Download or read book Biomarkers of Therapeutic Response in Bladder Cancer written by Andrew Edward Goodspeed and published by . This book was released on 2018 with total page 168 pages. Available in PDF, EPUB and Kindle. Book excerpt: We performed an unbiased, whole-genome CRISPR screen to identify mediators of cisplatin resistance in a bladder cancer cell line. The mismatch repair pathway and the mismatch repair gene, MSH2, were strongly enriched in the plasmids increasing cisplatin resistance. We hypothesized that bladder cancer cell lines and tumors with low levels of MSH2 protein would be more resistant to cisplatin-based chemotherapy regimens. shRNA-mediated reduction in MSH2 reduced cisplatin-mediated apoptosis in two bladder cancer cell lines. Publicly available data from 340 patients with MIBC was used to determine the clinical impact of low MSH2 on the response to platinum-based chemotherapy. As hypothesized, MIBC patients with tumors expressing low levels of MSH2 had poorer survival when treated with platinum-based chemotherapy compared to patients expressing higher levels of MSH2. There was no association between MSH2 and survival in patients without pharmacologic or radiation treatment, supporting MSH2 as a predictive biomarker of response to therapy and not prognostic of patient survival. Another portion of this work was to use pharmacogenomics from another cancer type to rationally select MIBCs for alternative therapies. We hypothesized that a gene expression signature derived from colorectal tumors would predict the response to EGFR inhibitors. A gene expression signature, the EGFRi67, was derived from training data of colorectal tumor response to the EGFR antibody cetuximab. This EGFRi67 was applied to bladder cancer cell lines to predict their response to several EGFR inhibitors. Using newly generated and publically available pharmacologic data, we found that EGFR inhibitors were more effective in the predicted sensitive cell lines, consistent with our hypothesis. Future validation studies in bladder cancer patients are needed to fully evaluate MSH2 and the EGFRi67 as effective biomarkers of therapeutic response in bladder cancer. Both of these biomarkers have the potential to improve clinical decision making by predicting response to treatment. MSH2 has the potential to identify patients unlikely to benefit from first-line therapy and may pursue other, perhaps more effective, alternative therapies. The EGFRi67 could assist in this decision-making process by identifying patients likely to respond to a specific targeted therapy, informing an alternative therapy for patients where platinum-therapy is ineffective. Collectively, this work expands our knowledge of pharmacogenomics in MIBC and may be used to improve the use of precision medicine.