The long-term objective of this project is to improve the detection of one of the common human cancers arising in the bladder by non-invasive voided urine-based tests. Bladder cancer is the 4th most frequent in men and 5th most common overall with approximately 70,500 new cases and 14,600 deaths from the disease in 2009 in the United States. It is estimated that nearly 300,000 patients are regularly monitored in the United States through a variety of non-invasive (urine) and minimally invasive (bladder barbotage, cystoscopy, and biopsy) techniques. Therefore, the development of novel biomarkers that can detect bladder tumors by a non-invasive approach is of major clinical significance. In this grant, we propose to complement the existing Multi-Institutional Aurora kinase A FISH Test Biomarker Validation Trial by novel FISH markers and explore the role of Aurora kinase A in bladder cancer progression. We will compare the specificity and sensitivity of aurora A FISH test complemented by a panel of novel FISH markers with other known noninvasive bladder cancer detection tests for voided urine sediments such as urine cytology and commercially available multi-chromosomal FISH kit known as UroVysion, and NMP22 point-of-care test. A panel of novel FISH markers will be developed by whole-organ histologic and genetic mapping (WOHGM) strategy combined with high resolution (IM) lllumina SNP-based genotyping, which provides unique information on the chronology of genomic alterations that parallel the development of bladder cancer from early field effects to invasive disease. Our strong preliminary data indicate that this approach offers a unique opportunity to design novel biomarkers that may address the specific phases of bladder cancer development along these superficial papillary and high grade nonpapillary Invasive pathways. Moreover, we propose to investigate the role of aurora kinase A and its regular pathway in bladder cancer progression to invasive disease and distant metastasis.
The specific aims of this project are as follows:
Specific Aim 1 : Develop a panel of novel FISH markers for bladder cancer.
Specific Aim 2 : Validate a novel set of FISH biomarkers for bladder cancer.
Specific Aim 3 : Investigate the role of Aurora kinase A in bladder cancer growth, angiogenesis, invasion and metastasis.
In this grant we propose to develop and validate a novel set of FISH markers and compare it with aurora A FISH test as a biomarker for the detection of bladder cancer in the multi-institutional validation protocol. In this trial the performance of novel FISH tests will be compared with cytology, UroVysion FISH, and NMP22 tests. Given the high frequency of bladder cancer, the development of specific and sensitive tests for the disease by a non-Invasive approach will have a great impact on its management. The clinical use of such a test will represent a novel standard of practice facilitating early treatment of bladder cancer and positively affecting the survival rates of the patients with bladder cancer. The biomarker studies will be complemented by mechanistic studies focused on the role of aurora kinase A in bladder cancer progression including invasion, angiogenesis, and metastasis.
|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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