Bladder cancer (BC) ranks the fifth among the most prevalent cancers in the United States, with -75,000 new cases diagnosed annually and a 5-year prevalence of over half a million cases. On a per-case basis, BC is the costliest cancer to diagnose and treat. However, in spite of its prevalence, clinical challenges and socioeconomic ramifications, BC is persistently one of the least researched and funded cancers. As a result, the pathogenesis of BC remains poorly understood;few biomarkers exist to reliably predict BC progression;and few novel therapeutics have been developed during the last three decades. Over the last two years, a group of investigators with strong, diverse yet complementary expertise in molecular pathways of BC, chemical carcinogenesis, molecular and cell biology and signal transduction have joined forces to tackle BC using a multidisciplinary approach. Under the leadership of Dr. Xue-Ru Wu, who has been studying bladder biology and cancer for over 24 years, the Team has collaborated closely and synergistically, resulting in the generation of large amounts of preliminary data and testable hypotheses that have laid the foundation for three inter-dependent research projects centering on a common theme - the molecular tumorigenesis for the two major BC pathways: low-grade non-invasive BC versus high-grade invasive BC. This P01 Program is designed to address several critical and pressing problems. What are the combinatorial molecular events that can drive BC formation along the divergent phenotypic pathways and how insights from developing and analyzing genetically engineered mice could benefit BC diagnostics and management (Project 1;P1)? Is acrolein an important carcinogen for tobacco-smoke-caused BC, and are distinct BC pathways underlined by different DNA damage and repair capacities (P2)? And, what are the novel role, upstream regulators, downstream effectors as well as the mechanisms of action of XIAP in BC invasion and progression (P3)? Results from this highly collaborative and synergetic team effort should contribute to the major leap forward in our understanding of the pathogenesis of BC, thus leading to the development of novel biomarkers and therapeutics for this highly prevalent but extremely under-studied disease.

Public Health Relevance

Although bladder cancer (BC) is highly prevalent and very difficult to treat, few concerted efforts exist to study its pathogenesis or discover effective therapies. The interdisciplinary team has built a highly integrated and collaborative program to define the molecular basis of BC formation and progression, which should spawn new, target- and pathway-specific biomarker panels and novel therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA165980-01A1
Application #
8543867
Study Section
Special Emphasis Panel (ZCA1-RPRB-B (M2))
Program Officer
Johnson, Ronald L
Project Start
2013-09-12
Project End
2018-08-31
Budget Start
2013-09-12
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$1,323,503
Indirect Cost
$538,152
Name
New York University
Department
Urology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Zeng, Xingruo; Xu, Zhou; Gu, Jiayan et al. (2016) Induction of miR-137 by Isorhapontigenin (ISO) Directly Targets Sp1 Protein Translation and Mediates Its Anticancer Activity Both In Vitro and In Vivo. Mol Cancer Ther 15:512-22
Xu, Zhou; Zeng, Xingruo; Xu, Jiawei et al. (2016) Isorhapontigenin suppresses growth of patient-derived glioblastoma spheres through regulating miR-145/SOX2/cyclin D1 axis. Neuro Oncol 18:830-9
Zhou, Haiping; He, Feng; Mendelsohn, Cathy L et al. (2016) FGFR3b Extracellular Loop Mutation Lacks Tumorigenicity In Vivo but Collaborates with p53/pRB Deficiency to Induce High-grade Papillary Urothelial Carcinoma. Sci Rep 6:25596
Wang, Y; Xu, J; Gao, G et al. (2016) Tumor-suppressor NFκB2 p100 interacts with ERK2 and stabilizes PTEN mRNA via inhibition of miR-494. Oncogene 35:4080-90
Zhou, Haiping; Wang, Xing; Mo, Lan et al. (2016) Role of isoenzyme M2 of pyruvate kinase in urothelial tumorigenesis. Oncotarget 7:23947-60
Madka, Venkateshwar; Mohammed, Altaf; Li, Qian et al. (2016) Targeting mTOR and p53 Signaling Inhibits Muscle Invasive Bladder Cancer In Vivo. Cancer Prev Res (Phila) 9:53-62
Liu, Zhongbo; Yokoyama, Noriko N; Blair, Christopher A et al. (2016) High Sensitivity of an Ha-RAS Transgenic Model of Superficial Bladder Cancer to Metformin Is Associated with ∼240-Fold Higher Drug Concentration in Urine than Serum. Mol Cancer Ther 15:430-8
Jiang, Guosong; Wu, Amy D; Huang, Chao et al. (2016) Isorhapontigenin (ISO) Inhibits Invasive Bladder Cancer Formation In Vivo and Human Bladder Cancer Invasion In Vitro by Targeting STAT1/FOXO1 Axis. Cancer Prev Res (Phila) 9:567-80
Wankel, Bret; Ouyang, Jiangyong; Guo, Xuemei et al. (2016) Sequential and compartmentalized action of Rabs, SNAREs, and MAL in the apical delivery of fusiform vesicles in urothelial umbrella cells. Mol Biol Cell 27:1621-34
Liang, Yuguang; Zhu, Junlan; Huang, Haishan et al. (2016) SESN2/sestrin 2 induction-mediated autophagy and inhibitory effect of isorhapontigenin (ISO) on human bladder cancers. Autophagy 12:1229-39

Showing the most recent 10 out of 42 publications