This proposed project aims to address the critical issue of bladder cancer, one of the Fiscal Year 2016 Peer Reviewed Cancer Research Program Topic Areas. This application is seeking a solution for more effective treatment for the most diagnosed types of bladder cancers. The proposed study responds to both of the Military Relevance Focus Areas: military-relevant risk factors associated with cancer, and gaps in cancer prevention, early detection/diagnosis, and treatment that have a particularly profound impact on the health and well-being of military Service members, Veterans, and their beneficiaries.
Bladder cancer is the fourth most common cancer in men. Seventy to 80 percent of bladder cancers are diagnosed at early stages and are treated by surgery under cystoscopy. Due to the high rate of recurrence after surgery, adjuvant therapies, such as intravesical chemotherapy and BCG (Bacillus Calmette–Guérin) vaccine, are used. However, recurrence, progression, and side effects remain important problems that make bladder cancer one of the most expensive cancers to treat. More effective and selective treatment options are direly needed.
We are developing a unique, visible light-based strategy to effectively and selectively treat early-stage bladder cancers by taking advantage of both the formation of protoporphyrin IX (a special compound used for fluorescence imaging and treatment) selectively in cancer cells and our new light-activatable prodrug (an inactive form of a drug that is changed to a drug inside the body with light). We expect that our prodrug will be effectively activated by cancer cell-specific protoporphyrin IX-based photodynamic therapy (PDT, a US Food and Drug Administration [FDA]-approved photochemistry-based light treatment), and thus greatly improve therapeutic efficacy with minimal damage to the bladder. Our long-term goal is to advance this combination strategy to clinical translation. The objective of this proposed work is to prove our concept using prodrugs of clinically available anticancer drugs in both in vitro (cultured cancer cells) and in vivo (animal) models. Specifically, a bladder cancer model made in rat bladder will be used to better mimic the physiology of human bladder cancers.
Our approach is expected to improve therapeutic efficacy and minimize side effects by using a unique and innovative combination strategy. Protoporphyrin IX will first be selectively formed in cancer cells, following the FDA-approved protocol for fluorescence cystoscopic detection (looking inside the bladder using a fluorescent dye). Non-toxic prodrug will be localized to mitochondria of cells. Then, the prodrug will be selectively activated in cancer cells by illumination with visible light. This new combination will be a valuable treatment option for bladder cancers that are resistant to current standard adjuvant therapies, like chemotherapy and BCG.
The proposed study aims to fill the gaps in prevention of cancer recurrence and treatment that have a particularly profound impact on the health of military members, Veterans, and their beneficiaries. Bladder cancer is the fourth most common type in US Veterans. Smoking is the leading risk factor for bladder cancer. The prevalence of smoking is much higher in Veterans (27%) than in non-Veterans (21%). Older Veterans who are cigarette smokers are at much higher risk for bladder cancers. In a recent report in Veterans and Agent Orange: Update 2014, bladder cancer was moved from “inadequate or insufficient” to “limited or suggestive” evidence of association. Based on the report from the US Department of Veterans Affairs, bladder cancer is one of the known adverse health conditions for those who were exposed to drinking water contaminated with industrial solvents, including benzene, at the US Marine Corps Base Camp at Lejeune, NC, from the 1950s to the 1980s.