The third international meeting on genetic disorders in the RAS/MAPK pathway: Towards a therapeutic approach

Korf, Bruce R.; Ahmadian, Reza; Allanson, Judith; Aoki, Yoko; Wright, Emma Burkitt; Denger, Brian; Elgersma, Ype; Gelb, Bruce D.; Gripp, Karen W.; Kerr, Bronwyn; Kontaridis, Maria I.; Lázaro, Conxi; Linardic, Corinne M.; Lozano, Reymundo; MacRae, Calum A.; Messiaen, Ludwine; Mulero‐Navarro, Sonia; Neel, Benjamin G.; Plotkin, Scott R.; Roberts, Amy; Silva, Alcino J.; Sittampalam, Sitta; Zhang, Chao; Schoyer, Lisa

doi:10.1002/ajmg.a.37089

Cited by 8 publications

(10 citation statements)

References 18 publications

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“…Adults with NS require long-term cardiac follow-up, given that a third have cardiac disorders that require either drugs for heart failure or arrhythmias, or have a defibrillator or pacemaker implanted (1). Given the clinical importance there has been significant interest in developing pharmacological treatments for cardiomyopathies in NS and NSML (24). It has been shown that inhibitors of the Akt/mTOR pathway can ameliorate HCM in the NSML model (25,26), whereas, genetic interference with, or pharmacologic inhibition of, MEK/ERK in a NS mouse model suppresses the development of CHD (27)(28)(29)(30).…”

Section: Introductionmentioning

confidence: 99%

Low-dose dasatinib rescues cardiac function in Noonan syndrome

Yi¹,

Huang²,

Kwaczala³

et al. 2016

JCI Insight

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Section: Introductionmentioning

confidence: 99%

Low-dose dasatinib rescues cardiac function in Noonan syndrome

Yi¹,

Huang²,

Kwaczala³

et al. 2016

JCI Insight

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“…about 5%, the receptor-mediated hyperactivation of the Rasdependent signal transduction pathway is a frequent event in human hepatocarcinogenesis (13)(14)(15)(16). Recently, application of Ras-pathway inhibitors has become an important therapeutic strategy for clinical cancer treatment including HCC (16,17).…”

mentioning

confidence: 99%

Differential Proteomic Analysis of Gender-dependent Hepatic Tumorigenesis in Hras12V Transgenic Mice

Rong

Fan

et al. 2017

Molecular & Cellular Proteomics

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Male prevalence is an outstanding characteristic of hepatocellular carcinoma (HCC), and the underlying mechanisms for this have remained largely unknown. In the present study, Hras12V transgenic mice, in which hepatocyte-specific expression of the oncogene induces male-biased hepatic tumorigenesis, were studied, and altered proteins were detected by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE). Protein samples from hepatic tumor tissues (T) and peritumor tissues (P) of transgenic males and females and the corresponding normal liver tissues (Wt) of nontransgenic males and females were subjected to pairwise comparisons based on proteomic analysis. Among 2381 autodetected protein spots, more than 1600 were differentially expressed based on a pairwise comparison (|ratio|> = 1.5, < = 0.05). Of these, 180 spots were randomly selected for matrix-assisted laser desorption ionization tandem time-of-flight mass spectrometry (MALDI-TOF/TOF MS) identification; finally, 89 distinct proteins were obtained. Among these 89 proteins, 7 and 50 proteins were further validated by Western blotting and literature investigation, respectively. Intriguingly, compared with Wt, the altered proteins were relatively concentrated in T in transgenic females but in P in transgenic males. Consistently, the levels of p-ERK and p-mTOR were significantly higher in the T of females compared with that of males. The pathway enrichment assay showed that 5 pathways in males but only 1 in females were significantly altered in terms of the upregulated proteins in T compared with Wt. These data indicate that female hepatocytes are disturbed by oncogenes with great difficulty, whereas male hepatocytes readily do so. In addition, 33 proteins were gender-dependently altered in hepatic tumorigenesis. Moreover, 4% DNA packaging and 4% homeostasis-related functional proteins were found in females but not in males, and more nucleus proteins were found in females (8%) than in males (3%). In conclusion, the proteomic data and comparative analysis presented here offer crucial clues for elucidating the mechanisms that underlie the male prevalence in HCC.

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“…The RASopathy research and patient advocacy communities have laid the foundations required for the development of clinical trials and possible effective therapies. In biennial RASopathy meetings over the past decade, the development of clinical trials and selection of adequate endpoints has been an important part of the agendas (Korf et al, ; Rauen et al, ; Stevenson et al, ). Individuals with a RASopathy are uniquely positioned to benefit from many of the RAS pathway‐targeted therapies developed for cancer therapy (Rauen et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…In summary, there are many potential therapeutic options for individuals with RASopathies, and the most effective therapeutic for each individual may be disease-or even genotype-specific. (Korf et al, 2015;Rauen et al, 2010;Stevenson et al, 2016). Individuals with a RASopathy are uniquely positioned to benefit from many of the RAS pathway-targeted therapies developed for cancer therapy .…”

Section: Therapeutic Clinical Trials For Individuals With Rasopathimentioning

confidence: 99%

Advancing RAS/RASopathy therapies: An NCI‐sponsored intramural and extramural collaboration for the study of RASopathies

Gross

Frone

Gripp

et al. 2020

American J of Med Genetics Pt A

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RASopathies caused by germline pathogenic variants in genes that encode RAS pathway proteins. These disorders include neurofibromatosis type 1 (NF1), Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC), and Costello syndrome (CS), and others. RASopathies are characterized by heterogenous manifestations, including congenital heart disease, failure to thrive, and increased risk of cancers. Previous work led by the NCI Pediatric Oncology Branch has altered the natural course of one of the key manifestations of the RASopathy NF1. Through the conduct of a longitudinal cohort study and early phase clinical trials, the MEK inhibitor selumetinib was identified as the first active therapy for the NF1‐related peripheral nerve sheath tumors called plexiform neurofibromas (PNs). As a result, selumetinib was granted breakthrough therapy designation by the FDA for the treatment of PN. Other RASopathy manifestations may also benefit from RAS targeted therapies. The overall goal of Advancing RAS/RASopathy Therapies (ART), a new NCI initiative, is to develop effective therapies and prevention strategies for the clinical manifestations of the non‐NF1 RASopathies and for tumors characterized by somatic RAS mutations. This report reflects discussions from a February 2019 initiation meeting for this project, which had broad international collaboration from basic and clinical researchers and patient advocates.

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The third international meeting on genetic disorders in the RAS/MAPK pathway: Towards a therapeutic approach

Cited by 8 publications

References 18 publications

Low-dose dasatinib rescues cardiac function in Noonan syndrome

Low-dose dasatinib rescues cardiac function in Noonan syndrome

Differential Proteomic Analysis of Gender-dependent Hepatic Tumorigenesis in Hras12V Transgenic Mice

Advancing RAS/RASopathy therapies: An NCI‐sponsored intramural and extramural collaboration for the study of RASopathies

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