The overall goal of these studies is to improve the treatment of non-muscle invasive bladder cancer by identifying second line agents that are effective in the scenario of BCG resistance and hopefully for all nonmuscle invasive bladder cancer in future years. During the course of the last cycle of SPORE funding, we provided strong evidence for effective gene transfer and potential clinical efficacy when intravesical adenoviral-mediated interferona(IFNa) gene therapy was administered with Syn3 (Ad-IFNa/Syn3). Approximately 50% of the treated patients, all of which were BCG resistant, obtained a complete remission (CR). We also found that Ad-IFNa induces cancer cell death in human bladder cancer cells that are insensitive to the recombinant IFNa protein itself, and that cell death occurs via direct and indirect (bystander) mechanisms. Moreover, normal urothelial cells appear to be resistant to Ad-IFNa. In this renewal we plan to complete a Phase IB study of intravesical Ad-IFNa/Syn3 to optimize the schedule by determining whether therapy on Day 1 and an additional instillation on Day 4 will enhance gene transfer and result in higher and more sustained urine IFNa levels than were achieved with a single treatment In patients achieving a CR at 90 days we will repeat treatment on Day 1 and 4 to determine whether redosing with this schedule will provide for effective gene transfer. TRAIL, M30 and M65 levels will also be measured in the urine as possible markers of clinical efficacy and tumor cell death. Subsequently we plan to participate in and lead a multicenter Phase II trial based upon the results of Phase IB study. The isolation and identification of the soluble factor(s) responsible for the Ad-IFNa produced bystander cell death on cancer cells will also be a focus. In addition to its obvious value as a biomarker of Ad-IFN activity, the bystander factor(s) could itself have clinical utility. Various methods will be utilized in these studies, including size exclusion concentration, size-exclusion FPLC column subfractionation and mass spectroscopy.

Public Health Relevance

Thoso studios have the potential to establish a new paradigm for the therapy of non-muscle invasive bladder cancer, which might qualitatively change the natural history of this disease. It also may provide the evidence for new biological markers such as M30 and M65 in the urine for the efficacy of Ad-IFN bladder cancer treatment and if the bystander factor(s) produced by Ad-IFN prove to be unique, such a factor may even develop into a new therapeutic or at least be another biological marker in the urine.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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University of Texas MD Anderson Cancer Center
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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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