Development of Novel Noninvasive Tests for Prognostic Predictions for Bladder Cancer

Topic Area: Bladder Cancer.

Military Focus Area: 'Gaps in cancer prevention, early detection/diagnosis, prognosis, treatment, and/or survivorship.….well-being of military Service members…'

Scientific Objective and Rationale: Bladder cancer (BCa) arises in the urothelial layer that is exposed to urine. These tumors may be low-grade or high-grade. Low-grade tumors mostly remain confined to the urothelial layer, but high-grade tumors have high propensity to invade the bladder muscle. Detection of BCa at muscle invasive stage (MIBCa) is associated with poor prognosis; 50% of these patients develop metastasis (cancer spreading to other organs). Tumors are resected from the bladder, if they are low-grade, but also high-grade tumors that are diagnosed at the non-muscle invasive stage. However, new tumors develop in the bladder (i.e., BCa recurrence) despite complete removal of the initial tumor. Fifty percent of patients with low-grade tumors and 80 percent of those with high-grade tumors develop a recurrence within 3 years. Therefore, patients are monitored for BCa recurrence by cystoscopy, an invasive procedure associated with considerable risk for pain, urinary tract infections and cost. Urine cytology and Food and Drug Administration-approved urine tests are not used for monitoring of BCa recurrence due to their sub-optimal efficacy. Patients also undergo additional bladder resections 6 weeks after the removal of a high-grade tumor that is non-muscle invasive. These additional resections are performed to exclude the possibility that the tumor was actually MIBCa. Hence, invasive workup by cystoscopy, additional bladder resections, frequent recurrence, and high tendency of MIBCa to metastasize associate with morbidity and mortality in patients with BCa, one of the costliest cancer to treat.

The major objective of this proposal is to evaluate the efficacy of novel urine tests to detect BCa recurrence and for early detection of MIBCa. Patients with MIBCa receive Gemcitabine plus cisplatin neoadjuvant chemotherapy (G+C-NAC) before undergoing bladder removal surgery (cystectomy). G+C-NAC is administered in order to ensure complete tumor removal by cystectomy and also to treat any undetectable tiny bladder tumors that might be growing elsewhere in the body. However, if a patient's cancer is resistance to G+C-NAC, then there is a danger that the cancer will actually grow and spread during treatment. Before starting G+C-NAC, if a urine test can identify such non-responders, then these patients can receive cystectomy without waiting for the completion of G+C-NAC that is not working. Therefore, evaluation of the accuracy of new urine tests, developed in our laboratory, to predict response to NAC is another objective of the study.

The overall rationale of this study is related to an unmet clinical need for accurate non-invasive biomarkers (e.g., urine tests) to monitor BCa recurrence, for early detection of MIBCa, and for predicting response to G+C-NAC. This rationale is based on our discovery of V1, a variant of a little studied gene in the hyaluronidase gene family. In a pilot study, V1-based urine tests showed promise to detect BCa and to evaluate its grade and the presence of MIBCa with high precision and accuracy. Therefore, the proposed study will evaluate V1-based urine tests for their diagnostic and predictive capabilities at various stages of BCa. This study will also investigate how and why V1 and its effectors promote malignant phenotype and resistance to chemotherapy, and consequently, whether these functions drive the accuracy of V1-based urine tests at various stages in the management of BCa.

Applicability of Research and Relevance to Military Beneficiaries: Compared to the general population, Veterans and active Service members are twice as likely to be active or previous smokers. Recently a possible link between Agent Orange and BCa was also recognized. Smoking and chemical exposure are the major risk factors for BCa; smokers are eight times more likely to develop BCa. Therefore, BCa is a major healthcare problem in the general population and notably in US Service members. A short-term goal of this project is to evaluate the efficacy of novel V1-based urine tests for detecting BCa recurrence, and early detection of MIBCa, and furthermore, to evaluate the efficacy of these tests for predicting response to G+C-NAC. If one or more V1-based tests show efficacy, it should pave the way for multi-center trials in the future (long-term goal). If successful, V1-based urine tests should reduce the morbidity and costs associated with frequent cystoscopies for monitoring BCa recurrence and additional bladder resections. If validated for predicting response to G+C-NAC, V1-based urine tests may allow clinicians to individualize treatment for MIBCa patients, i.e., G+C-NAC followed by cystectomy or immediate cystectomy. If V1 and its effectors are established as molecular drivers of malign .......