Background:  Oncogenes serve as rationale drug targets due to the strong and sustained reliance of tumor cells on the pathways they activate, a concept that has served as the basis for the successful development of molecularly targeted therapies for multiple cancers.  In contrast, molecularly targeted therapy has not yet made an impact on the management of bladder cancer.  Encouragingly, bladder cancer genomic sequencing has revealed candidate oncogenes potentially amenable to inhibition with drugs.  Through genomic data analysis, we identified a potentially oncogenic pathway regulating transcription that is genetically altered in about one quarter of bladder cancers.  While the genomic data raises the possibility that the pathway is oncogenic, there was previously no direct functional data supporting this view.

Year one achievements: The goal of the first year was to prove that somatic gene alterations in the pathway indeed hyperactive the pathway and generate pro-tumorgenic signals. In year one, we made significant progress toward these goals.  1)  We generated several cell line models showing that mutant versions of the candidate oncogenes are indeed hyperactive as assessed by transcriptional measurements.  2)  We showed that the candidate oncogenes can drive proliferation of bladder cells using a novel bladder cell culturing system developed in my laboratory.  3)  We began structure-function studies to identify the structural basis by which the oncogenic mutation leads to pathway activation, an element of the work that will be particularly important for the rationale development of drugs targeting the pathway.

Year two achievements:  In year two we extended on our year one achievements.  1)  We have begun generating data suggesting the oncogenic mutation drives tumor development in vivo.  2)  We have further advanced our structure function studies, explaining the mechanism by which a single point mutation is able to lead to hyper-activation of the oncogenic pathway.  3)  We have initiated studies to determine if targeting the oncogenic pathway in bladder cancer cells derived from human patients has an anti-tumor affect.  If successful, we believe this finding will provide a compelling basis for drug development against this pathway.

Background: Oncogenes serve as rationale drug targets due to the strong and sustained reliance of tumor cells on the pathways they activate, a concept that has served as the basis for the successful development of molecularly targeted therapies for multiple cancers. In contrast, the management of metastatic bladder cancer has been stagnant with platinum based chemotherapy regimens serving as the only proven life- prolonging treatment for metastatic bladder cancer for ~30 years, despite it being the 5th most common malignancy in the US. Encouragingly, bladder cancer genomic sequencing has revealed candidate oncogenes potentially amenable to inhibition with drugs. Through genomic data analysis, we identified a potentially oncogenic pathway regulating transcription that is genetically altered in about one quarter of bladder cancers. While the genomic data raises the possibility that the pathway is oncogenic, there was previously no direct functional data supporting this view.

Year one achievements: The goal of the first year was to prove that somatic gene alterations in the pathway indeed hyperactive the pathway and generate pro-tumorgenic signals. In year one, we made significant progress toward these goals. 1) We have generated several cell line models showing that mutant versions of the candidate oncogenes are indeed hyperactive as assessed by transcriptional measurements. 2) We have shown that the candidate oncogenes can drive proliferation of bladder cells using a novel bladder cell culturing system developed in my laboratory. 3) We have begun structure-function studies to identify the structural basis by which the oncogenic mutation leads to pathway activation, an element of the work that will be particularly important for the rationale development of drugs targeting the pathway.

Year two goals: In year two we will try to extend our findings by demonstrating that he candidate oncogenic pathway not only drives proliferation of bladder cells, but also enable cellular transformation in an in vivo mouse model: in other words, that the pathway is indeed oncogenic. The technology for this approach was largely worked out in year 1 and now will be applied to the genes of interest for this study. We will then establish that the pathway remains important in tumor cells using shRNA knock-down experiments. These experiments will be critical to establishing the pathway as an oncogenic drug target. We will also further our structure-function studies with the goal of setting the stage for future drug development.