A study of obesity and related metabolic changes on bladder cancer incidence and deaths, and a plan to use stem cells to grow novel urinary tubes are among 10 research projects awarded funding by the Johns Hopkins Greenberg Bladder Cancer Institute.
The institute is a collaborative initiative of the Johns Hopkins Kimmel Cancer Center, the Brady Urological Institute, the Bloomberg School of Public Health and the School of Medicine, aims to develop new clinical strategies for combating bladder cancer through intensive, collaborative and innovative research, awards grants of up to $50,000 each year to encourage young investigators to take on research that advances the science and treatment of bladder cancer and to leverage existing resources and expertise. The grants, renewable for up to three years, are awarded in the following areas: genetic and epigenetic approaches; immunotherapy; targeted therapies; patient care, prevention and screening; and pioneering studies. This is the second year of grant awards for the institute, which started in May 2014.
“I am really excited about the tremendous group of investigators that the institute will be funding,” says William B. Isaacs, Ph.D., a genitourinary cancer expert at the Johns Hopkins Brady Urologic Institute and Kimmel Cancer Center. “We have projects by outstanding and inspired new investigators, a very talented young epidemiologist, and perhaps the most seasoned bladder cancer investigator in the world, in addition to a prostate cancer molecular biologist who has been enticed to join the fight against bladder cancer. In addition, four of last year’s funded investigators will receive additional support for another year, as they were judged to be making excellent progress on their research projects. I am confident that this group of investigators will make major inroads in bladder cancer both in the short term and well into the future.”
The awardees include six new projects and four renewed projects. The new recipients and their projects are:
- Corinne Joshu, Ph.D., M.P.H., assistant professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health and assistant professor of oncology at the Johns Hopkins Kimmel Cancer Center, for “Investigating the Influence of Obesity and Metabolic Perturbations on Bladder Cancer Risk”
Joshu’s project will explore the potential influence of obesity and its associated metabolic changes on bladder cancer incidence and mortality. She will analyze data from the Atherosclerosis Risk in Communities Study (ARIC), a long-term epidemiologic study of 16,000 men and women from four U.S. communities. ARIC participants have undergone repeated clinical visits, where measures of body size, and metabolic, lipid and inflammatory markers have been collected. They have been followed for health outcomes, including well-characterized bladder cancer, for over 25 years.
- Anirudha Singh, Ph.D., assistant professor of urology at the Johns Hopkins University School of Medicine, for “Regenerative Urology: From Micro Ureters to Mini Bladders”
Singh’s laboratory has developed a collagen molding technology that mimics the features of processing methods that shape synthetic plastics into desired structures. They plan to engineer hollow and tubular collagen systems ranging from microsized tubings similar to ureterlike structures to complex seaweed or grapelike structures as multiple “minibladders” for regenerative urology applications. Specifically, they plan to develop biologically functional artificial urinary tubes by seeding the scaffolds with stem cells derived from human fat tissue that can result in the formation of cell layers normally seen in urinary tissues.
- Margaret Knowles, Ph.D., professor of experimental cancer research at the University of Leeds, United Kingdom, for “Characterization of Gender-Related Mutation of KDM6A/UTY in Bladder Cancer”
Knowles will look to identify gender-related molecular features of bladder cancers and develop relevant in vitro models. Her group already has identified mutations in the tumor suppressor gene KDM6A in more than one-half of low-grade stage Ta bladder tumors, and data suggest that bladder cancer in females has distinct epigenetic features. Now, she will conduct a more comprehensive analysis of mutations and alterations in KDM6A in tumors of all grades and stages from both men and women, and in a related gene, UTY, in males.
- Alexander Baras, M.D., Ph.D., assistant professor of pathology and urology at the Johns Hopkins University School of Medicine, for “Characterization of Neoadjuvant Chemotherapy Response Predictors and the Immunological Microenvironment in Muscle Invasive Urothelial Carcinoma of the Bladder”
Baras will develop and validate biomarkers of response to treatment with conventional cisplatin-based chemotherapy given prior to surgery in patients with muscle-invasive bladder cancer, looking at expression of certain proteins and at DNA sequencing. He also aims to characterize how the interaction of muscle-invasive bladder cancer and the immune system impacts response to cisplatin-based chemotherapy. The results could enable therapy to be tailored so only patients likely to benefit from the treatment will receive it.
- Shawn E. Lupold, Ph.D., associate professor of urology, oncology, and radiation oncology and molecular radiation sciences at the Johns Hopkins University School of Medicine, for “Identification and Characterization of Genetic Factors That Contribute to Exceptional Therapeutic Responses in Locally Advanced Bladder Cancer”
Lupold’s project will use technology called high-throughput RNA interference screens to look for genes that, when deactivated, contribute to a better response to cancer treatment. During the study, Lupold’s team will look at 40 genes commonly mutated and deleted in bladder cancers. In the lab, bladder cancer cells will be pretreated with genetic material called small interfering RNA to knock down individual gene function, and then will be treated with chemotherapy or radiation therapy. Cells that respond very well or very poorly to treatment may predict genetic mutations associated with exceptional response or therapeutic resistance, potentially helping identify new genetic markers for personalized bladder cancer therapy.
- Michael Johnson, M.D., instructor of urology at the Johns Hopkins University School of Medicine, for “Rapid Lymphocyte Enrichment and Expansion Using Tumor-Specific Neoantigens in Urothelial Cell Carcinoma”
Johnson and colleagues will use a novel technique to expand immune cells that are designed to recognize cancer. They will perform genome sequencing on bladder tumors to predict protein sequences that are specific to tumor cells and capable of initiating an immune response (neoantigens). Then, using artificial antigen presenting cells (aAPCs), they will isolate and expand populations of white blood cells that recognize neoantigens in blood, lymph nodes and tumors. Their hypothesis is that T cells can be activated with tumor-specific proteins, and the combination of neoantigens and aAPCs can be used to pursue personalized cancer immunotherapies, such as cancer vaccines.
The awardees of renewed grants, and their projects, are:
- Trinity Bivalacqua, M.D., Ph.D., associate professor of urology, surgery and oncology at the Johns Hopkins University School of Medicine and director of urologic oncology at the Johns Hopkins Kimmel Cancer Center, for “Nanoparticle Approaches to Improving the Immunologic Response to Intravesical Therapy for NMIBC (Nonmuscle-Invasive Bladder Cancer)”
Bivalacqua and colleagues will continue work on the development of nonadhesive, biodegradable nanoparticles loaded with chemotherapy and other solutions in the treatment of bladder cancer. His team created rat models of bladder cancer and will continue characterizing the tumors by analyzing gene and protein expression. They also have started comparing the delivery of cisplatin (chemotherapy) versus Bacillus Calmette-Guerin — the main biological treatment for nonmuscle-invasive bladder cancer — in these models and will measure the difference in the resulting numbers of immune cells activated in the bladder to prevent tumor recurrence and progression. Additionally, the group will continue work demonstrating that cisplatin-based nanoparticle therapy can be localized to the bladder, sparing other healthy tissue. They will use the therapy alone and in combination with gemcitabine to demonstrate the ability to prevent cancer progression in murine models of bladder cancer.
- George Netto, M.D., professor of pathology, urology and oncology at the Johns Hopkins University School of Medicine, for “TERT-Promoter Mutations Assay for Early Detection and Monitoring of Bladder Cancer”
Netto will continue work on a noninvasive, urine-based test to identify mutations in the “on/off switch” of a gene called telomerase reverse transcriptase (TERT), which is present in a range of bladder cancer precursor lesions. His team sequences patients’ bladder tumors to identify TERT promoter mutations and compares the information to the presence or absence of the same mutations in patients’ urine. As of last summer, the group had sequenced 1,167 samples — 758 urine samples and 409 bladder tumor samples — for TERT mutations. They will assess 1,000 additional urine samples in the next year. The team also developed an expanded genetic assay to include alterations in 11 additional genes that are commonly mutated in bladder cancer. In 169 bladder cancers sequenced using the new assay, at least one alteration has been found in over 90 percent of tumors. They will test the complete set of collected urine samples and corresponding tumor samples using the new assay.
- Peter O’Donnell, M.D., assistant professor of medicine at the University of Chicago, for “Genetic Diversity of T Cell Receptors Impacting Anti-Tumor Effects in Bladder Cancer”
In their first year of funding, O’Donnell and colleagues genetically characterized the T cell receptors of tumor-infiltrating T lymphocytes (TILs), white blood cells found in tumors that kill cancer cells. They also found that patients whose TILs had low genetic diversity in the receptors had significantly longer recurrence-free survival. Building on that work, the team now plans to study bladder cancer tissue samples to look for potential key proteins that may drive the expansion of T cells against tumors. They also will take blood samples from patients with and without bladder cancer recurrence to see if artificial proteins genetically engineered in the lab can stimulate the expansion of T cell populations.
- Armine Smith, M.D., assistant professor of urology at the Johns Hopkins University School of Medicine, for “Pilot Study of TRAIL and BCG Combination Therapy in Bladder Cancer”
Smith and colleagues are looking to characterize chemical pathways that are dysregulated in cell lines resistant to BCG (Bacillus Calmette-Guerin), the main biological treatment for nonmuscle-invasive bladder cancer. They also are beginning use a combination of BCG and a protein called TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), which kick-starts the process of cell death, to treat mice with tumors that either have never been treated with BCG or that are resistant to BCG. They will also look for levels of TRAIL receptors in stored tissue samples from bladder cancer patients.
Applications will be made available online this summer for the next round of funding, Isaacs says.