Project Summary/Abstract
Background Over 83,000 Americans will be diagnosed with bladder cancer in 2021 with over 17,000 dying of
the disease during this period. Unfortunately, both the absolute numbers of cases and deaths from bladder
cancer have increased by 57 and 41%, respectively, since 2000. When detected early (i.e., NMIBC or stage 1),
the 5-yr survival rate is >90%, compared to a significant reduction in survival if the disease is noted to be MIBC
(stage 2; 50% 5-yr survival) or metastatic (stages 3 and 4; <20% 5-yr survival). Thus, the prevailing idea is that
early detection of bladder cancer in high risk individuals (i.e., individuals exposed to certain carcinogens) will
likely be the best modality to address advanced bladder cancer’s dismal outcomes. Currently, the evaluation of
at risk individuals remains a challenge, and as such, there are no modalities available to effectively screen this
high risk population. Previously, we have a) identified a bladder cancer-associated diagnostic “signature”
comprised of 10 biomarkers, b) developed a multiplex immunoassay to query the “signature” in voided urine
samples and c) performed analytical validation of the multiplex immunoassay. Using the multiplex immunoassay,
we have generated encouraging preliminary data from a cohort of 362 subjects (46 cancers) (AUC 0.95;
sensitivity 0.93, specificity 0.93, positive predictive value 0.65 and negative predictive value 0.99). Thus, for the
first time, we possess a robust assay that can be used to non-invasively detect bladder cancer. Utilizing this
assay in our ongoing prospective study surveilling patients with a history of bladder cancer, we have noted an
elevation of our ‘signature’ as early as 18 months prior to the clinical diagnosis of cancer and an actual positive
multiplex immunoassay in all cancer patients 12 months prior to the clinical diagnosis of cancer. Furthermore,
we have evidence that 9 of our 10 biomarkers within the “signature” are expressed in relevant carcinogen induced
mouse bladder cancer model. Hypothesis: A bladder cancer-associated signature exists that can be leveraged
to indicate the presence of bladder cancer from a single voided urine sample months to years prior to the clinical
presentation and diagnosis of bladder cancer. Specific Aims: 1) To perform a pilot study to evaluate the
multiplex immunoassay’s ability to early detect bladder cancer and 2) To use a relevant carcinogen induced
mouse bladder cancer model to identify early changes within the tumor microenvironment which could serve as
biomarkers candidates for testing in human samples. Significance This research will open the door for
improving on the non-invasive methods for the early detection of bladder cancer, and as such, it will have a
marked impact on patient survival. Methodology We will conduct a prospective pilot study (n=150) to
demonstrate the feasibility of identifying, following and testing high risk individuals for bladder cancer. Then
utilizing a relevant carcinogen induced mouse bladder cancer model, we will study the spatial and temporal
association of our “signature” and link it to key changes within the tumor microenvironment, identifying novel
biomarkers for future clinical development. Expected Results There exists an unmet clinical need for reliable
biomarkers to early detect bladder cancer when its more treatable with improved survival rates.
