MiRNA-drug resistance mechanisms Summary Hypothesis: The interplay between miRNAs, signaling...
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Transcript of MiRNA-drug resistance mechanisms Summary Hypothesis: The interplay between miRNAs, signaling...
miRNA-drug resistance mechanisms Summary
Hypothesis:The interplay between miRNAs, signaling pathways and epigenetic and genetic alterations are responsible for the development of drug resistance
Signaling pathwaysCopy Number
Variations (CNVs) EpigeneticsMicroRNAs
Tamoxifen resistance
miRNAmRNAproteinMethylationChIP-seq
Trastuzumab sensitiveERBB2+
SKBr3 and BT474
Trastuzumab resistant
0 6 12 18 24 30 weeks
DNA, RNA, miRNA, protein isolation
miRNA, mRNA, protein, methylation analysis
ER+
Trastuzumab resistance: Dynamic analysis
Aim 1: Classify miRNA, mRNA, protein expression and methylation status profile of tamoxifen and trastuzumab resistance phenotype to identify key molecular signatures as markers for resistance and treatment response.
Ward et al, Oncogene 2012
Unpublished data: Ward et al
Previous work:
Aim 1: Classify miRNA, mRNA, protein expression and methylation status profile of tamoxifen and trastuzumab resistance phenotype to identify key molecular signatures as markers for resistance and treatment response.
Aim 2: Identify early and late epigenetic and/or genetic changes during the process of trastuzumab resistance which can be used as a predictive marker for resistance development.
Aim 3: Classify miRNA, mRNA, protein expression and methylation status profile of tamoxifen and trastuzumab resistance phenotype in metastasis compared to primary tumor in vivo (xenograft mouse models and patient samples?)
Aim 1: Classify miRNA, mRNA, protein expression and methylation status profile of tamoxifen and trastuzumab resistance phenotype to identify key molecular signatures as markers for resistance and treatment response.
Aim 2: Identify early and late epigenetic and/or genetic changes during the process of trastuzumab resistance which can be used as a predictive marker for resistance development.
Aim 3: Classify miRNA, mRNA, protein expression and methylation status profile of tamoxifen and trastuzumab resistance phenotype in metastasis compared to primary tumor in vivo (xenograft mouse models and patient samples?)
Aim 4: Identify biomarkers (e.g. circulating miRNAs) in the plasma of xenograft mouse models and breast cancer patients (?) as an early onset marker for resistance development
Aim 5: Understand the molecular mechanisms what causes the alterations in the miRNA expression.
Aim 6: Identify the molecular mechanisms how genetic and epigenetic changes are responsible for the development of tamoxifen and trastuzumab resistance phenotype in vitro and in vivo.
Previous work:
Ward et al, Oncogene 2012 EMT: epithelial to mesenchymal transition MTDH: metadherin
Aim 5: Understand the molecular mechanisms what causes the alterations in the miRNA expression.
Aim 6: Identify the molecular mechanisms how genetic and epigenetic changes are responsible for the development of tamoxifen and trastuzumab resistance phenotype in vitro and in vivo.
Aim 7: Identify and test new potential targets to overcome tamoxifen and trastuzumab resistance and find new strategies for breast cancer therapies.
e.g. combination with - signaling pathways inhibitor- miRNAs inhibitors- HDAC inhibitors…
miRNA-drug resistance mechanisms Internal Networking
Aim 1-3+5
Aim 3+7
Aim 6
Aim 3,4,6,7
Aim 3+4
Aim 6
Aim 2
Aim 7