EARLY DETECTION OF URINARY BLADDER CANCER

该项目的总体目标是开发早期检测隐匿性膀胱肿瘤及其即将发展为侵袭性临床侵袭性膀胱癌的标志物。本研究的核心初步数据来自于我们的全基因组模型，该模型描述了膀胱癌从隐匿原位癌前病变到浸润性癌的进展。数据是由我们实验室开发的全器官组织学和遗传图谱策略生成的。使用这种方法，我们将遗传和分子改变的模式与疾病的自然史相匹配，即从肿瘤前状态到侵袭性癌症的进展。我们的模型提供了超过30个推测的肿瘤抑制基因位点的数据，这些基因位点与膀胱癌的发生和发展有关。从这些数据中，我们选择了最有希望的推定肿瘤抑制基因位点，用于开发检测早期隐匿性膀胱肿瘤及其侵袭性变异的标志物。此外，我们假设存在膀胱癌进展的分子机制，基于负责基因组稳定性的新型致癌激酶STK 15/BTAK的扩增和过表达。这种酶的过度表达似乎是导致染色体异常分离的基因组不稳定的原因。我们计划利用3、9、10和13号染色体的几个靶抑制基因位点的等位基因缺失以及STK15/BTAK的扩增/过表达作为早期检测膀胱肿瘤及其进展为侵袭性临床侵袭性膀胱癌的标志物。该项目应提供两个主要产品：(1)所有检测标记物及其诊断探针性能的公共数据库共享数据库，可用于开发诊断标记物和鉴定靶基因，不仅在泌尿系癌，而且在其他类型的癌症。这一数据将补充我们的膀胱癌进展的全基因组模型，并将作为靶向膀胱癌和其他癌症类型的肿瘤抑制基因的指南。此外，关于涉及20q扩增子的最小扩增区域的信息将为标志物的开发和识别参与膀胱癌和可能的其他癌症进展的显性激活转化基因提供有价值的信息。(2)诊断相关的大约10个FISH和10个高变DNA探针，用于早期检测膀胱隐匿性癌前病变及其进展为侵袭性癌症的侵袭性变异，用于主要的临床验证试验。如果该项目获得资助，我们的商业合作伙伴Urocor打算提交一份补充的SBIR申请（附UroSciences Group副总裁兼总经理Robert W. Veltri博士的支持信）。

The overall goal of this project is to develop markers for early detection of occult urinary bladder neoplasia and its imminent progression to invasive clinically aggressive urinary bladder cancer. The core preliminary data for this proposal is provided by our genome-wide model of urinary bladder cancer progression from occult in situ preneoplastic conditions to invasive cancer. The data was generated by a strategy of whole organ histologic and genetic mapping developed in our laboratory. Using this approach we matched the patterns of genetic and molecular alterations with the natural history of disease, i.e its progression from preneoplastic conditions to invasive cancer. Our model provides data on over 30 putative tumor supressor gene loci involved in the development and progression of urinary bladder cancer. From this data, the most promising putative tumors supressor gene loci were selected for the development of markers to detect early occult urinary bladder neoplasia and its aggressive variants. In addition we hypothesize that there is a molecular mechanism of bladder cancer progression based on the amplification and overexpression of novel oncogenic kinase STK 15/BTAK responsible for genomic stability. Overexpression of this enzyme appears to be responsible for genomic instability causing abnormal segregation of chromosomes. We plan to use allelic losses in several target suppressor gene loci of chromosomes 3, 9, 10, and 13 as well as amplification/over expression of STK15/BTAK as markers for early detection of urinary bladder neoplasia and its progression to invasive clinically aggressive bladder cancer. This project should provide two major products: (1) Public repository of shared data base on all tested markers and their performance as diagnostic probes, that can be used for the development of diagnostic markers and identification of target genes not only in the urinary cancer, but in other cancer types. This data will compliment our genome wide model of bladder cancer progression and will serve as a guide for targeting tumor suppressor genes involved in bladder cancer and other cancer types. In addition, information on minimal amplified regions involving 20q amplicon will provide valuable information for markers development and for identification of dominantly activated transforming genes involved in progression of bladder cancer and possibly other cancers. (2) Diagnostically relevant panel of approximately ten FISH and ten hypervariable DNA probes for early detection of occult preneoplastic changes in the urinary bladder and their aggressive variants progressing to invasive cancer for major clinical validation trial. If this project is funded, it is the intent of our commercial partner Urocor to submit a supplemental SBIR application (letter of support from Dr. Robert W. Veltri, Vice President and General Manager of the UroSciences Group, is attached).