Strong, multi-disciplinary and inter-institutional collaborations are the foundation and major strength of the translational bladder cancer research program that is anchored by the GU SPORE in Bladder Cancer. Within MD Anderson Cancer Center (MDACC), these collaborations involve faculty within the Departments of Urology, Genitourinary Medical Oncology, Pathology, Cancer Biology, Epidemiology, and Biostatistics. Given the paucity of funding for bladder cancer, collaborations outside of the SPORE are necessary to make sufficient progress in this disease, and our program was expanded beyond MDACC with the inclusion of Drs. Dan Theodorescu and David Ross from the University of Colorado to our established SPORE research team. The current SPORE has 4 projects.
Project 1: Improving Diagnosis of Bladder Cancer
Dr. Bogdan Czerniak, Professor of Pathology
Dr. H. Barton Grossman, Professor of Urology
The overall goal of this project is further improvement of diagnosis of bladder cancer by the development of effective novel biomarkers and diagnostic strategies for early detection of bladder cancer and its progression from in situ carcinoma to invasive disease. Dr. Czerniak and colleagues will study the use of novel biomarkers (aurora kinase A FISH test) complemented with a novel set of FISH probes specifically designed to identify distinct phases of bladder cancer development via its dual-track pathway. More specifically they plan to improve the screening, detection, and monitoring of bladder cancer by complementing aurora kinase A FISH test and other commercially available diagnostic test such as NMP22 and UroVysion with a novel panel of FISH tests designed by using a whole-organ mapping strategy coupled with a high resolution SNP genome-wide Illumina platform.
Project 2: Role of MicroRNA in Bladder Cancer Risk and Outcome: A genome-wide analysis
Dr. Xifeng Wu, Professor and Chair of Epidemiology
Dr. Ashish Kamat, Associate Professor or Urology
Bladder cancer provides an excellent model for studying environmental and genetic causes of cancer. Cigarette smoking and occupational exposure are the top two predominant risk factors for bladder cancer. Recent genome-wide scan association studies (GWAS) by us and other groups have unequivocally identified at least 10 genetic susceptibility loci for sporadic bladder cancer. It is expected that many more such loci are existing. Non-muscle invasive bladder cancer (NMIBC) accounts for about 80% of newly diagnosed cases, and comprise a heterogeneous group whose individual prognoses are difficult to predict. Over half of NMIBCs recur within 4 years and up to a quarter may progress to invasive disease. It is imperative to identify those patients who are more likely to recur and progress, so they can be selected for personalized cancer care. MicroRNAs (miRNAs) are a class of small non-coding endogenous RNAs playing important roles in post-transcriptional regulation of up to a third of human genes. Somatic alterations of miRNAs have been suggested as promising biomarkers of early detection, prognosis and treatment response. Germline genetic variations in miRNA pathways have been associated with cancer risk and prognosis. In addition, circulating miRNAs in serum or plasma have been suggested as biomarkers of early detection and prognosis. The study of miRNAs in bladder cancer has been almost exclusively focusing on somatic alterations in tumor tissues. In this project, Dr. Wu and associates propose a systematic study of miRNAs in bladder cancer etiology, prognosis, and BCG response, including germline SNP genotyping, somatic miRNA profiling, and detection of circulating miRNA.
Project 3: Targeting FGFR and EGFR in Bladder Cancer
Dr. David McConkey, Professor of Urology - Research
Dr. Colin Dinney, Professor and Chair of Urology
Dr. Arlene Siefker-Radtke, Associate Professor Genitourinary Medical Oncology
Activating mutations in the type-3 receptor for fibroblast growth factors (FGFR3) occur in half of non-muscle invasive and a quarter of muscle-invasive bladder cancers (BCs), and preclinical studies have established that the mutant receptors drive ligand-independent autocrine tumor cell proliferation in model cell lines. Basic FGF (FGF2) secreted by BC cells also plays an important role in angiogenesis. Thus, FGFR inhibition is an extremely attractive but at present a clinically untested therapeutic approach. McConkey, Dinney, and colleagues previously discovered that epithelial-to-mesenchymal transition (EMT) drives resistance to inhibitors of the epidermal growth factor receptor (EGFR) in BC cells, and their preliminary data indicate that EMT also drives in vitro resistance to FGFR inhibitors. Conversely, expression of basic FGF is confined to the “mesenchymal” subset of BC cell lines, suggesting that mesenchymal tumors may be more dependent on paracrine bFGF signaling to drive angiogenesis.
The main translational goal of their work is to use preclinical models in a collaborative effort that involves the FGFR to learn how to prospectively identify FGFR3-dependent tumors and to measure pharmacodynamic markers of pathway inhibition in tissue sections, and then use these methods within the context of a neoadjuvant clinical trial to determine whether clinically achievable doses of FGFR3 inhibitors will inhibit the pathway in primary tumors.
Project 4: Targeting Ral GTPases in Bladder Cancer
Dr. Dan Theodorescu, Professor of Surgery and Pharmacology
University of Colorado
Dr. David Ross, Chair of Pharmaceutical Sciences, Professor of Toxicology
University of Colorado
Metastatic bladder cancer is usually fatal. Targeting the molecular machinery underlying this process would advance treatment of this disease. Dr. Theodurescu and associates from the University of Colorado recently found that Ral GTPases serve as the molecular nodes of a therapeutically tractable signaling pathway that allows bladder cancer cells to grow in the lung, the most common visceral metastatic site. The clinical significance of this pathway and validity of Ral as a therapeutic target is supported by finding high tumor expression of Ral in patients and the requirement of such expression for lung metastasis in animal models of bladder cancer. Their guiding hypothesis is that small molecules targeting Ral provide effective therapy for metastatic bladder cancer.
Dr. David McConkey, Professor, Urology - Research
Dr. William Benedict, Professor, Genitourinary Medical Oncology
The aim of the SPORE Developmental Research Program is to provide initial funding for promising pilot studies in bladder cancer. The research is designed to generate clinically testable hypotheses. It is also geared toward reducing the incidence and mortality of bladder cancer or improving the quality of life for bladder cancer patients.