Periodic Reporting for period 1 - EPOCH28 (Epigenetic Profiling of Chemotherapy Efficacy)
Okres sprawozdawczy: 2015-11-01 do 2017-04-30
The limited capacity to predict a patient's response to distinct chemotherapeutic agents is a major hurdle in cancer management. It is known that cancer derives from a combination of genetic and epigenetic mutations and recent evidence demonstrate that the misregulation of chromatin regulators contributes to tumorigenesis, heterogeneity and the cellular response to anticancer drugs. Indeed, the efficiency of a large fraction of current cancer therapeutics (radio- and chemotherapies) is influenced by chromatin structure, and reciprocally, alterations in chromatin organization may affect resistance mechanisms. For these reasons, the misexpression of chromatin regulators (factors involved in the establishment and maintenance of functional chromatin domains) have the potential to be novel biomarkers for drug response.
Docetaxel is one of the most active anticancer agents and is used in the treatment of breast, lung, prostate, stomach and head/neck cancers, yet less than half of the patients respond and resistance is a major challenge. Notably, there is no clinically available predictive marker for docetaxel efficacy. The overall aim of our work was to test whether the expression of chromatin regulators could be used as novel predictive biomarkers for docetaxel treatment. In our study, we used 21 patient-derived xenograft (PDX) models of triple negative breast cancer (TNBC) to correlate gene expression data of 551 chromatin regulators with docetaxel response. Using Random Forest classification, we identified a panel of 19 chromatin regulators whose expression strongly correlates to docetaxel efficiency. Moreover, expression of these 19 chromatin regulators readily distinguishes high responders and low responders. Importantly, this signature could not distinguish responders among samples treated with cyclophosphamide and doxorubicin, indicating that it is specific for docetaxel response prediction. We next identified a cohort of 23 HER2+ breast cancer patients treated at the Institut Curie (Paris, France) who received docetaxel as the sole cytotoxic agent, in combination with the anti- HER2 molecularly targeted therapy trastuzumab (Herceptin). By analyzing expression data for the same 551 chromatin regulators in samples from these patients, we were able to identify a panel of 18 chromatin regulators that robustly distinguish four classes of treatment response (complete response, major partial response, partial response and stable disease/no response). Interestingly, these two genetic expression signatures contained several components of the SWI/SNF chromatin remodeler complex, suggesting its involvement in docetaxel response. Finally, we wanted to test whether the ability of these chromatin regulators to classify docetaxel responders was valid in a cancer model for a different organ so we utilized organoids derived from colorectal cancer patients. Interestingly, we found that 10 chromatin regulator genes exhibit the same selective trend for docetaxel as seen in the TNBC PDX models.
Overall, our work demonstrates that the expression of a panel of chromatin regulator genes correlates with the docetaxel response in several systems, highlighting the necessity to validate the clinical value of distinct chromatin regulators to identify docetaxel-sensitive patients in larger cohorts and their potential to predict sensitivity to other drugs.
Docetaxel is one of the most active anticancer agents and is used in the treatment of breast, lung, prostate, stomach and head/neck cancers, yet less than half of the patients respond and resistance is a major challenge. Notably, there is no clinically available predictive marker for docetaxel efficacy. The overall aim of our work was to test whether the expression of chromatin regulators could be used as novel predictive biomarkers for docetaxel treatment. In our study, we used 21 patient-derived xenograft (PDX) models of triple negative breast cancer (TNBC) to correlate gene expression data of 551 chromatin regulators with docetaxel response. Using Random Forest classification, we identified a panel of 19 chromatin regulators whose expression strongly correlates to docetaxel efficiency. Moreover, expression of these 19 chromatin regulators readily distinguishes high responders and low responders. Importantly, this signature could not distinguish responders among samples treated with cyclophosphamide and doxorubicin, indicating that it is specific for docetaxel response prediction. We next identified a cohort of 23 HER2+ breast cancer patients treated at the Institut Curie (Paris, France) who received docetaxel as the sole cytotoxic agent, in combination with the anti- HER2 molecularly targeted therapy trastuzumab (Herceptin). By analyzing expression data for the same 551 chromatin regulators in samples from these patients, we were able to identify a panel of 18 chromatin regulators that robustly distinguish four classes of treatment response (complete response, major partial response, partial response and stable disease/no response). Interestingly, these two genetic expression signatures contained several components of the SWI/SNF chromatin remodeler complex, suggesting its involvement in docetaxel response. Finally, we wanted to test whether the ability of these chromatin regulators to classify docetaxel responders was valid in a cancer model for a different organ so we utilized organoids derived from colorectal cancer patients. Interestingly, we found that 10 chromatin regulator genes exhibit the same selective trend for docetaxel as seen in the TNBC PDX models.
Overall, our work demonstrates that the expression of a panel of chromatin regulator genes correlates with the docetaxel response in several systems, highlighting the necessity to validate the clinical value of distinct chromatin regulators to identify docetaxel-sensitive patients in larger cohorts and their potential to predict sensitivity to other drugs.