Bladder cancer is the fourth most common cancer in the US. Due to its easily accessible location and relatively early diagnosis, bladder cancer is one of the least lethal cancers and there are ~540,000 survivors in the US. At presentation, >80% of bladder tumors are organ-confined, separated clinically into two groups. The most common group is the nonmuscle-invading tumors, accounting for about 70-80% of cases. This group is managed by surgery, plus neo- or adjuvant intravesical immunotherapy or chemotherapy. Intravesical therapy involves instilling a drug solution into the bladder through an indwelling catheter. Recurrence is common and occurs in 40 to 80% of patients. Between 10 to 20% of recurrences are accompanied by grade and/or stage progression (including the more fatal metastatic disease). The second group, the muscle-invading tumors, is managed by partial or complete cystectomy (removal of bladder), which presents significant risks and is not well-tolerated by older patients. The most commonly used chemotherapeutic agents for intravescial therapy are mitomycin C (MMC) and doxorubicin. Through a series of preclinical and clinical studies, our group has established that the efficacy of these agents is limited by two factors: inadequate drug delivery to tumors and low chemosensitivity (especially for the more aggressive tumors). Next, we identified a method that uses pharmacokinetic (PK) interventions to maximize the MMC delivery to nonmuscle-invading bladder tumors. This method was tested in a multi-center, randomized phase III trial;the results confirm our hypothesis that improving the drug delivery significantly improves the 5-yr recurrence-free rate (from 23.5% to 42.6%). These data also indicate that a new drug delivery approach is needed for the remaining patients, those with muscle-invading tumors, who are not adequately managed by intravesical therapy. This R43 application proposes a new drug delivery approach via an alternative administration route: intra-bladder injection of controlled release formulations (CRF) of MMC and suramin, such that therapeutic active drug levels are delivered to deeper tissues. Suramin is used to enhance the sensitivity of human tumors to MMC by 2- to 3-fold. The two aims are to (a) develop biocompatible polymeric CRF of MMC and suramin and (b) conduct in vivo evaluation of the drug-loaded CRF to determine the feasibility of using intra-bladder CRF to treat deeper tumors. Upon demonstration of feasibility, we will investigate, in the later R44 project, the therapeutic efficacy of the combination in tumor-bearing animals (e.g., dogs with naturally occurring bladder tumors), in preparation for the eventual clinical evaluation. This R43 project has the potential to lead to a new treatment modality and significantly improve the management of bladder cancer while the disease is still localized in the bladder. Given the extremely high lifetime health care costs for these patients (over $10 billion in 2003 dollars), an additional potential benefit is cost containment.
This R43 project has the potential to lead to a new treatment modality and significantly improve the management of bladder cancer while the disease is still localized in the bladder. Given the extremely high lifetime health care costs for these patients (over $10 billion in 2003 dollars), an additional potential benefit is cost containment.
|Au, Jessie L-S; Yeung, Bertrand Z; Wientjes, Michael G et al. (2016) Delivery of cancer therapeutics to extracellular and intracellular targets: Determinants, barriers, challenges and opportunities. Adv Drug Deliv Rev 97:280-301|