Matches in SemOpenAlex for { <https://semopenalex.org/work/W2256332034> ?p ?o ?g. }
Showing items 1 to 78 of
78
with 100 items per page.
- W2256332034 abstract "Introduction: At present, drug screening studies are commonly performed using monolayer or spheroid culture and xenograft models of tumor cell lines. However these do not fully replicate the primary tumor9s microenvironment and fail to accurately predict clinical endpoints. Vivo Biosciences has developed a novel MicroTumor 3D matrix based assay system that emulates primary tumor multicellular growth and biology ex vivo, providing an advanced drug screening platform. We postulated that MicroTumors established from patient-derived xenograft (PDX) tumors will allow for accurate analysis of drug response and preserve molecular signaling of parent tumors. Glioblastoma multiforme (GBM), the most common primary brain malignancy, was used to test our hypothesis. MicroTumors were evaluated by comparing kinome activation profiles of GBM-MicroTumors with corresponding parental orthotopically implanted PDX; and determining single and combination treatment effects of small molecule kinase inhibitors (SMI) on GBM MicroTumors. Methods: We investigated 6 GBM PDX tumor lines representing the 4 known molecular subtypes: Classical (JX10, X1016, X1046); Proneural (XD456); Mesenchymal (JX22P); and Neural (JX10). Four SMIs (primary kinase target indicated) were studied: WP1066 (JAK2), selumetinib (MEK1/2), crizotinib (c-MET, ALK), and cediranib (VEGFR, FLT-1, FLT-4, c-KIT, PDGFR). MTT assays and Calcein AM imaging were used for cytotoxicity assessment and PamStation 12 Kinomic analyses were performed (UAB Kinome Core). Results: Kinomic analyses of GBM orthotopic PDX and GBM-MicroTumors revealed similar kinase signaling profiles based on comparison of commonly shared, most-variant phosphopeptides. Upstream kinase analyses identified these peptides as substrates of EGFR, AXL, ZAP70 and MERTK kinases. Initial drug response studies demonstrated dose dependency and PDX-specific responses for each drug used independently informing doses for ongoing combination studies. Interestingly, the least cytotoxic drug across all 6 MicroTumors, selumetinib, did impact MicroTumor morphology observed with Calcein AM imaging. Conclusions: We identified kinomic alterations that may correlate MicroTumor and patient tumor biology and guide the use of molecularly targeted SMIs. SMI activities towards these targets highlighted that this novel 3D translational model for GBM can provide relevant drug sensitivity information. Future studies with in vivo PDX tumors will examine the most promising SMI combinations based on MicroTumor data. We believe this two-stage approach (Microtumor screening to predict PDX sensitivities) will improve preclinical drug screening in GBM and other cancers. Citation Format: Christopher D. Willey, Ashley N. Gilbert, Rachael Shevin, Catherine P. Langford, Raj Singh, Joshua C. Anderson, G. Yancey Gillespie. Profiling drug sensitivity and kinomic pathways utilizing a novel human tumor derived MicroTumor assay. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 312. doi:10.1158/1538-7445.AM2015-312" @default.
- W2256332034 created "2016-06-24" @default.
- W2256332034 creator A5013810239 @default.
- W2256332034 creator A5014191604 @default.
- W2256332034 creator A5025228395 @default.
- W2256332034 creator A5031842530 @default.
- W2256332034 creator A5058429452 @default.
- W2256332034 creator A5067067884 @default.
- W2256332034 creator A5076961227 @default.
- W2256332034 date "2015-08-01" @default.
- W2256332034 modified "2023-09-26" @default.
- W2256332034 title "Abstract 312: Profiling drug sensitivity and kinomic pathways utilizing a novel human tumor derived MicroTumor assay" @default.
- W2256332034 doi "https://doi.org/10.1158/1538-7445.am2015-312" @default.
- W2256332034 hasPublicationYear "2015" @default.
- W2256332034 type Work @default.
- W2256332034 sameAs 2256332034 @default.
- W2256332034 citedByCount "0" @default.
- W2256332034 crossrefType "proceedings-article" @default.
- W2256332034 hasAuthorship W2256332034A5013810239 @default.
- W2256332034 hasAuthorship W2256332034A5014191604 @default.
- W2256332034 hasAuthorship W2256332034A5025228395 @default.
- W2256332034 hasAuthorship W2256332034A5031842530 @default.
- W2256332034 hasAuthorship W2256332034A5058429452 @default.
- W2256332034 hasAuthorship W2256332034A5067067884 @default.
- W2256332034 hasAuthorship W2256332034A5076961227 @default.
- W2256332034 hasConcept C143998085 @default.
- W2256332034 hasConcept C150903083 @default.
- W2256332034 hasConcept C184235292 @default.
- W2256332034 hasConcept C185592680 @default.
- W2256332034 hasConcept C207001950 @default.
- W2256332034 hasConcept C2776232967 @default.
- W2256332034 hasConcept C2776256026 @default.
- W2256332034 hasConcept C2779422266 @default.
- W2256332034 hasConcept C502942594 @default.
- W2256332034 hasConcept C54174078 @default.
- W2256332034 hasConcept C71924100 @default.
- W2256332034 hasConcept C86803240 @default.
- W2256332034 hasConcept C95444343 @default.
- W2256332034 hasConceptScore W2256332034C143998085 @default.
- W2256332034 hasConceptScore W2256332034C150903083 @default.
- W2256332034 hasConceptScore W2256332034C184235292 @default.
- W2256332034 hasConceptScore W2256332034C185592680 @default.
- W2256332034 hasConceptScore W2256332034C207001950 @default.
- W2256332034 hasConceptScore W2256332034C2776232967 @default.
- W2256332034 hasConceptScore W2256332034C2776256026 @default.
- W2256332034 hasConceptScore W2256332034C2779422266 @default.
- W2256332034 hasConceptScore W2256332034C502942594 @default.
- W2256332034 hasConceptScore W2256332034C54174078 @default.
- W2256332034 hasConceptScore W2256332034C71924100 @default.
- W2256332034 hasConceptScore W2256332034C86803240 @default.
- W2256332034 hasConceptScore W2256332034C95444343 @default.
- W2256332034 hasLocation W22563320341 @default.
- W2256332034 hasOpenAccess W2256332034 @default.
- W2256332034 hasPrimaryLocation W22563320341 @default.
- W2256332034 hasRelatedWork W1558425822 @default.
- W2256332034 hasRelatedWork W2005335453 @default.
- W2256332034 hasRelatedWork W2046550399 @default.
- W2256332034 hasRelatedWork W2272190705 @default.
- W2256332034 hasRelatedWork W2336591903 @default.
- W2256332034 hasRelatedWork W2342934823 @default.
- W2256332034 hasRelatedWork W2400149688 @default.
- W2256332034 hasRelatedWork W2484891052 @default.
- W2256332034 hasRelatedWork W2565914818 @default.
- W2256332034 hasRelatedWork W2594108931 @default.
- W2256332034 hasRelatedWork W2793898515 @default.
- W2256332034 hasRelatedWork W2806564245 @default.
- W2256332034 hasRelatedWork W2887441570 @default.
- W2256332034 hasRelatedWork W2954220677 @default.
- W2256332034 hasRelatedWork W2955828947 @default.
- W2256332034 hasRelatedWork W2993938654 @default.
- W2256332034 hasRelatedWork W3083299479 @default.
- W2256332034 hasRelatedWork W3095550339 @default.
- W2256332034 hasRelatedWork W3099376746 @default.
- W2256332034 hasRelatedWork W3181740840 @default.
- W2256332034 isParatext "false" @default.
- W2256332034 isRetracted "false" @default.
- W2256332034 magId "2256332034" @default.
- W2256332034 workType "article" @default.