Renal cell carcinoma (RCC) is the most lethal urologic malignancy. The RCC incidence exceeds that of leukemia and pancreatic cancer in men, and equal to that of ovarian and pancreatic cancer in women. The overall age-adjusted RCC incidence is 65.3/100,000 in those >65 years and it now accounts for almost 4% of adult malignancies. Due to increased general diagnostic use of abdominal imaging, the incidental discovery of occult small renal masses has increased. However, radiologic screening is impractical and expensive. Additionally, CT imaging, while detecting renal masses, cannot reliably differentiate RCC from a benign mass. The unmet need is a sensitive and specific tumor marker, for differential diagnosis of imaged renal masses and for population screening and detection of RCC. We have shown that urine aquaporin 1 (AQP1) and perilipin 2 (PLIN2) concentrations are sensitive and specific biomarkers for early noninvasive detection of clear cell or papillary RCC (together accounting for almost 90% of RCC) These biomarkers have cleared the first three hurdles of diagnostic cancer biomarker development: identifying promising biomarkers (phase 1), establishing that the biomarkers identify clinical disease from potential confounding diseases (phase 2), and validating that the biomarkers detect early pre-clinical disease and defined a screen positive rule for urine AQP1 and PLIN2 in a 720 patient cohort (phase 3). We recently developed novel nanotechnology-based assays for AQP1 and PLIN2, achieving greater laboratory sensitivity and specificity, with less expense, and quicker results. Our hypothesis is that nanoAQP1 and nanoPLIN2 assays will have analytical and clinical validity, and clinical utility to achieve rapid differential diagnosis of imaged renal masses in th radiologic setting and for population screening for RCC. We seek to establish phase 4 of biomarker development and define the true detection and the false negative rates of this streamlined nanotechnology-based biomarker assay in a novel prospective 25,000 patient virtual clinical study mimicking population screening, with 1-time cross-sectional evaluation, to measure urine biomarkers, and correlate with clinical diagnoses and available abdominal imaging. The use of nano-AQP1 and nano-PLIN2 assays to differentiate renal tumor subtypes will be tested in another virtual clinical study encompassing 1600 patients with an imaged renal mass. The overall research goal is translation and definitive validation, in a large-scale single-center clinical investigation, of urine AQP1 and PLIN2 as noninvasive biomarkers for 1) differential diagnosis of imaged renal masses, to inform decisions when to surgically intervene, and 2) population screening to detect RCC and enable early and curative intervention. When successfully completed, this research will have translated the basic discovery of RCC biomarkers into a first-ever clinical method for detecting RCC. Thus, our nanotechnology-based biomarker assay to non-invasively diagnose an imaged renal mass and screen for RCC will fundamentally change the course of a silent, lethal disease, and enable better patient outcome.

Public Health Relevance

Renal cell carcinoma (RCC) is the most lethal urologic malignancy with an incidence exceeding that of leukemia and pancreatic cancer in men, and that of ovarian and pancreatic cancer in women. It now accounts for almost 4% of adult malignancies. Due to increased general diagnostic use of abdominal imaging, the incidental discovery of occult small renal masses has increased. However, radiologic screening is impractical, expensive, and cannot reliably differentiate RCC from a benign mass. The unmet need is a sensitive and specific tumor marker for the differential diagnosis of imaged renal masses and population screening to detect RCC We have identified novel urine biomarkers of RCC, determined their clinical validity, and developed nanotechnology-based assays for these markers. Here we determine the clinical utility of the nano-assays in a 25,000 patient screening protocol. Successful completion will provide a non-invasive means of detecting kidney cancer and an adjunct to accurately diagnose renal images.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA141521-06
Application #
9257285
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Mckee, Tawnya C
Project Start
2009-07-01
Project End
2020-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
6
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Washington University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Wang, Congzhou; Tadepalli, Sirimuvva; Luan, Jingyi et al. (2017) Metal-Organic Framework as a Protective Coating for Biodiagnostic Chips. Adv Mater 29:
Hu, Rong; Luan, Jingyi; Kharasch, Evan D et al. (2017) Aromatic Functionality of Target Proteins Influences Monomer Selection for Creating Artificial Antibodies on Plasmonic Biosensors. ACS Appl Mater Interfaces 9:145-151
Luan, Jingyi; Liu, Keng-Ku; Tadepalli, Sirimuvva et al. (2016) PEGylated Artificial Antibodies: Plasmonic Biosensors with Improved Selectivity. ACS Appl Mater Interfaces 8:23509-16
Wang, Congzhou; Luan, Jingyi; Tadepalli, Sirimuvva et al. (2016) Silk-Encapsulated Plasmonic Biochips with Enhanced Thermal Stability. ACS Appl Mater Interfaces 8:26493-26500
Morrissey, Jeremiah J; Mellnick, Vincent M; Luo, Jingqin et al. (2015) Evaluation of Urine Aquaporin-1 and Perilipin-2 Concentrations as Biomarkers to Screen for Renal Cell Carcinoma: A Prospective Cohort Study. JAMA Oncol 1:204-12
Morrissey, Jeremiah J; Mobley, Jonathan; Figenshau, R Sherburne et al. (2015) Urine aquaporin 1 and perilipin 2 differentiate renal carcinomas from other imaged renal masses and bladder and prostate cancer. Mayo Clin Proc 90:35-42
Tian, Limei; Tadepalli, Sirimuvva; Park, Sang Hyun et al. (2014) Bioplasmonic calligraphy for multiplexed label-free biodetection. Biosens Bioelectron 59:208-15
Morrissey, Jeremiah J; Mobley, Jonathan; Song, Joseph et al. (2014) Urinary concentrations of aquaporin-1 and perilipin-2 in patients with renal cell carcinoma correlate with tumor size and stage but not grade. Urology 83:256.e9-14
Morrissey, Jeremiah J; Kharasch, Evan D (2013) The specificity of urinary aquaporin 1 and perilipin 2 to screen for renal cell carcinoma. J Urol 189:1913-20
Abbas, Abdennour; Tian, Limei; Morrissey, Jeremiah J et al. (2013) Hot Spot-Localized Artificial Antibodies for Label-Free Plasmonic Biosensing. Adv Funct Mater 23:1789-1797

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