Date Published: July 29, 2012
Publisher: Hindawi Publishing Corporation
Author(s): Kyle G. Potts, Mary M. Hitt, Ronald B. Moore.
Bladder carcinoma is the second most common malignancy of the urinary tract. Up to 85% of patients with bladder cancer are diagnosed with a tumor that is limited to the bladder mucosa (Ta, T1, and CIS). These stages are commonly termed as non-muscle-invasive bladder cancer (NMIBC). Although the treatment of NMIBC has greatly improved in recent years, there is a need for additional therapies when patients fail bacillus Calmette-Guérin (BCG) and chemotherapeutic agents. We propose that bladder cancer may be an ideal target for oncolytic viruses engineered to selectively replicate in and lyse tumor cells leaving normal cells unharmed. In support of this hypothesis, here we review current treatment strategies for bladder cancer and their shortcomings, as well as recent advancements in oncolytic viral therapy demonstrating encouraging safety profiles and antitumor activity.
In the United States, it is estimated that 73,510 men and women (55,600 men and 17,910 women) will be diagnosed with and 14,880 will die of cancer of the urinary bladder in 2012, making it the fourth and ninth most common cancers among men and women, respectively . The most common cause for bladder cancer is smoking and other toxin exposure (i.e., petrochemical industry), where the carcinogen is removed from the body by the kidney and stored for long periods of time in the bladder. This results in destabilization of the urothelium resulting in a field effect.
Standard therapy combines intravesical therapy with or without transurethral resection (TUR). TUR is typically the first treatment for visible lesions, although this surgery sometimes incompletely removes the tumor, necessitating a second TUR [15, 16]. For patients at low risk of tumor recurrence (and without a bladder wall puncture), early instillation of a chemotherapeutic agent following TUR is now the standard treatment recommendation. Intravesical chemotherapy, however, is not without risk given that the urothelium is already potentially destabilized by the field effect of carcinogen exposure . Mitomycin C, epirubicin, and doxorubicin have all been determined to be valuable options . High-grade Ta, T1, or CIS tumors put patients at an increased risk for recurrence and, more significantly, progression. Recommended treatment for patients with these high-grade tumors is TUR followed by intravesical treatment with the immunotherapeutic agent Bacillus Calmette-Guérin (BCG) and maintenance immunotherapy for at least 1 year [19, 20].
Oncolytic virus therapy exploits the altered environment in the tumor cell, allowing the viruses to replicate in and lyse tumor cells, but not normal cells (reviewed in [30–32]). Many different viruses have been examined in preclinical studies for oncolytic properties with several moving into early phase clinical trials. The urinary bladder is an excellent organ to evaluate local oncolytic viral therapy for a number of reasons: (1) the urethra permits easy intravesical instillation allowing the tumor to be exposed to large titers of vector ; (2) the bladder is an isolated organ and the trilaminar (asymmetric) unit membrane limits systemic exposure [34–36]; (3) the success of BCG therapy has shown the immunosensitivity of bladder cancer providing a basis for examination of other immunomodulatory agents for therapy ; (4) the papillary configuration of NMIBC increases surface area for topical application; (5) there is an urgent need for more bladder-sparing therapies for patients failing conventional therapies.
Ad is a nonenveloped, linear, double-stranded DNA virus with a genome of approximately 36 kb. The human Ad subgroup C, which contains 2 of the most studied serotypes (types 2 and 5), is widespread in the population and associated with a mild upper respiratory tract infection. Wild-type Ads have been genetically modified to take advantage of the altered tumor environment to allow selective replication. Two general approaches have been used to generate this tumor selectivity. The first is to delete gene functions that are critical for efficient viral replication in normal cells but are expendable in tumor cells [38, 39]. ONYX-015 (dl1520 or CI-1042) was the first conditionally replication-competent engineered Ad to enter a clinical trial. It contains a deletion of the E1B-55 kDa gene and demonstrated oncolytic activity in cancer cells with mutant p53, but only limited cytotoxicity in normal human cells with wild-type p53 function [40, 41] (however, it has become clear that this is not the reason for selective replication) . A second general approach is to limit the expression of the E1A gene product through the use of tumor- and/or tissue-specific promoters [43, 44]. E1A functions to stimulate S phase and transcriptional activation of both cellular and viral genes, allowing virus replication to proceed. An example is the CN706 virus in which the E1A gene is transcriptionally controlled by the PSA promoter, resulting in a virus that selectively replicates in tissue with high PSA levels . There are many other examples of selectively replicating oncolytic Ads that have been reviewed elsewhere [46, 47].
HSV is a large (150–200 nm diameter) enveloped virus  with a double-stranded DNA genome of approximately 150 kb . HSV commonly causes infections in the orofacial region (HSV-1) and in the genital region (HSV-2) (reviewed in ). Multiple genetic manipulations to HSV have allowed the development of viruses that selectively replicate in cancer cells. One mutation that has been examined is the inactivation of the viral ICP6 (UL39) gene, which codes for the large subunit of ribonucleotide reductase (RR) [63, 64]. RR plays a key role in making the deoxyribonucleotides (dNTPs) that are needed for DNA synthesis . The RR levels are elevated in dividing tumor cells but low in normal cells. This mutation therefore renders the virus dependent on the cellular enzyme resulting in tumor selectivity. A second modification that has been investigated is the inactivation of the Υ-34.5 gene that encodes the ICP34.5 protein which is important for viral replication , viral exit from cells , prevention of the early shut-off of protein synthesis , and neurovirulence  (Figure 1). In normal cells, the double-stranded-RNA-(dsRNA-) dependent protein kinase (PKR) shuts off protein synthesis and prevents viral replication . Tumor cells often have defects in this signaling pathway and thus allow viral replication . Mutation of the viral thymidine kinase (UL23) gene also renders the virus dependent on host cell TK expression .
Reoviridae are a family of viruses that includes viruses that infect the gastrointestinal tract and respiratory system. Human reoviruses contain 10 segments of double-stranded RNA and a double shell of proteins that compose the inner capsid or core and the outer capsid.
VAC has a large (~200 kb) linear double-stranded DNA genome that replicates exclusively in the cytoplasm. VAC infects many different cell types with high efficiency. VAC encodes many of the proteins required for robust virus replication in normal cells (reviewed in [103–105]).
Surgery, BCG, and chemotherapy dramatically slow the progress of bladder cancer but do not eradicate the disease totally. Patients with NMIBC that fail BCG therapy are in need of other bladder-sparing treatment options. This paper discussed the potential of oncolytic viruses as a treatment option in bladder cancer. Encouraging safety profiles and antitumor activity have been demonstrated with a variety of oncolytic viruses. However, very little preclinical, let alone clinical, data have been reported for oncolytic viruses in bladder cancer.