Project description:We report that previously described molecular subtypes of colorectal cancer are associated with the response to therapy in patients with metastatic disease. We also identified a patient population with high FOLFIRI sensitivity, as indicated by their 2.7-fold longer overall survival when treated with FOLFIRI, as first-line regimen, instead of FOLFOX. Our results demonstrate the interest of molecular classifications to develop tailored therapies for patients with metastatic colorectal cancer.
Project description:We report that previously described molecular subtypes of colorectal cancer are associated with the response to therapy in patients with metastatic disease. We also identified a patient population with high FOLFIRI sensitivity, as indicated by their 2.7-fold longer overall survival when treated with FOLFIRI, as first-line regimen, instead of FOLFOX. Our results demonstrate the interest of molecular classifications to develop tailored therapies for patients with metastatic colorectal cancer.
Project description:Consensus molecular subtypes classification of colorectal cancer as a predictive factor for chemotherapeutic efficacy against metastatic colorectal cancer
Project description:Cell plasticity of Triple negative breast cancer (TNBC) contributes to tumor heterogeneity and is one of the major reasons for the limited success of chemo- or combination therapies in the clinics. The molecular mechanisms of therapy-induced tumor cell plasticity and associated resistance to chemo or targeted therapies are largely unknown. Using a genome wide CRISPR-Cas9 screen we investigated the escape mechanisms of Notch driven TNBC, when treated with targeted therapy. We describe molecularly a reciprocal inhibitory feedback mechanism between Notch signaling and the pluripotency associated transcription factor SOX2, which shapes divergent cell states, EMT, cancer stem cell features and associates with therapeutic response and escape to targeted therapy. Moreover, we performed and assessed monotherapy and drug combination treatments in Notch-inhibitor sensitive and resistant TNBC xenotransplant and identified combination and second line treatment options which were able to induce tumor control and reduce metastatic burden.
Project description:Cell plasticity of Triple negative breast cancer (TNBC) contributes to tumor heterogeneity and is one of the major reasons for the limited success of chemo- or combination therapies in the clinics. The molecular mechanisms of therapy-induced tumor cell plasticity and associated resistance to chemo or targeted therapies are largely unknown. Using a genome wide CRISPR-Cas9 screen we investigated the escape mechanisms of Notch driven TNBC, when treated with targeted therapy. We describe molecularly a reciprocal inhibitory feedback mechanism between Notch signaling and the pluripotency associated transcription factor SOX2, which shapes divergent cell states, EMT, cancer stem cell features and associates with therapeutic response and escape to targeted therapy. Moreover, we performed and assessed monotherapy and drug combination treatments in Notch-inhibitor sensitive and resistant TNBC xenotransplant and identified combination and second line treatment options which were able to induce tumor control and reduce metastatic burden.
Project description:Cell plasticity of Triple negative breast cancer (TNBC) contributes to tumor heterogeneity and is one of the major reasons for the limited success of chemo- or combination therapies in the clinics. The molecular mechanisms of therapy-induced tumor cell plasticity and associated resistance to chemo or targeted therapies are largely unknown. Using a genome wide CRISPR-Cas9 screen we investigated the escape mechanisms of Notch driven TNBC, when treated with targeted therapy. We describe molecularly a reciprocal inhibitory feedback mechanism between Notch signaling and the pluripotency associated transcription factor SOX2, which shapes divergent cell states, EMT, cancer stem cell features and associates with therapeutic response and escape to targeted therapy. Moreover, we performed and assessed monotherapy and drug combination treatments in Notch-inhibitor sensitive and resistant TNBC xenotransplant and identified combination and second line treatment options which were able to induce tumor control and reduce metastatic burden.
Project description:Currently there is a lack of effective therapies which result in long-term durable response for patients presenting with advanced and metastatic clear cell renal cell carcinoma (ccRCC). This is due in part to a lack of molecular factors which can be targeted pharmacologically. In order to identify novel tumor-specific targets, we performed high throughput gene array analysis screening numerous patient ccRCC tumor tissues across all stages of disease, and compared their gene expression levels to matched normal kidney. Our results identify a number of genes which demonstrate tumor-specific overexpression, and may present as novel targets for therapy. Patient tissue samples were sorted into disease stages based on pathology reports. RNA was extracted from flash frozen patient tumor and normal samples. Gene array analysis was performed, and resulting expression levels were compared between normal and tumor samples.
Project description:Triple negative breast cancer (TNBC) is an aggressive subtype that lack targeted clinical therapies. In addition, TNBC is heterogeneous and was recently further sub-classified into seven TNBC subtypes that displayed unique gene expression patterns. To develop therapeutic treatment regimens, we established seven patient-derived xenograft models from TNBC tumors. These xenograft models not only retained the histology and clinical markers of the corresponding patient tumors, but also bearing the same mutations and deletions identified in the patient tumors. Moreover, as part of evaluation of these models, we performed microarrays on the xenograft tumors to assess their TNBC subtypes.
