Unknown,Transcriptomics,Genomics,Proteomics

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Analysis of Gene Expression of Human Renal Cell Carcinoma by DNA Microaray in Patients treated with Sunitinib. An Exploratory Study

ABSTRACT: Gene Evaluation of DNA expression from snap-frozen renal cell cancer tissue from 5 patients with locally advanced non-metastatic tumors, submitted to nephrectomy after being treated with 2 cycles of neoadjuvant Sunitinib were compared to match controls comprising of 6 patients with no neoadjuvant intervension using microarray platform Affymetrix Human Genome U133 Plus 2.0 containing 54675 probes. Validation followed using qRT-PCR Exploratory, prospective evaluation of gene expression in renal cell tumor snap frozen tissue after neoadjuvant Sunitinib compared to a control group with no neoadjuvant treatment

ORGANISM(S): Homo sapiens

SUBMITTER: Glauber Brito

PROVIDER: E-GEOD-68629 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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. Study was comprised of three experimental groups (pre-treatment, response, escape). All tumors came from the same PDX model. There were four biological replicates in each group. Four mice were used, with each of the 3 groups per mouse. There were no control or reference samples.

Dataset Information

Analysis of Gene Expression of Human Renal Cell Carcinoma by DNA Microaray in Patients treated with Sunitinib. An Exploratory Study

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