Central to the Johns Hopkins Greenberg Bladder Cancer Institute’s mission of advancing bladder cancer care is funding research projects that help advance the state of science and clinical practice in bladder cancer.

Through our grant program — made possible by the generous gift from the Greenberg family and a co-investment from The Johns Hopkins University, as well as our partnership with the Bladder Cancer Advocacy Network — the institute funds young investigators, conducts outreach to recruit new projects and talent, and leverages existing resources and expertise.

Grants of $35,000 to $50,000 are awarded in the research areas of cancer genetics, immunotherapy, biomarkers, targeted therapy, pioneering studies, and patient care, prevention and screening.

2017 Grant Recipients

The Greenberg Bladder Cancer Institute granted three awards in 2017.

Sexual Function Outcomes and Sexual Dysfunction in Women with Bladder Cancer: a Mixed-Methods Analysis of Patient-Reported Outcomes after Radical Cystectomy for Urothelial Bladder Cancer

Dr. Bhandavia (USC) and Dr. Porten (UCSF) will investigate the extent of sexual dysfunction experienced by women after radical cystectomy, and its impact on them and their partners. This will be a multi-site, mixed methods study, that seeks to understand this important domain of quality of life in an in-depth way, with the goal of improving survivorship for women with bladder cancer.

Nuclear receptor-activated transcriptomic signatures in human urothelium for the deconvolution of tumour transcriptomes.

Simon Baker, PhD, & Jenny Southgate, PhD Department of Biology University of York, UK

Although nuclear receptors (NRs) play a key role in regulating urothelial differentiation and the molecular landscape of bladder cancer, the contribution of individual NRs to downstream transcriptional networks is poorly resolved. Here we propose to generate comprehensive transcriptional subnetworks from normal human urothelial cells as a framework from which to identify and target specific cancer-related programs.

Understanding Sexual Dysfunction in Women with Bladder Cancer Undergoing Radical Cystectomy

Sexual dysfunction is a significant quality of life issue among women undergoing radical cystectomy for bladder cancer. The purpose of this study is to gain an understanding of the components of sexual health and dysfunction among women undergoing radical cystectomy and to assess variations in national practice patterns among urologists regarding operative techniques that can impact sexual function in women.

The chromatin landscape of male and female urothelial cells

This project will investigate the regulation of gene expression in the normal bladder lining of males and females.  If fundamental gender-related differences are identified, these may contribute to the observed differences in bladder cancer incidence and in the molecular features of bladder tumors in males and females.

2016 Grant Recipients

Announced in June 2017, the awardees included two Young Investigator Awards and two Development Research Program Grants.

• Young Investigator Awards
• Developmental Research Program Grants

Young Investigator Awards

Pembrolizumab, Gemcitabine and Concurrent Hypofractionated Radiation Therapy for Muscle-Invasive Bladder Cancer

Arjun Balar, M.D., New York University School of Medicine, New York, NY

The purpose of this trial is to assess the efficacy of pembrolizumab (MK3475) when added to concurrent radiation and gemcitabine in managing patients with muscle-invasive urothelial cancer who either decline or are not candidates for radical cystectomy. Investigators hypothesize that heightening immune surveillance (pembrolizumab is an anti-PD-1 inhibitor) may increase eradication both of the local tumor and the micrometastases.

Defining the translational landscape of metastatic bladder cancer and its role in therapeutic response to chemotherapy

Brian Winters, M.D., University of Washington, Seattle, WA

Winters aims to discover new biomarkers and previously unrecognized therapeutic targets in bladder cancer relative to cisplatin-based chemotherapy by conducting the first comprehensive analysis of chemotherapy-sensitive, chemotherapy-resistant, and metastatic bladder cancer translation, utilizing ribosome profiling, which, to date, has not been applied to bladder cancer. The investigation has the potential to revolutionize the overall understanding of bladder cancer pathogenesis and guide future, related research.

Developmental Research Program Grants

Characterization of Urothelial Cancer Circulating Tumor Cells with a Novel Selection-Free Method

Heather Chalfin, M.D., Brady Urological Institute, Johns Hopkins University

To date, most research investigating circulating tumor cells (CTCs) as biomarkers of urothelial carcinoma (UC) has utilized an assay whose sensitivity is limited because of its reliance on positive selection of CTCs expressing the cell surface protein EpCAM. Chalfin’s study utilized a novel selection-free method to enumerate and characterize CTCs in patients with UC across a range of stages. Study results proved positive: CTCs were detected at all UC stages and exhibited phenotypic diversity for cell size and EpCAM expression.

Identification of Molecular Subtypes in Non-muscle Invasive Bladder Cancer

Woonyoung Choi, Ph.D., The University of Texas MD Anderson Cancer Center

Dr. Choi’s research strives to enhance our understanding of the molecular landscape of bladder cancer. The ability to identify molecular subtypes in non-muscle invasive bladder cancer may eventually support the use of personalized therapy in bladder cancer—that is, treatment aimed at targeting specific molecular characteristics of individual patients’ disease.

2015 Grant Recipients

Announced in March 2016, the awardees included six new projects and four renewed projects in the following areas:

• Cancer Genetics
• Immunotherapy
• Biomarkers
• New Technologies
• Patient Care, Prevention and Screening

Cancer Genetics

Characterization of Gender-Related Mutation of KDM6A/UTY in Bladder Cancer

Margaret Knowles, Ph.D., professor of experimental cancer research at the University of Leeds, United Kingdom

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.

Identification and Characterization of Genetic Factors That Contribute to Exceptional Therapeutic Responses in Locally Advanced Bladder Cancer

 

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

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, then 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.

Rapid Lymphocyte Enrichment and Expansion Using Tumor-Specific Neoantigens in Urothelial Cell Carcinoma

 

Michael Johnson, M.D., assistant professor of urology at the Johns Hopkins University School of Medicine

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.

Genetic Diversity of T Cell Receptors Impacting Antitumor Effects in Bladder Cancer (Renewed Grant)

 

Peter O’Donnell, M.D., assistant professor of medicine at the University of Chicago

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.

Immunotherapy

Pilot Study of TRAIL and BCG Combination Therapy in Bladder Cancer (Renewed Grant)

 

Armine Smith, M.D., assistant professor of urology at the Johns Hopkins University School of Medicine

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.

Rapid Lymphocyte Enrichment and Expansion Using Tumor-Specific Neoantigens in Urothelial Cell Carcinoma

 

Michael Johnson, M.D., assistant professor of urology at the Johns Hopkins University School of Medicine

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.

Genetic Diversity of T Cell Receptors Impacting Antitumor Effects in Bladder Cancer (Renewed Grant)

 

Peter O’Donnell, M.D., assistant professor of medicine at the University of Chicago

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.

Biomarkers

Characterization of Neoadjuvant Chemotherapy Response Predictors and the Immunological Microenvironment in Muscle Invasive Urothelial Carcinoma of the Bladder

 

Alexander Baras, M.D., Ph.D., assistant professor of pathology and urology at the Johns Hopkins University School of Medicine

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 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.

TERT-Promoter Mutations Assay for Early Detection and Monitoring of Bladder Cancer (Renewed Grant)

 

Georges Netto, M.D., professor of pathology, urology and oncology at the Johns Hopkins University School of Medicine

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. 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.

New Technologies

Regenerative Urology: From Micro Ureters to Mini Bladders

 

Anirudha Singh, Ph.D., assistant professor of urology at the Johns Hopkins University School of Medicine

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 “mini bladders” 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.

Nanoparticle Approaches to Improving the Immunologic Response to Intravesical Therapy for NMIBC (Nonmuscle-Invasive Bladder Cancer) (Renewed Grant)

 

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

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.

Patient Care, Prevention and Screening

Investigating the Influence of Obesity and Metabolic Perturbations on Bladder Cancer Risk

 

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 University School of Medicine

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 (ARIC) Study, 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.

2014 Grant Recipients

The Greenberg Bladder Cancer Institute announced its first six research grant recipients in November 2014, four of which were renewed in 2015.

Grants were awarded for projects in the following research areas:

• Cancer Genetics
• Immunotherapy
• Biomarkers
• New Technologies
• Patient Care, Prevention and Screening

Cancer Genetics

Genetic Diversity of T Cell Receptors Impacting Antitumor Effects in Bladder Cancer

Peter H. O’Donnell, M.D., assistant professor of medicine at the University of Chicago Medicine Comprehensive Cancer Center

O’Donnell’s study will test the idea that as some bladder cancers progress, they acquire certain mutations that may activate and expand the number of tumor-infiltrating T lymphocytes (TILs), white blood cells found in tumors that kill cancer cells. Investigators will look for genetic changes in TILs that predict robustness of immune responses against bladder cancer to see if they contribute to better recurrence-free and overall survival.

Immunotherapy

Dissecting the Phenotype of CD4 and CD8 Tumor-Infiltrating Lymphocytes in Advanced Bladder Cancer

Charles Drake, M.D., Ph.D., associate professor of oncology, urology and immunology at the Johns Hopkins University School of Medicine

Drake and others will catalog the sequences of RNA — strings of chemical letters that form the “read out” of DNA and help construct proteins — from bladder cancer samples of people with advanced disease. He aims to identify new and existing molecules on the surface of lymphocytes — white blood cells that penetrate tumors and kill cancer cells — that regulate how the immune system identifies and marks cancer cells for destruction. The findings could help discover new targets for cancer immunotherapy.

Pilot Study of TRAIL and BCG Combination Therapy in Bladder Cancer

Armine Smith, M.D., assistant professor of urology at the Johns Hopkins University School of Medicine

Smith’s study will see if stimulating a protein called TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), which kick-starts the process of cell death, will increase the effect of BCG (Bacillus Calmette-Guerrin), the main biological treatment for nonmuscle-invasive bladder cancer, in mice. Investigators also will collect tissue from patients with bladder cancer to identify levels of TRAIL receptors before and after BCG treatment, and correlate them with treatment outcomes.

Genetic Diversity of T Cell Receptors Impacting Antitumor Effects in Bladder Cancer

Peter H. O’Donnell, M.D., assistant professor of medicine at the University of Chicago Medicine Comprehensive Cancer Center

O’Donnell’s study will test the idea that as some bladder cancers progress, they acquire certain mutations that may activate and expand the number of tumor-infiltrating T lymphocytes (TILs), white blood cells found in tumors that kill cancer cells. Investigators will look for genetic changes in TILs that predict robustness of immune responses against bladder cancer to see if they contribute to better recurrence-free and overall survival.

Biomarkers

TERT-Promoter Mutations Urine Assay for Early Detection and Monitoring of Bladder Cancer

Georges Netto, M.D., director of surgical pathology molecular diagnostics and professor of pathology, oncology and urology at the Johns Hopkins University School of Medicine

Netto’s project 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. New experiments will determine how well a test for TERT mutations can detect bladder cancer in urine samples of individuals at high risk for bladder cancer, determine the utility of detecting TERT mutations among urine samples taken during follow-up of bladder cancer patients to monitor disease recurrence and see if it is worth expanding the test to include additional genetic mutations found in bladder cancer.

New Technologies

Nanomedicine Approaches for Improving Intravesical Delivery of Chemotherapeutic Agents

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

Bivalacqua and colleagues will develop nonadhesive, biodegradable nanoparticles loaded with chemotherapy and other solutions. They will compare the effectiveness of their nanoparticles with standard ways of delivering chemotherapy in a mouse model of bladder cancer. The hypothesis is that the nanoparticles will better sustain delivery of chemotherapy into bladder tissue, preventing tumor recurrence and progression.

Patient Care, Prevention and Screening

The Role of AGL, a Glycogen Debranching Enzyme in Bladder Cancer

Dan Theodorescu, M.D., Ph.D., professor of urology and director of the University of Colorado Cancer Center

Theodorescu’s research will study the role of AGL, an enzyme that suppresses bladder tumor growth. Patients with metastatic bladder cancer have lower levels of AGL. Scientists will track levels of AGL and another enzyme called HAS2 to determine their correlation with patient outcomes. The researchers will also study mice that do not express AGL to see if they are more susceptible to bladder cancer.