Matches in SemOpenAlex for { <https://semopenalex.org/work/W2954013886> ?p ?o ?g. }
Showing items 1 to 72 of
72
with 100 items per page.
- W2954013886 endingPage "2141" @default.
- W2954013886 startingPage "2141" @default.
- W2954013886 abstract "Abstract Ewing sarcomas (ES) are bone and soft tissue tumors that affect children and adolescents. These cancers are driven by chromosomal translocations that most frequently result in expression of the abnormal EWSR1-FLI1 fusion protein, a transcriptional activator and modulator of RNA splicing, or similar fusion proteins. Despite significant advances in therapies for pediatric hematological malignancies over the past 30 years, there has been less progress in the development of curative therapies for advanced or metastatic pediatric solid tumors. Approximately 35% of ES are resistant to standard-of-care chemotherapeutic agents, and nearly 70% of ES patients with metastatic disease at the time of diagnosis die within 5 years. Therefore, there is a need to develop new, targeted therapies for ES that improve patient survival and decrease toxicity. We performed high-content phenotypic screens of natural product libraries to identify compounds with selective actions against pediatric solid tumor types and found that the fungal metabolite altertoxin II (ATXII) has highly selective cytotoxic activity against 6 ES cells lines compared to a panel of other pediatric and adult cancer cell lines. On average, the IC50 of ATXII is 94-fold higher (range 16- to 400-fold) in rhabdomyosarcoma (RMS) cells than in ES cells, indicating high selectivity for ES. Mechanistic studies were conducted to determine this compound’s mechanisms of actions in ES cells, with the goal of identifying new molecular targets for the treatment of ES. We found that 100 nM ATXII, a concentration that has no effect on RMS cell viability, induces cell cycle accumulation in ES cells in the S and G2/M phases, and rapid phosphorylation of histone H2A.X (gamma-H2A.X) and checkpoint kinase 1, suggesting ATXII selectively induces cell cycle arrest and DNA damage in ES cells. To determine if ES sensitivity to ATXII is a dominant or recessive phenotype, we hybridized sensitive EW8 cells (ES) with resistant Rh30 cells (RMS) and determined the sensitivity of these hybrids to ATXII. Five single-cell subclones derived from these hybrids were resistant to ATXII, suggesting that sensitivity to ATXII is a recessive phenotype in ES cells. Ongoing studies are aimed at determining the cellular uptake and binding kinetics of radiolabeled ATXII and identifying genes that mediate sensitivity and resistance to this compound by performing a genome-wide CRISPR/Cas9 knockout screen. Citation Format: Andrew J. Robles, Wentao Dai, Robert H. Cichewicz, Susan L. Mooberry, Peter J. Houghton. Mechanistic studies of altertoxin II: A fungal metabolite with selective activity against Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2141." @default.
- W2954013886 created "2019-07-12" @default.
- W2954013886 creator A5004354574 @default.
- W2954013886 creator A5004648382 @default.
- W2954013886 creator A5041205100 @default.
- W2954013886 creator A5046557969 @default.
- W2954013886 creator A5073277560 @default.
- W2954013886 date "2019-07-01" @default.
- W2954013886 modified "2023-09-27" @default.
- W2954013886 title "Abstract 2141: Mechanistic studies of altertoxin II: A fungal metabolite with selective activity against Ewing sarcoma" @default.
- W2954013886 doi "https://doi.org/10.1158/1538-7445.am2019-2141" @default.
- W2954013886 hasPublicationYear "2019" @default.
- W2954013886 type Work @default.
- W2954013886 sameAs 2954013886 @default.
- W2954013886 citedByCount "0" @default.
- W2954013886 crossrefType "journal-article" @default.
- W2954013886 hasAuthorship W2954013886A5004354574 @default.
- W2954013886 hasAuthorship W2954013886A5004648382 @default.
- W2954013886 hasAuthorship W2954013886A5041205100 @default.
- W2954013886 hasAuthorship W2954013886A5046557969 @default.
- W2954013886 hasAuthorship W2954013886A5073277560 @default.
- W2954013886 hasConcept C104317684 @default.
- W2954013886 hasConcept C121608353 @default.
- W2954013886 hasConcept C126322002 @default.
- W2954013886 hasConcept C138626823 @default.
- W2954013886 hasConcept C142724271 @default.
- W2954013886 hasConcept C2777477808 @default.
- W2954013886 hasConcept C2777937962 @default.
- W2954013886 hasConcept C2778256501 @default.
- W2954013886 hasConcept C2778629024 @default.
- W2954013886 hasConcept C2780844630 @default.
- W2954013886 hasConcept C2993561819 @default.
- W2954013886 hasConcept C502942594 @default.
- W2954013886 hasConcept C54355233 @default.
- W2954013886 hasConcept C71924100 @default.
- W2954013886 hasConcept C86803240 @default.
- W2954013886 hasConceptScore W2954013886C104317684 @default.
- W2954013886 hasConceptScore W2954013886C121608353 @default.
- W2954013886 hasConceptScore W2954013886C126322002 @default.
- W2954013886 hasConceptScore W2954013886C138626823 @default.
- W2954013886 hasConceptScore W2954013886C142724271 @default.
- W2954013886 hasConceptScore W2954013886C2777477808 @default.
- W2954013886 hasConceptScore W2954013886C2777937962 @default.
- W2954013886 hasConceptScore W2954013886C2778256501 @default.
- W2954013886 hasConceptScore W2954013886C2778629024 @default.
- W2954013886 hasConceptScore W2954013886C2780844630 @default.
- W2954013886 hasConceptScore W2954013886C2993561819 @default.
- W2954013886 hasConceptScore W2954013886C502942594 @default.
- W2954013886 hasConceptScore W2954013886C54355233 @default.
- W2954013886 hasConceptScore W2954013886C71924100 @default.
- W2954013886 hasConceptScore W2954013886C86803240 @default.
- W2954013886 hasIssue "13_Supplement" @default.
- W2954013886 hasLocation W29540138861 @default.
- W2954013886 hasOpenAccess W2954013886 @default.
- W2954013886 hasPrimaryLocation W29540138861 @default.
- W2954013886 hasRelatedWork W1984728765 @default.
- W2954013886 hasRelatedWork W2066817268 @default.
- W2954013886 hasRelatedWork W2132005948 @default.
- W2954013886 hasRelatedWork W2523222294 @default.
- W2954013886 hasRelatedWork W2792864352 @default.
- W2954013886 hasRelatedWork W2912456485 @default.
- W2954013886 hasRelatedWork W2969533880 @default.
- W2954013886 hasRelatedWork W3083761066 @default.
- W2954013886 hasRelatedWork W4232432980 @default.
- W2954013886 hasRelatedWork W4285082525 @default.
- W2954013886 hasVolume "79" @default.
- W2954013886 isParatext "false" @default.
- W2954013886 isRetracted "false" @default.
- W2954013886 magId "2954013886" @default.
- W2954013886 workType "article" @default.