Browse
Submit Data
Databases
API
Help

Dataset Information

25 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Metabolic Rewiring in Radiation Oncology Toward Improving the Therapeutic Ratio.

ABSTRACT: To meet the anabolic demands of the proliferative potential of tumor cells, malignant cells tend to rewire their metabolic pathways. Although different types of malignant cells share this phenomenon, there is a large intracellular variability how these metabolic patterns are altered. Fortunately, differences in metabolic patterns between normal tissue and malignant cells can be exploited to increase the therapeutic ratio. Modulation of cellular metabolism to improve treatment outcome is an emerging field proposing a variety of promising strategies in primary tumor and metastatic lesion treatment. These strategies, capable of either sensitizing or protecting tissues, target either tumor or normal tissue and are often focused on modulating of tissue oxygenation, hypoxia-inducible factor (HIF) stabilization, glucose metabolism, mitochondrial function and the redox balance. Several compounds or therapies are still in under (pre-)clinical development, while others are already used in clinical practice. Here, we describe different strategies from bench to bedside to optimize the therapeutic ratio through modulation of the cellular metabolism. This review gives an overview of the current state on development and the mechanism of action of modulators affecting cellular metabolism with the aim to improve the radiotherapy response on tumors or to protect the normal tissue and therefore contribute to an improved therapeutic ratio.

SUBMITTER: van Gisbergen MW

PROVIDER: S-EPMC8143268 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

N-Myc-induced metabolic rewiring creates novel therapeutic vulnerabilities in neuroblastoma.

Project description:N-Myc is a transcription factor that is aberrantly expressed in many tumor types and is often correlated with poor patient prognosis. Recently, several lines of evidence pointed to the fact that oncogenic activation of Myc family proteins is concomitant with reprogramming of tumor cells to cope with an enhanced need for metabolites during cell growth. These adaptions are driven by the ability of Myc proteins to act as transcriptional amplifiers in a tissue-of-origin specific manner. Here, we describe the effects of N-Myc overexpression on metabolic reprogramming in neuroblastoma cells. Ectopic expression of N-Myc induced a glycolytic switch that was concomitant with enhanced sensitivity towards 2-deoxyglucose, an inhibitor of glycolysis. Moreover, global metabolic profiling revealed extensive alterations in the cellular metabolome resulting from overexpression of N-Myc. Limited supply with either of the two main carbon sources, glucose or glutamine, resulted in distinct shifts in steady-state metabolite levels and significant changes in glutathione metabolism. Interestingly, interference with glutamine-glutamate conversion preferentially blocked proliferation of N-Myc overexpressing cells, when glutamine levels were reduced. Thus, our study uncovered N-Myc induction and nutrient levels as important metabolic master switches in neuroblastoma cells and identified critical nodes that restrict tumor cell proliferation.

| S-EPMC7188804 | biostudies-literature

Novel biological strategies to enhance the radiation therapeutic ratio.

Project description:Successful anticancer strategies require a differential response between tumor and normal tissue (i.e., a therapeutic ratio). In fact, improving the effectiveness of a cancer therapeutic is of no clinical value in the absence of a significant increase in the differential response between tumor and normal tissue. Although radiation dose escalation with the use of intensity modulated radiation therapy has permitted the maximum tolerable dose for most locally advanced cancers, improvements in tumor control without damaging normal adjacent tissues are needed. As a means of increasing the therapeutic ratio, several new approaches are under development. Drugs targeting signal transduction pathways in cancer progression and more recently, immunotherapeutics targeting specific immune cell subsets have entered the clinic with promising early results. Radiobiological research is underway to address pressing questions as to the dose per fraction, irradiated tumor volume and time sequence of the drug administration. To exploit these exciting novel strategies, a better understanding is needed of the cellular and molecular pathways responsible for both cancer and normal tissue and organ response, including the role of radiation-induced accelerated senescence. This review will highlight the current understanding of promising biologically targeted therapies to enhance the radiation therapeutic ratio.

| S-EPMC6226138 | biostudies-other

Metabolic rewiring in keratinocytes by miR-31-5p identifies therapeutic intervention for psoriasis

Project description:Besides genetic alterations, the cellular environment also determines disease onset and progression. When different cell types contribute to disease outcome, this imposes environmental challenges as different cell types likely differ in their extracellular dependencies. Hsa-microRNA-31-5p (miR-31), is highly expressed in keratinocytes of psoriatic skin, and we show that expression in keratinocytes is induced by limited glucose availability and enables increased survival under limiting glucose conditions, by increasing glutamine metabolism. In addition, miR-31 expression results in secretion of specific metabolites (aspartate and glutamate) but also secretion of immuno-modulatory factors. We show that this miR-31-induced secretory phenotype is sufficient to induce Th17 cell differentiation, a hallmark of psoriasis. Inhibitors of miR31-induced metabolic rewiring and metabolic crosstalk with immune cells alleviate psoriasis pathology in a mouse model of psoriasis. Together our data illustrate an emerging concept of metabolic interaction across cell compartments that characterizes disease development, which can be employed to design effective treatment options for disease, as shown here for psoriasis.

| S-SCDT-10_15252-EMMM_202215674 | biostudies-other

Evolving role of biomaterials in diagnostic and therapeutic radiation oncology.

Project description:Radiation therapy to treat cancer has evolved significantly since the discovery of x-rays. Yet, radiation therapy still has room for improvement in reducing side effects and improving control of cancer. Safer and more effective delivery of radiation has led us to novel techniques and use of biomaterials. Biomaterials in combination with radiation and chemotherapy have started to appear in pre-clinical explorations and clinical applications, with many more on the horizon. Biomaterials have revolutionized the field of diagnostic imaging, and now are being cultivated into the field of theranostics, combination therapy, and tissue protection. This review summarizes recent development of biomaterials in radiation therapy in several application areas.

| S-EPMC7036731 | biostudies-literature

Improving Quality and Consistency in NRG Oncology Radiation Therapy Oncology Group 0631 for Spine Radiosurgery via Knowledge-Based Planning.

Project description:PURPOSE:To use knowledge-based planning (KBP) as a method of producing high-quality, consistent, protocol-compliant treatment plans in a complex setting of spine stereotactic body radiation therapy on NRG Oncology Radiation Therapy Oncology Group (RTOG) 0631. METHODS AND MATERIALS:An internally developed KBP model was applied to an external validation cohort of 22 anonymized cases submitted under NRG Oncology RTOG 0631. The original and KBP plans were compared via their protocol compliance, target conformity and gradient index, dose to critical structures, and dose to surrounding normal tissues. RESULTS:The KBP model generated plans meeting all protocol objectives in a single optimization when tested on both internal and protocol-submitted NRG Oncology RTOG 0631 cases. Two submitted plans that were considered to have a protocol-unacceptable deviation were made protocol compliant through the use of the model. There were no statistically significant differences in protocol spinal cord metrics (D10% and D0.03cc) between the manually optimized plans and the KBP plans. The volume of planning target volume receiving prescription dose increased from 93.3% ± 3.2% to 98.3% ± 1.4% (P = .01) when using KBP. High-dose spillage to surrounding normal tissues (V105%) showed no significant differences (2.1 ± 7.3 cm3 for manual plans to 1.8 ± 0.6 cm3 with KBP), and dosimetric outliers with large amounts of spillage were eliminated through the use of KBP. Knowledge-based planning plans were also found to be significantly more consistent in several metrics, including target coverage and high dose outside of the target. CONCLUSION:Incorporation of KBP models into the clinical trial setting may have a profound impact on the quality of trial results, owing to the increase in consistency and standardization of planning, especially for treatment sites or techniques that are nonstandard.

| S-EPMC5915303 | biostudies-literature

Metabolic rewiring directs melanoma immunology.

Project description:Melanoma results from the malignant transformation of melanocytes and accounts for the most lethal type of skin cancers. In the pathogenesis of melanoma, disordered metabolism is a hallmark characteristic with multiple metabolic paradigms involved in, e.g., glycolysis, lipid metabolism, amino acid metabolism, oxidative phosphorylation, and autophagy. Under the driving forces of oncogenic mutations, melanoma metabolism is rewired to provide not only building bricks for macromolecule synthesis and sufficient energy for rapid proliferation and metastasis but also various metabolic intermediates for signal pathway transduction. Of note, metabolic alterations in tumor orchestrate tumor immunology by affecting the functions of surrounding immune cells, thereby interfering with their antitumor capacity, in addition to the direct influence on tumor cell intrinsic biological activities. In this review, we first introduced the epidemiology, clinical characteristics, and treatment proceedings of melanoma. Then, the components of the tumor microenvironment, especially different populations of immune cells and their roles in antitumor immunity, were reviewed. Sequentially, how metabolic rewiring contributes to tumor cell malignant behaviors in melanoma pathogenesis was discussed. Following this, the proceedings of metabolism- and metabolic intermediate-regulated tumor immunology were comprehensively dissertated. Finally, we summarized currently available drugs that can be employed to target metabolism to intervene tumor immunology and modulate immunotherapy.

| S-EPMC9393691 | biostudies-literature

Ncl1-mediated metabolic rewiring critical during metabolic stress.

Project description:Nutritional limitation has been vastly studied; however, there is limited knowledge of how cells maintain homeostasis in excess nutrients. In this study, using yeast as a model system, we show that some amino acids are toxic at higher concentrations. With cysteine as a physiologically relevant example, we delineated the pathways/processes that are altered and those that are involved in survival in the presence of elevated levels of this amino acid. Using proteomics and metabolomics approach, we found that cysteine up-regulates proteins involved in amino acid metabolism, alters amino acid levels, and inhibits protein translation-events that are rescued by leucine supplementation. Through a comprehensive genetic screen, we show that leucine-mediated effect depends on a transfer RNA methyltransferase (NCL1), absence of which decouples transcription and translation in the cell, inhibits the conversion of leucine to ketoisocaproate, and leads to tricarboxylic acid cycle block. We therefore propose a role of NCL1 in regulating metabolic homeostasis through translational control.

| S-EPMC6696984 | biostudies-literature

Applying Precision Oncology Principles in Radiation Oncology.

Project description:Radiation therapy is a critical component in the curative management of many solid tumor types, and advances in radiation delivery techniques during the past decade have led to improved disease control and quality of life for patients. During the same period, remarkable advances have also been made in understanding the genomic landscape of tumors; however, treatment decisions in radiation oncology continue to depend primarily on clinical and histopathologic characteristics rather than on the genetic features of the tumor or the patient. With the development of novel genomic techniques and their increasing use in clinical practice, radiation oncology is uniquely positioned to leverage these advances to identify novel biomarkers that could inform radiation dose, field, and the use of concurrent systemic agents. Here, we summarize efforts to use genomic techniques to guide radiation decisions, and we highlight some of the current opportunities and challenges that exist in attempting to apply precision oncology principles in radiation oncology.

| S-EPMC7446508 | biostudies-literature

Labeling for Big Data in radiation oncology: The Radiation Oncology Structures ontology.

Project description:Leveraging Electronic Health Records (EHR) and Oncology Information Systems (OIS) has great potential to generate hypotheses for cancer treatment, since they directly provide medical data on a large scale. In order to gather a significant amount of patients with a high level of clinical details, multicenter studies are necessary. A challenge in creating high quality Big Data studies involving several treatment centers is the lack of semantic interoperability between data sources. We present the ontology we developed to address this issue.Radiation Oncology anatomical and target volumes were categorized in anatomical and treatment planning classes. International delineation guidelines specific to radiation oncology were used for lymph nodes areas and target volumes. Hierarchical classes were created to generate The Radiation Oncology Structures (ROS) Ontology. The ROS was then applied to the data from our institution.Four hundred and seventeen classes were created with a maximum of 14 children classes (average = 5). The ontology was then converted into a Web Ontology Language (.owl) format and made available online on Bioportal and GitHub under an Apache 2.0 License. We extracted all structures delineated in our department since the opening in 2001. 20,758 structures were exported from our "record-and-verify" system, demonstrating a significant heterogeneity within a single center. All structures were matched to the ROS ontology before integration into our clinical data warehouse (CDW).In this study we describe a new ontology, specific to radiation oncology, that reports all anatomical and treatment planning structures that can be delineated. This ontology will be used to integrate dosimetric data in the Assistance Publique-Hôpitaux de Paris CDW that stores data from 6.5 million patients (as of February 2017).

| S-EPMC5774757 | biostudies-literature

Machine learning of cellular metabolic rewiring.

Project description:Metabolic rewiring allows cells to adapt their metabolism in response to evolving environmental conditions. Traditional metabolomics techniques, whether targeted or untargeted, often struggle to interpret these adaptive shifts. Here, we introduce MetaboLiteLearner, a machine learning framework that harnesses the detailed fragmentation patterns from electron ionization (EI) collected in scan mode during gas chromatography/mass spectrometry (GC/MS) to predict abundance changes in metabolically adapted cells. When tested on breast cancer cells with different preferences to metastasize to specific organs, MetaboLiteLearner predicted the impact of metabolic rewiring on metabolites withheld from the training dataset using only the EI spectra, without metabolite identification or pre-existing knowledge of metabolic networks. The model learned captures shared and unique metabolomic shifts between brain- and lung-homing metastatic lineages, suggesting potential organ-tailored cellular adaptations. Integrating machine learning and metabolomics paves the way for new insights into complex cellular adaptations.

| S-EPMC10462012 | 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