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.
|Choi, Woonyoung; Porten, Sima; Kim, Seungchan et al. (2014) Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 25:152-65|
|Hoang, Anthony N; Agarwal, Piyush K; Walton-Diaz, Annerleim et al. (2014) Clinical significance of ureteric 'skip lesions' at the time of radical cystectomy: the M.D. Anderson experience and literature review. BJU Int 113:E28-33|
|Benedict, W F; Fisher, M; Zhang, X-Q et al. (2014) Use of monitoring levels of soluble forms of cytokeratin 18 in the urine of patients with superficial bladder cancer following intravesical Ad-IFN?/Syn3 treatment in a phase l study. Cancer Gene Ther 21:91-4|
|Figueroa, Jonine D; Ye, Yuanqing; Siddiq, Afshan et al. (2014) Genome-wide association study identifies multiple loci associated with bladder cancer risk. Hum Mol Genet 23:1387-98|
|Culp, Stephen H; Dickstein, Rian J; Grossman, H Barton et al. (2014) Refining patient selection for neoadjuvant chemotherapy before radical cystectomy. J Urol 191:40-7|
|Chakravarti, Deepavali; Su, Xiaohua; Cho, Min Soon et al. (2014) Induced multipotency in adult keratinocytes through down-regulation of ?Np63 or DGCR8. Proc Natl Acad Sci U S A 111:E572-81|
|Cancer Genome Atlas Research Network (2014) Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507:315-22|
|Dinney, Colin P N; Hansel, Donna; McConkey, David et al. (2014) Novel neoadjuvant therapy paradigms for bladder cancer: results from the National Cancer Center Institute Forum. Urol Oncol 32:1108-15|
|Yan, Chao; Liu, Degang; Li, Liwei et al. (2014) Discovery and characterization of small molecules that target the GTPase Ral. Nature 515:443-7|
|Lee, Eugene K; Ye, Yuanquing; Kamat, Ashish M et al. (2013) Genetic variations in regulator of G-protein signaling (RGS) confer risk of bladder cancer. Cancer 119:1643-51|
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