Tumors that express mutant protein kinases are usually dependent upon them for growth and survival. Activating mutations in FGFR3 occur in over half of low-grade non-muscle invasive bladder cancers (BCs) and in a quarter of muscle-invasive tumors, and small molecule and antibody-based FGFR3 inhibitors have exhibited potent growth-inhibitory activities in some BC cell lines and xenografts in preclinical studies. However, clinical translation of these observations has not occurred, in part because dose escalation trials have revealed that FGFR inhibitors produce some toxicity, and whether the extent of target inhibition at non-toxic doses is sufficient to produce apoptosis and/or growth arrest is not clear. We have assembled a collaborative group involving the GU Cancers team at Astra-Zeneca and Dr. Margaret Knowles (University of Leeds, UK) to conclusively determine the value of FGFR3 as a therapeutic target in BC. Our approach will be to use our unique panel of cell lines and xenografts to (1) isolate biomarkers that predict FGFR3 dependency better than FGFR3 mutational status alone and (2) develop pharmacodynamic approaches to determine the extent of tumor FGFR3 pathway inhibition and correlate it with biological response. We will also explore the effects of the novel tumor suppressive """"""""forerunner"""""""" gene ARL11 on Ras pathway activation and define the relationships between ARL11 downregulatlon, FGFR3 and Ras mutational status, and Ras pathway activation in primary tumors, studies that are based on novel findings obtained in Project 1. We will then perform a neoadjuvant clinical trial to determine whether the doses of AZD4547 that can be safely achieved in patients produce sufficient target inhibition to cause apoptosis and/or growth arrest in primary tumors. This methodical approach will provide the strong mechanistic information required for the intelligent design of subsequent Phase II studies in low-grade and muscle-invasive BCs as well as in hematological and other tumors.
Activating mutations in FGFR3, a growth-promoting receptor, occur In a large number of BCs, and Inhibitors of FGFR3 have already been developed for cancer therapy. The goal of this project is to learn how to predict which tumors will respond to these inhibitors and confirm that the level of inhibition achieved In patients Is sufficient to produce desirable biological effects in patients.
|Duplisea, Jonathan J; Mokkapati, Sharada; Plote, Devin et al. (2018) The development of interferon-based gene therapy for BCG unresponsive bladder cancer: from bench to bedside. World J Urol :|
|Choi, Woonyoung; McConkey, David (2018) Reply to Joshua A. Linscott, Angela B. Smith, and Jesse D. Sammon's Letter to the Editor re: Woonyoung Choi, Andrea Ochoa, David J. McConkey, et al. Genetic Alterations in the Molecular Subtypes of Bladder Cancer: Illustration in the Cancer Genome Atlas D Eur Urol 73:e104-e105|
|Zhang, Miao; Adeniran, Adebowale J; Vikram, Raghunandan et al. (2018) Carcinoma of the urethra. Hum Pathol 72:35-44|
|Wang, Gang; Xiao, Li; Zhang, Miao et al. (2018) Small cell carcinoma of the urinary bladder: a clinicopathological and immunohistochemical analysis of 81 cases. Hum Pathol 79:57-65|
|Zhang, Shizhen; Wang, Yan; Bondaruk, Jolanta et al. (2018) Detection of Bladder Cancer in Urine Sediments by a Novel Multicolor Fluorescence In Situ Hybridization (Quartet) Test. Eur Urol Focus :|
|Jazzar, Usama; Yong, Shan; Klaassen, Zachary et al. (2018) Impact of psychiatric illness on decreased survival in elderly patients with bladder cancer in the United States. Cancer 124:3127-3135|
|Westhoff, Ellen; Wu, Xifeng; Kiemeney, Lambertus A et al. (2018) Dietary patterns and risk of recurrence and progression in non-muscle-invasive bladder cancer. Int J Cancer 142:1797-1804|
|von Rundstedt, Friedrich-Carl; Mata, Douglas A; Kryvenko, Oleksandr N et al. (2017) Utility of Clinical Risk Stratification in the Selection of Muscle-Invasive Bladder Cancer Patients for Neoadjuvant Chemotherapy: A Retrospective Cohort Study. Bladder Cancer 3:35-44|
|Huo, Jinhai; Chu, Yiyi; Chamie, Karim et al. (2017) Increased Utilization of Positron Emission Tomography/Computed Tomography (PET/CT) Imaging and Its Economic Impact for Patients Diagnosed With Bladder Cancer. Clin Genitourin Cancer :|
|Roth, Beat; Jayaratna, Isuru; Sundi, Debasish et al. (2017) Employing an orthotopic model to study the role of epithelial-mesenchymal transition in bladder cancer metastasis. Oncotarget 8:34205-34222|
Showing the most recent 10 out of 247 publications