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Insights into pediatric rhabdomyosarcoma research: Challenges and goals.

ABSTRACT: Overall survival rates for pediatric patients with high-risk or relapsed rhabdomyosarcoma (RMS) have not improved significantly since the 1980s. Recent studies have identified a number of targetable vulnerabilities in RMS, but these discoveries have infrequently translated into clinical trials. We propose streamlining the process by which agents are selected for clinical evaluation in RMS. We believe that strong consideration should be given to the development of combination therapies that add biologically targeted agents to conventional cytotoxic drugs. One example of this type of combination is the addition of the WEE1 inhibitor AZD1775 to the conventional cytotoxic chemotherapeutics, vincristine and irinotecan.

SUBMITTER: Yohe ME

PROVIDER: S-EPMC6707829 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Insights into pediatric rhabdomyosarcoma research: Challenges and goals.

Yohe Marielle E ME Heske Christine M CM Stewart Elizabeth E Adamson Peter C PC Ahmed Nabil N Antonescu Cristina R CR Chen Eleanor E Collins Natalie N Ehrlich Alan A Galindo Rene L RL Gryder Berkley E BE Hahn Heidi H Hammond Sharon S Hatley Mark E ME Hawkins Douglas S DS Hayes Madeline N MN Hayes-Jordan Andrea A Helman Lee J LJ Hettmer Simone S Ignatius Myron S MS Keller Charles C Khan Javed J Kirsch David G DG Linardic Corinne M CM Lupo Philip J PJ Rota Rossella R Shern Jack F JF Shipley Janet J Sindiri Sivasish S Tapscott Stephen J SJ Vakoc Christopher R CR Wexler Leonard H LH Langenau David M DM

Pediatric blood & cancer 20190621 10

Overall survival rates for pediatric patients with high-risk or relapsed rhabdomyosarcoma (RMS) have not improved significantly since the 1980s. Recent studies have identified a number of targetable vulnerabilities in RMS, but these discoveries have infrequently translated into clinical trials. We propose streamlining the process by which agents are selected for clinical evaluation in RMS. We believe that strong consideration should be given to the development of combination therapies that add b ...[more]

PMID: 31222885

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Project description:Neuroendocrine systems integrate both extrinsic and intrinsic signals to regulate virtually all aspects of an animal's physiology. In aquatic toxicology, studies have shown that pollutants are capable of disrupting the neuroendocrine system of teleost fish, and many chemicals found in the environment can also have a neurotoxic mode of action. Omics approaches are now used to better understand cell signaling cascades underlying fish neurophysiology and the control of pituitary hormone release, in addition to identifying adverse effects of pollutants in the teleostean central nervous system. For example, both high throughput genomics and proteomic investigations of molecular signaling cascades for both neurotransmitter and nuclear receptor agonists/antagonists have been reported. This review highlights recent studies that have utilized quantitative proteomics methods such as 2D differential in-gel electrophoresis (DIGE) and isobaric tagging for relative and absolute quantitation (iTRAQ) in neuroendocrine regions and uses these examples to demonstrate the challenges of using proteomics in neuroendocrinology and neurotoxicology research. To begin to characterize the teleost neuroproteome, we functionally annotated 623 unique proteins found in the fish hypothalamus and telencephalon. These proteins have roles in biological processes that include synaptic transmission, ATP production, receptor activity, cell structure and integrity, and stress responses. The biological processes most represented by proteins detected in the teleost neuroendocrine brain included transport (8.4%), metabolic process (5.5%), and glycolysis (4.8%). We provide an example of using sub-network enrichment analysis (SNEA) to identify protein networks in the fish hypothalamus in response to dopamine receptor signaling. Dopamine signaling altered the abundance of proteins that are binding partners of microfilaments, integrins, and intermediate filaments, consistent with data suggesting dopaminergic regulation of neuronal stability and structure. Lastly, for fish neuroendocrine studies using both high-throughput genomics and proteomics, we compare gene and protein relationships in the hypothalamus and demonstrate that correlation is often poor for single time point experiments. These studies highlight the need for additional time course analyses to better understand gene-protein relationships and adverse outcome pathways. This is important if both transcriptomics and proteomics are to be used together to investigate neuroendocrine signaling pathways or as bio-monitoring tools in ecotoxicology.

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Insights into pediatric rhabdomyosarcoma research: Challenges and goals.

Publications

Insights into pediatric rhabdomyosarcoma research: Challenges and goals.

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