Treatment for advanced urothelial carcinoma (UC) has changed little in 20 years. While some potential therapeutic targets have been identified, identification of new clinically relevant therapeutic targets and predictive biomarkers is critical to improve outcomes for this disease. Limited information exists regarding the changes that occur in tumors that ultimately metastasize, the lethal phenotype of UC. For patients with metastatic UC, clinical prognostic variables are able to identify broad risk groups. However, the variability of outcomes within these groups is significant, and the ability to accurately prognosticate is limited. To identify novel biomarkers and therapeutic targets in patients with metastatic UC, a cohort of 94 patients who subsequently developed distant metastases and received uniform treatment were identified and thoroughly clinically annotated. Genomic DNA copy number analysis was performed on primary tumors by array comparative genomic hybridization, an unbiased approach. DNA copy number gains (CNG) and losses were assessed for association with overall survival, controlling for known clinical prognostic factors. CNG of a short region of chromosome 1q23.3 was associated with a very poor median overall survival (7.3 months), compared to 18 months for patients without 1q23.3 CNG (p = 0.007). By confirming the lethality of 1q23.3 CNG in another cohort, and beginning to characterize the underlying biology of 1q23.3 CNG, this grant is expected to facilitate the identification of a critical factor in UC pathogenesis and lethality, and may in fact identify a new therapeutic target in UC.
The specific aims for this project include confirmation of chromosome 1q23.3 CNG as a biomarker of lethality in an independent cohort of UC patients using a novel DNA copy number technology (NanoString CNV). Performing external validation in an unrelated cohort of metastatic UC tumors will establish the clinical relevance of the association of 1q23.3 CNG with lethality. In addition, this grant will identify specific genes residing on 1q23.3 that drive lethality in UC. It is predicted that chromosome 1q23.3 CNG will alter expression of candidate genes in that region, and that changes in gene expression will lead to phenotypic changes in model systems such as increased proliferation and invasion, and decreased programmed cell death. We will evaluate mRNA expression of transcripts in and around the region of 1q23.3 CNG in UC tumors with known gain or loss using NanoString mRNA quantification, and characterize phenotypic changes in model systems.
This aim will explore the biological underpinnings of 1q23.3 CNG, and serve as preliminary data for future research to determine the exact mechanism of UC lethality. Ultimately, this biomarker could identify patients destined to develop lethal disease while they still have early-stage disease, and direct them towards different and hopefully curative therapy (e.g. early cystectomy for non-invasive UC). This work will provide the foundation for future studies to develop the 1q23.3 biomarker as a potential clinical test, as well as explore the biology of 1q23.3 CNG in xenograft models and in larger clinical datasets.
Urothelial carcinoma (UC) is among the most expensive malignancy to treat due to the invasive nature of surveillance and treatment, and metastatic UC remains a terminal illness with few effective treatment options. Early identification of patients destined to develop lethal UC will allow for more appropriate treatment for those patients, and potentially identify critical biological pathways that drive this disease. This grant will support work to confirm and characterize the biological underpinnings of chromosome 1q23.3 amplification in UC to determine why it is associated with lethal disease.
|Riester, Markus; Werner, Lillian; Bellmunt, Joaquim et al. (2014) Integrative analysis of 1q23.3 copy-number gain in metastatic urothelial carcinoma. Clin Cancer Res 20:1873-83|
|Rosenberg, Jonathan E; Bambury, Richard M; Van Allen, Eliezer M et al. (2014) A phase II trial of AS1411 (a novel nucleolin-targeted DNA aptamer) in metastatic renal cell carcinoma. Invest New Drugs 32:178-87|