Enhancing chemotherapy response in triple negative.. (TNBChemiRNet)
Enhancing chemotherapy response in triple negative breast cancer (TNBC) by modulating miRNA-target network and identifying biomarkers of response
Start date: Jul 1, 2014,
End date: Jun 30, 2018
Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer and therapies are primarily limited to conventional chemotherapy. TNBC patients who respond to neo-adjuvant chemotherapy with a pathological complete response (pCR) have excellent 5-year survival (up to 94%). However, this represents the minority of TNBC patients (25-40%). The remaining patients have less than 60% 5-year survival due to aggressive relapse. Therefore, increasing the pCR rate of chemotherapy in TNBC holds great promise for improving survival. Furthermore, it is important to identify biomarkers to predict/stratify TNBC patients with higher probability of response to chemotherapy. Recently, microRNAs (miRNAs), which are 20-22 nucleotide small RNAs, emerged as master regulators of several oncogenic processes including therapy resistance and have great potential to be used as therapeutics due to their ability to repress several oncogenic proteins simultaneously. Moreover, miRNAs have also been shown to be promising biomarkers for diagnosis, prognosis and therapy response in cancer. Herein I propose to study the potential for modulation of miRNAs/their target networks to enhance the response to chemotherapy and to identify biomarker of chemotherapy response in TNBC. In this line, I will develop in vivo chemoresistant models using both xenografts and tumor transplants from an established TNBC mouse model. Combining whole genome miRNA/mRNA sequencing, bioinformatics and network biology, miRNAs/their target network involved in chemoresistance will be identified, and targeted to enhance the chemoresponse of TNBC models. Finally, the biomarker potential of identified miRNAs/targets in TNBC patient tumors will be tested with inter-(national) collaborations from two different countries. Overall, this interdisciplinary study will provide pre-clinical data to enhance chemotherapy response in TNBC and identify biomarkers stratifying patients with higher response rate to chemotherapy.
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