AACR Henry Shepard Bladder Cancer Research Grants

2009-2010 AACR Henry Shepard Bladder Cancer Research Grant Recipients

Gregory J. Czarnota, M.D., Ph.D., F.R.C.P.C.
University of Toronto Sunnybrook Health Science Center, Toronto, Canada
Project: Ultrasound Microbubble Enhancement of Bladder Cancer Treatment

"We have invented a novel method that uses microbubbles and ultrasound to sensitize tumours to ionizing radiation. The procedure relies on the fact that microbubble agents exposed to ultrasound can perturb vascular endothelial cells in blood vessels, rendering tissues and tumours more sensitive to the therapeutic effects of radiation. Our invention consists of ultrasound radiation in the presence of gas bodies to enhance tumour responses to radiation by perturbing the vasculature. By directing the ultrasound exposure using image guidance, radiosensitization thus produced can be targeted to a region such as a tumour, thus minimizing undesired effects on neighbouring normal tissue. We envisage this method being used in the future prior to, during or shortly after the delivery of radiation to enhance the regional effects of radiation. This method could be used with low- or high-energy X-rays, electrons, neutrons, protons or any form of ionizing radiation. Image guidance can be achieved using ultrasound, magnetic resonance, x-ray, positron emission tomography or other imaging methods. This approach is potentially applicable not only to elicit the conformal targeting of radioenhancement in association with external beam radiation but can be used to conformally target radioenhancement with other forms of radiation.

We will apply this research to advancing the treatment of bladder cancer: (i) it makes novel use of advanced ultrasound technology to damage endothelial cells in order to sensitize them to radiation; (ii) it capitalizes on recent innovative observations that radiation effects in tumours may be elicited through endothelial cell death of the tumour vasculature; and (iii) it capitalizes on the fact that radiation is increasingly being used for bladder-sparing treatments.

The funds provided by the AACR will permit proof-of-principle experiments in animal xenograft models of bladder cancer and will hopefully lead to improved treatments in human patients with bladder cancer."

Peter A. Jones, Ph.D.
University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA  
Project: Epigenetic Therapy for the Treatment and Prevention of Bladder Cancer

"Bladder cancer is the fifth most commonly diagnosed cancer in the United States and has a high rate of recurrence. It is one of the most expensive cancers to treat due to the need for numerous follow-up visits and additional treatments. Therefore, the ideal therapy for bladder cancer would, in addition to targeting tumors themselves, help to prevent future recurrences. Frequent recurrences may be caused areas across bladders that appear "normal" to a pathologist but are changed at the cellular level and predisposed to form new tumors. We have discovered that these changes include the incorrect placement of a particular marker on DNA called DNA methylation which allows cells to start to divide uncontrollably and eventually develop into a tumor. The advantages of targeting defects in DNA methylation with therapy is that these alterations are reversible by treatment with DNA methylation inhibitors. Currently there are two such DNA methylation inhibitors, Vidaza and Decitabine, which have been approved by the FDA to treat a particular type of leukemia. Our goal is to demonstrate that this type of drug can be used to treat bladder cancer and help to prevent future recurrences by reversing the changes we have found in the "normal" urothelium. In order to do this, we will take advantage of a clinical trial being conducted with Vidaza at our Cancer Center on leukemia patients and determine whether DNA methylation markers in the cells that line their bladders are changed after treatment. Our second aim is to study the mechanism behind the changes in DNA methylation marks that we have found across the bladders of patients with cancer in the hopes of better understanding how to prevent or reverse such changes. Our proposal has the potential to directly impact the treatment of bladder cancer if we find that DNA methylation in bladders can be altered by Vidaza therapy. Clinical trials in bladder cancer could commence relatively quickly since the FDA has already approved this compound for the treatment of a type of leukemia and much is known about tolerable doses and toxicity."

Long-Cheng Li, M.D.
University of California, San Francisco, San Francisco, CA 
Project: Preclinical Evaluation of saRNA-guided p21 Activation for Bladder Cancer     

"Bladder cancer is the fourth most common cancer in men and the tenth most common cancer in women in the United States. Superficial or early stage bladder cancer is usually treated with transurethral resection (TUR). After TUR, intravesical chemotherapy or immunotherapy is followed to eradicate residual tumors. Despite that, most cancer will return with one third of them assuming a more aggressive form and at higher stage. Once a tumor invades the muscle of the bladder wall, the bladder has to be removed by a procedure known as radical cystectomy. Therefore, there is an urgent need to develop new therapeutic agents for treating residual tumor after TUR and for treating advanced bladder cancer. Recently we have devised a novel method of stimulating the expression of tumor suppressor genes, which are often turned off in cancer through different mechanisms, using small RNA molecules that target their complementary regulatory DNA sequence also known as gene promoter. We have termed this new method RNA activation or RNAa and such small RNA molecules saRNA (small activating RNA). In our previous studies, we have demonstrated that saRNA targeting the p21 gene promoter stimulates the expression of p21 gene, a key inhibitor of the cell cycle, and leads to a dramatic growth inhibition of cultured bladder cancer cells. In the present project, we will conduct a preclinical evaluation of p21 saRNA for the treatment of bladder cancer. We will first maximize in vitro anti-growth effects of p21 saRNAs on bladder cancer cells through optimizing saRNA target location and sequence composition, and by introducing chemical modifications to saRNA. We will then establish human bladder tumors in mouse bladder and treat the tumors with p21 saRNAs delivered directly to mouse bladder. Although small RNA-based drugs currently have unsolved problems of systemic delivery, the bladder represents a unique model for testing local delivery of small RNAs. The proposed study will generate critical safety and pharmacology data for saRNA-based drugs delivered directly to the bladder and may offer a new avenue for treating bladder cancer."

Matthew I. Milowsky, M.D.

Genetic mutations are frequent in bladder cancer and may predict the likelihood of response to targeted therapies such as the recent identification of resistance to EGFR targeted agents in patients with colon cancer harboring KRAS mutations. In addition to HRAS, the first human oncogene identified in urothelial cancers, there are a number of genes in bladder cancer that are known to harbor frequent mutations including FGFR3, CDKN2A, PIK3CA, RB1, and TP53. Other less common mutations involve the genes EGFR, KRAS, BRAF, RET, PDGFRA as well as others. To date, the frequency of many of these genetic mutations in human bladder cancers is not well characterized despite the potential significant therapeutic implications. The current project seeks to characterize the frequency of known mutations and to determine the presence of additional novel or less common mutations in human bladder cancers using an integrated genomics approach by building a bladder cancer specific matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) assay with the goal to correlate mutational status with outcome; and to predict for sensitivity or resistance to novel targeted therapies such as selective kinase inhibitors. The MALDI-TOF MS technology is unique in its ability to assess for multiple mutations with excellent sensitivity in real time thereby providing information that can have an immediate impact on patient care. This work will provide the foundation for clinical trials designed to evaluate novel targeted agents in patients who are most likely to respond and, thereby, accelerate the development of promising therapies.