Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Effect of Sunitinib treatment withdrawal on Immunodeficient mice bearing MDA-MB231 tumors

ABSTRACT: Immunodeficient RAG1-/- mice bearing MDA-MB231-LUC+ tumors of 50-70 mm3 were daily administrated by gavage with vehicle (containing, 0.5% carboxymethylcellulose, 1.8 % NaCl, 0.4 % Tween-80, 0.9 %. benzyl alcohol, and ultrapure water adjusted to pH 6.0) or sunitinib (40mg/kg/day) for 30 days followed by treatment withdrawal for 3-4 weeks to allow the tumor regrowth until reaching the same volume as that of the vehicle treated group. Mice were sacrificed when tumor reached the volume of 350-400 mm3 and RNAs of two tumors from two different mice treated with sunitinib or vehicle were extracted. One color experiment with 2 experimental conditions: Sunitinib vs Vehicle (n=2), corresponding to a total of 4 samples.

ORGANISM(S): Mus musculus

SUBMITTER: Kevin Lebrigand

PROVIDER: E-GEOD-50795 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Blocking lipid synthesis overcomes tumor regrowth and metastasis after antiangiogenic therapy withdrawal.

Sounni Nor Eddine NE Cimino Jonathan J Blacher Silvia S Primac Irina I Truong Alice A Mazzucchelli Gabriel G Paye Alexandra A Calligaris David D Debois Delphine D De Tullio Pascal P Mari Bernard B De Pauw Edwin E Noel Agnes A

Cell metabolism 20140710 2

The molecular mechanisms responsible for the failure of antiangiogenic therapies and how tumors adapt to these therapies are unclear. Here, we applied transcriptomic, proteomic, and metabolomic approaches to preclinical models and provide evidence for tumor adaptation to vascular endothelial growth factor blockade through a metabolic shift toward carbohydrate and lipid metabolism in tumors. During sunitinib or sorafenib treatment, tumor growth was inhibited and tumors were hypoxic and glycolytic ...[more]

PMID: 25017943

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Project description:Transcriptome analysis was used to identify gene expression changes during development of sunitinib resistance in a renal cell carcinoma patient-derived xenograft (PDX) model. During the response phase, tumors exhibited a 91% reduction in volume, characterized by induction of TNFRSF1A, TNFAIP3, NFKB2, CCL2, CCL20, BIRC3, and MOAP1. Ingenuity Pathway Analysis indicated decreased expression of cell survival genes during tumor response to sunitinib. In this model, after 4 weeks of treatment, tumors developed resistance despite continued administration of the tyrosine kinase inhibitor (TKI) sunitinib (40 mg/kg/d p.o.). Resistance was associated with increased expression of VEGFA, EPO, IL-8, ANGPT2, TNFRSF12, MAPK3/7, MAPKBP1, and increased cell survival genes, suggesting activation of angiogenesis and MAPK/ERK pathways. Tumor lysate mRNA evaluated for murine gene expression to examine the contribution of host effects, indicated that tumor response was associated with downregulation of immune cell trafficking, cellular movement, and inflammatory response genes. During tumor escape, genes associated with cellular movement, inflammatory response, and immune cell trafficking were strongly induced, along with intratumoral accumulation of myeloid derived suppressor cells (MDSC), indicating a role for host factors during emergence of sunitinib resistance. The same PDX model was used to assess anti-tumor efficacy of sunitinib combined with MEK inhibitor (MEKi) PD-0325901 (4 mg/kg/d p.o.) using different schedules. The most effective treatment regimen was either continuous treatment with both drugs or switching from sunitinib to PD-0325901 monotherapy at d30, which reduced tumor volume by 78.6% (p=0.0241) and 88.5% (p=0.0068), respectively. The combination of MEKi with TKI (sunitinib, axitinib, or pazopanib) suppressed levels of phospho-MEK1/2 and phospho-ERK1/2, and decreased intratumoral MDSC. Thus, continuous treatment with sunitinib alone did not maintain tumor response, and addition of a MEKi abrogated resistance leading to prolonged survival.

Dataset Information

Effect of Sunitinib treatment withdrawal on Immunodeficient mice bearing MDA-MB231 tumors

Publications

Blocking lipid synthesis overcomes tumor regrowth and metastasis after antiangiogenic therapy withdrawal.

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