Bladder cancer is the fifth most common cancer in the US and the fourth most common in men. Radical surgery remains the standard of care for patients with high grade, muscle-invasive disease but despite multi-modality treatment, approximately half of such patients develop metastatic disease, which is with rare exception fatal. Here, a custom next generation sequencing assay will be employed to define the spectrum of co-mutational events in muscle-invasive bladder cancers with a focus on defining the prevalence and prognostic relevance of mutations in the PI3 kinase/AKT/mTOR pathway. To avoid selection bias, this analysis will be performed using a large, prospectively collected, sequential cohort of patients with muscle-invasive disease undergoing radical cystectomy. A field cancerization effect is observed in patients with bladder cancer whereby multiple primary tumors develop within the urinary tract. To explore a genetic basis for this phenomenon, the analysis will be extended by comparing the genomic profile of normal appearing bladder epithelium to primary tumors to matched metastatic lymph nodes and distant metastatic sites. One goal of these studies will be to determine the temporal sequence of mutational events in bladder cancer with a focus on the timing of PI3 kinase alterations in disease progression. Functional studies will focus on genes that are commonly co-mutated with PI3 kinase pathway alterations to identify aberrations that enhance or abrogate tumor invasion and/or PI3 kinase and mTORC1-dependence. Finally, preliminary genomic data indicate that PI3 kinase pathway alterations are common and occur in a mutually exclusive pattern in patients with bladder cancer, suggesting overlapping functional effects. To directly compare the functional consequences of PTEN and TSC1 loss in bladder cancer in depth, we will compare the phenotype of genetically engineered mouse (GEM) models with conditional inactivation of the Pten and Tsc1 genes in the bladder epithelium. Mice with bladder specific and inducible expression of shRNAs will also be generated to determine whether continued suppression of Pten and/or p53 is required for tumor maintenance in mice with established tumors. The long-term objective will be to develop GEM mice that model the pattern of co-mutations identified in human bladder cancer with the goal of using these mice to understand the contribution of specific genomic alterations to bladder cancer progression and as models to study novel therapeutic strategies.
The goals of this project are to define in patients with muscle invasive and metastatic bladder cancer the prevalence of PI3 kinase alterations, the pattern of co-mutational events, their prognostic significance and their temporal sequence in bladder cancer initiation and progression. Functional studies will be performed using cell line and animal models.
|Owczarek, Tomasz B; Kobayashi, Takashi; Ramirez, Ricardo et al. (2017) ARF Confers a Context-Dependent Response to Chemotherapy in Muscle-Invasive Bladder Cancer. Cancer Res 77:1035-1046|
|Teo, Min Yuen; Bambury, Richard M; Zabor, Emily C et al. (2017) DNA Damage Response and Repair Gene Alterations Are Associated with Improved Survival in Patients with Platinum-Treated Advanced Urothelial Carcinoma. Clin Cancer Res 23:3610-3618|
|Mandelker, Diana; Zhang, Liying; Kemel, Yelena et al. (2017) Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. JAMA 318:825-835|
|AACR Project GENIE Consortium (2017) AACR Project GENIE: Powering Precision Medicine through an International Consortium. Cancer Discov 7:818-831|
|Isharwal, Sumit; Audenet, François; Drill, Esther et al. (2017) Prognostic Value of TERT Alterations, Mutational and Copy Number Alterations Burden in Urothelial Carcinoma. Eur Urol Focus :|
|Zehir, Ahmet; Benayed, Ryma; Shah, Ronak H et al. (2017) Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med 23:703-713|
|Al-Ahmadie, Hikmat A; Iyer, Gopa; Lee, Byron H et al. (2016) Frequent somatic CDH1 loss-of-function mutations in plasmacytoid variant bladder cancer. Nat Genet 48:356-8|
|Desai, Neil B; Scott, Sasinya N; Zabor, Emily C et al. (2016) Genomic characterization of response to chemoradiation in urothelial bladder cancer. Cancer 122:3715-3723|
|Kim, Philip H; Cha, Eugene K; Sfakianos, John P et al. (2015) Genomic predictors of survival in patients with high-grade urothelial carcinoma of the bladder. Eur Urol 67:198-201|
|Sfakianos, John P; Cha, Eugene K; Iyer, Gopa et al. (2015) Genomic Characterization of Upper Tract Urothelial Carcinoma. Eur Urol 68:970-7|