The AACR Henry Shepard Bladder Cancer Research Grants provide up to $250,000 in total support for innovative cancer research projects designed to accelerate the discovery, development and application of new agents to treat bladder cancer and/or for preclinical research with direct therapeutic intent.
2009 GRANTEES
Gregory J. Czarnota, M.D., Ph.D.Clinical Scientist, University of Toronto Sunnybrook Health Sciences Centre, Toronto, Canada
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."
Top of Page
Long-Cheng Li, M.D.
Assistant Professor, University of California, San Francisco, CA
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."
Top of Page