In 2009 over 70,000 Americans were diagnosed with urinary bladder cancer, and in that same year over 14,000 Americans died of bladder cancer. Low funding for bladder cancer helps explain the slow progress in both the identification of biomarkers and the development of new treatments for metastatic bladder cancer. Nonetheless, novel diagnostic biomarkers are needed to aid in the early identification of patients with bladder cancer, and also to determine which patients are likely to progress. Vanderbilt researchers have identified such a biomarker whose expression is reduced and lost during progression of bladder cancer.
The treatment of bladder cancer places tremendous fiscal burden on the health care system, as per capita, it is one of the most expensive malignancies to manage clinically. Vanderbilt researchers have identified a biomarker for the progression of bladder cancer, FOXA1, a transcription factor that plays an important role in urothelial differentiation. The FOXOA1 biomarker technology is suited for development into a urine or biopsy-based assay to monitor muscle invasive bladder cancer progression and likelihood of metastasis. Specifically, loss of FOXOA1 expression can be used to detect a subset of bladder cancers that display a squamous or “basal” phenotype. Knowledge of the FOXOA1 status of a bladder cancer would be clinically useful as these “basal” bladder cancers respond differently to neoadjuvant chemotherapy than other bladder cancers.
DeGraff and colleagues have accumulated a host of data demonstrating a progressive reduction of FOXA1 as tumor invasion stage increases (top graph). Analysis of over 160 human bladder cancer tumors obtained both from Vanderbilt University Hospital and the University of Virginia indicates that FOXA1 expression is absent in 40% of urothelial cell carcinomas, and over 80% of squamous cell carcinomas of the bladder. The images to the right further illustrate the loss of FOXA1 from healthy tissue (top two images) to cancerous (lower two images). This test has the potential to be performed on cells isolated from urine, or a biopsy, and is important, not only because it is a biomarker for bladder cancer, but may be a biomarker for the most deadly types of invasive bladder cancer.
DeGraff DJ, Clark PE, Cates JM, Yamashita H, Robinson VL, Yu X, Smolkin ME, Chang SS, Cookson MS, Herrick MK, Shariat SF, Steinberg GD, Frierson HF, Wu XR, Theodorescu D, Matusik RJ. Loss of the urothelial differentiation marker FOXA1 is associated with high grade, late stage bladder cancer and increased tumor proliferation. PLoS One. 2012;7(5):e36669. .
Reddy OL, Cates JM, Gellert LL, Crist HS, Yang Z, Yamashita H, Taylor JA 3rd, Smith JA Jr, Chang SS, Cookson MS, You C, Barocas DA, Grabowska MM, Ye F, Wu XR, Yi Y, Matusik RJ, Kaestner KH, Clark PE, DeGraff DJ. Loss of FOXA1 Drives Sexually Dimorphic Changes in Urothelial Differentiation and Is an Independent Predictor of Poor Prognosis in Bladder Cancer. Am J Pathol. 2015 May;185(5):1385-95. .
A US patent application has been filed.