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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA091846-11
Application #
8230254
Study Section
Special Emphasis Panel (ZCA1-RPRB-M (O1))
Project Start
2011-09-01
Project End
2017-08-31
Budget Start
2012-09-19
Budget End
2012-08-31
Support Year
11
Fiscal Year
2012
Total Cost
$203,201
Indirect Cost
$66,291
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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
Shore, Neal D; Boorjian, Stephen A; Canter, Daniel J et al. (2017) Intravesical rAd-IFN?/Syn3 for Patients With High-Grade, Bacillus Calmette-Guerin-Refractory or Relapsed Non-Muscle-Invasive Bladder Cancer: A Phase II Randomized Study. J Clin Oncol 35:3410-3416
Lin, Moubin; Zhang, Liren; Hildebrandt, Michelle A T et al. (2017) Common, germline genetic variations in the novel tumor suppressor BAP1 and risk of developing different types of cancer. Oncotarget 8:74936-74946
Metcalfe, Michael J; Ferguson, James E; Li, Roger et al. (2017) Impact of High-risk Features and Effect of Neoadjuvant Chemotherapy in Urothelial Cancer Patients with Invasion into the Lamina Propria on Transurethral Resection in the Absence of Deep Muscle Invasion. Eur Urol Focus 3:577-583

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