason for this difference is not known but may involve differences in the type of patients that are recruited, the study conditions that are chosen and the degree to which biases such as reporting bias are operative. Other directly acting CB receptor ligands such as biased agonists and allosteric receptor modulators have not yet reached the clinic. Amongst indirectly acting compounds targeting the enzymes responsible for the synthesis and catabolism of the eCBs anandamide and 2-arachidonoylglycerol, fatty acid amide hydrolase (FAAH) inhibitors have been investigated clinically but were per se not useful for the treatment of pain, although they may be useful for the treatment of post-traumatic stress disorder and cannabis use disorder. Dual-acting compounds targeting this enzyme and other targets such as cyclooxygenase-2 or transient potential vanilloid receptor 1 may be a way forward for the treatment of pain.

| S-EPMC8358957 | biostudies-literature

Novel Approaches for the Treatment of Familial Hypercholesterolemia: Current Status and Future Challenges.

Project description:Familial hypercholesterolemia (FH) is an autosomal-dominant disorder that is characterized by high plasma low-density lipoprotein cholesterol (LDL-c) levels and an increased risk of cardiovascular disease. Despite the use of high-dose statins and the recent addition of proprotein convertase subtilisin/kexin type 9 inhibitors as a treatment option, many patients with homozygous FH fail to achieve optimal reductions of LDL-c levels. Gene therapy has become one of the most promising research directions for contemporary life sciences and is a potential treatment option for FH. Recent studies have confirmed the efficacy of a recombinant adeno-associated virus 8 vector expressing the human LDL-c receptor gene in a mouse model, and this vector is currently in phase 2 clinical trials. Much progress has also been achieved in the fields of antisense oligonucleotide- and small interfering RNA-based gene therapies, which are in phase 1-2 clinical trials. In addition, novel approaches, such as the use of minicircle DNA vectors, microRNAs, long non-coding RNAs, and the CRISPR/Cas9 gene-editing system, have shown great potential for FH therapy. However, the delivery system, immunogenicity, accuracy, and specificity of gene therapies limit their clinical applications. In this article, we discuss the current status of gene therapy and recent advances that will likely affect the clinical application of gene therapy for the treatment of FH.

| S-EPMC6099065 | biostudies-literature

Personal genome sequencing: current approaches and challenges.

Project description:The revolution in DNA sequencing technologies has now made it feasible to determine the genome sequences of many individuals; i.e., "personal genomes." Genome sequences of cells and tissues from both normal and disease states have been determined. Using current approaches, whole human genome sequences are not typically assembled and determined de novo, but, instead, variations relative to a reference sequence are identified. We discuss the current state of personal genome sequencing, the main steps involved in determining a genome sequence (i.e., identifying single-nucleotide polymorphisms [SNPs] and structural variations [SVs], assembling new sequences, and phasing haplotypes), and the challenges and performance metrics for evaluating the accuracy of the reconstruction. Finally, we consider the possible individual and societal benefits of personal genome sequences.

| S-EPMC2827837 | biostudies-literature

Novel approaches and challenges to treatment of central nervous system viral infections.

Project description:Existing and emerging viral central nervous system (CNS) infections are major sources of human morbidity and mortality. Treatments of proven efficacy are currently limited predominantly to herpesviruses and human immunodeficiency virus (HIV). Development of new therapies has been hampered by the lack of appropriate animal model systems for some important viruses and by the difficulty in conducting human clinical trials for diseases that may be rare, or in the case of arboviral infections, often have variable seasonal and geographic incidence. Nonetheless, many novel approaches to antiviral therapy are available, including candidate thiazolide and pyrazinecarboxamide derivatives with potential broad-spectrum antiviral efficacy. New herpesvirus drugs include viral helicase-primase and terminase inhibitors. The use of antisense oligonucleotides and other strategies to interfere with viral RNA translation has shown efficacy in experimental models of CNS viral disease. Identifying specific molecular targets within viral replication cycles has led to many existing antiviral agents and will undoubtedly continue to be the basis of future drug design. A promising new area of research involves therapies based on enhanced understanding of host antiviral immune responses. Toll-like receptor agonists and drugs that inhibit specific cytokines as well as interferon preparations have all shown potential therapeutic efficacy. Passive transfer of virus-specific cytotoxic T lymphocytes has been used in humans and may provide an effective therapy for some herpesvirus infections and potentially for progressive multifocal leukoencephalopathy. Humanized monoclonal antibodies directed against specific viral proteins have been developed and in several cases evaluated in humans in settings including West Nile virus and HIV infection and in pre-exposure prophylaxis for rabies.

| S-EPMC4052367 | biostudies-literature

Therapeutic Targeting of FLT3 in Acute Myeloid Leukemia: Current Status and Novel Approaches.

Project description:FMS-like tyrosine kinase 3 (FLT3) is mutated in approximately 30% of acute myeloid leukemia (AML) patients. The presence of FLT3-ITD (internal tandem duplication, 20-25%) mutation and, to a lesser extent, FLT3-TKD (tyrosine kinase domain, 5-10%) mutation is associated with poorer diagnosis and therapy response since the leukemic cells become hyperproliferative and resistant to apoptosis after continuous activation of FLT3 signaling. Targeting FLT3 has been the focus of many pre-clinical and clinical studies. Hence, many small-molecule FLT3 inhibitors (FLT3is) have been developed, some of which are approved such as midostaurin and gilteritinib to be used in different clinical settings, either in combination with chemotherapy or alone. However, many questions regarding the best treatment strategy remain to be answered. On the other hand, various FLT3-dependent and -independent resistance mechanisms could be evolved during FLT3i therapy which limit their clinical impact. Therefore, identifying molecular mechanisms of resistance and developing novel strategies to overcome this obstacle is a current interest in the field. In this review, recent studies of approved FLT3i and knowledge about major resistance mechanisms of clinically approved FLT3i's will be discussed together with novel treatment approaches such as designing novel FLT3i and dual FLT3i and combination strategies including approved FLT3i plus small-molecule agents targeting altered molecules in the resistant cells to abrogate resistance. Moreover, how to choose an appropriate FLT3i for the patients will be summarized based on what is currently known from available clinical data. In addition, strategies beyond FLT3i's including immunotherapeutics, small-molecule FLT3 degraders, and flavonoids will be summarized to highlight potential alternatives in FLT3-mutated AML therapy.

| S-EPMC9719701 | biostudies-literature

Targeting angiogenesis in gastrointestinal tumors: current challenges.

Project description:Colorectal cancer (CRC) is one of the few cancers where screening modalities are standardized, but it still remains the third leading cause of cancer related mortality. For more than a decade now, the approval of anti-angiogenic therapy has led to an increase in the rate of overall survival (OS) of patients with advanced colon cancer. The drawback of the anti-angiogenic therapy is that their effect is short-lived and many patients progress through these therapies. Various mechanisms of resistance have been hypothesized, but overcoming this has been challenging. Also, there are no standardized predictive biomarkers that could aid in selecting patients who responds to the therapy upfront. This review focuses on the basis of angiogenesis, describing the approved anti-angiogenic therapies, discusses the challenges in terms of resistance to anti-angiogenic therapy and also the role of biomarkers. In the future, hopefully newer targeted therapies, immunotherapy, combination therapies and the standardization of biomarkers may result in improved outcomes and cure rates.

| S-EPMC5244743 | biostudies-literature

Targeting KRAS in Solid Tumors: Current Challenges and Future Opportunities of Novel KRAS Inhibitors.

Project description:Activating mutations in RAS family proteins are found in ~25% of all human cancers. Different solid tumors are correlated with mutations in certain isoforms of RAS, with Kirsten RAS (KRAS) being the most frequently mutated isoform. Historically, KRAS has been acknowledged as "undruggable", largely because the RAS proteins do not appear to present suitable pockets to which small inhibitory molecules can bind. However, this scenario has changed over the last years with the advent of novel KRAS inhibitors. In this review, we describe the role of KRAS mutation across different solid tumors, providing data on novel KRAS inhibitors currently under development and an updated overview of ongoing research in this field. A literature search was performed to select papers, abstracts, and oral presentation on KRAS inhibitory strategies in KRAS mutated solid tumors. Overall, the most promising therapeutic results have been obtained with molecules targeting KRAS G12C, thus paving the way for a significant therapeutic improvement in non-small cell lung cancer. Unfortunately, KRAS G12C mutation is rather uncommon in other solid tumors, namely pancreatic ductal adenocarcinoma and colorectal cancer. Several combination strategies are currently under evaluation in clinical trials, in order to bypass the resistance mechanisms responsible for the intrinsic resistance of mutated KRAS to the main therapeutic strategies adopted to date. Results suggest that the therapeutic scenario of KRAS has started to change, and further research will bring therapeutic results in this field.

| S-EPMC8147792 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data