Pancreatic cancer is the fifth leading cause of cancer death in the USA. This is due, in part, to the lack of early detection methods for this particularly aggressive form of cancer. None of the biomarkers of pancreatic cancer that have been identified to date are sufficiently predictive to be useful as a diagnostic or screening test. We hypothesize that a multi-marker panel will have high sensitivity and specificity for early detection of pancreatic cancer. We propose to use novel Luminex LabMAP technology that allows for simultaneous evaluation of multiple (up to 100) biomarkers in one sample. Our preliminary results suggest that our Luminex panel has significant predictive power. Our goal is to develop a reliable serum-based assay for early detection of pancreatic cancer based on the longitudinal patterns of multiple biomarkers. This project is firmly based on biomarker discoveries and strong preliminary data developed and include a team of basic cancer researchers and clinicians supported by faculty with requisite expertise in biostatistics/bioinformatics. Our immediate objectives are (i) to further expand our pancreatic cancer panel with additional pancreatic cancer-relevant biomarkers including circulating antibodies and (ii) to interpret the panel longitudinally and validate the resultant assay for patient use. To accomplish these objectives the following Specific Aims are proposed: 1. Generate and optimize a comprehensive multiplexed assay for detection of highly relevant pancreatic cancer markers. Luminex-based assay will be developed for multiplex analysis of most of the known pancreatic cancer serological biomarkers including cytokines, chemokines, angiogenic and growth factors and their receptors, as well as circulating antibodies against pancreatic antigens. 2. Use Luminex-based biomarker panels identified to select a combined multimarker panel that distinguishes patients with pancreatic cancer from healthy controls or patients with benign disease (Phase 2 validation study). Performance characteristics of biomarker panels developed in Aim I will be evaluated in a definitive cohort with adenocarcinoma of the pancreas, chronic pancreatitis, acute pancreatitis, and patients with other peri-ampullary tumors and age-, sex- and smoking status-matched healthy controls. A combination of markers allowing distinguishing patients with pancreatic cancer from those without cancer or with benign disease will be selected. The cancer-specificity of this panel will be assessed. An optimized statistical model for analyzing and combining multimarker panels will be developed. 3. Validate/optimize this multimarker panel in retrospective longitudinal study (Phases 3-4 validation study). Diagnostic utility of the multimarker assay in a general population will be validated in available prospective studies. At the conclusion of this study, we expect to develop strategies for the early detection of pancreatic cancer that are practical and efficient and can be projected to offer the best opportunity to reduce the mortality from this disease. This research study will be conducted in the context of UPCI EDRN/BDL directed by Dr. Anna Lokshin, who brings extensive experience in cancer biomarkers and Luminex multiplexed technology research. The combined team comprises an outstanding and productive group of clinical and translational cancer researchers focused on cancer biomarkers discovery, evaluation, and validation. These efforts will strongly support the research and clinical goals of the EDRN. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA117452-03
Application #
7285693
Study Section
Special Emphasis Panel (ZCA1-SRRB-Y (M2))
Program Officer
Wagner, Paul D
Project Start
2005-09-12
Project End
2009-07-31
Budget Start
2007-09-25
Budget End
2008-07-31
Support Year
3
Fiscal Year
2007
Total Cost
$557,662
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Nolen, Brian M; Brand, Randall E; Prosser, Denise et al. (2014) Prediagnostic serum biomarkers as early detection tools for pancreatic cancer in a large prospective cohort study. PLoS One 9:e94928
Nolen, Brian M; Lokshin, Anna E (2013) Biomarker testing for ovarian cancer: clinical utility of multiplex assays. Mol Diagn Ther 17:139-46
Nolen, Brian M; Orlichenko, Lidiya S; Marrangoni, Adele et al. (2013) An extensive targeted proteomic analysis of disease-related protein biomarkers in urine from healthy donors. PLoS One 8:e63368
Nolen, Brian M; Langmead, Christopher J; Choi, Sunguk et al. (2011) Serum biomarker profiles as diagnostic tools in lung cancer. Cancer Biomark 10:3-12
Nolen, Brian M; Lokshin, Anna E (2011) -The advancement of biomarker-based diagnostic tools for ovarian, breast, and pancreatic cancer through the use of urine as an analytical biofluid. Int J Biol Markers 26:141-52
Brand, Randall E; Nolen, Brian M; Zeh, Herbert J et al. (2011) Serum biomarker panels for the detection of pancreatic cancer. Clin Cancer Res 17:805-16
Levina, Vera; Marrangoni, Adele; Wang, Tingting et al. (2010) Elimination of human lung cancer stem cells through targeting of the stem cell factor-c-kit autocrine signaling loop. Cancer Res 70:338-46
Feng, Rentian; Rios, Jorge A; Onishi, Tomifumi et al. (2010) Cell-based and cytokine-directed chemical screen to identify potential anti-multiple myeloma agents. Leuk Res 34:917-24
Nolen, Brian M; Lokshin, Anna E (2010) Targeting CCL11 in the treatment of ovarian cancer. Expert Opin Ther Targets 14:157-67
Haab, Brian B; Porter, Andrew; Yue, Tingting et al. (2010) Glycosylation variants of mucins and CEACAMs as candidate biomarkers for the diagnosis of pancreatic cystic neoplasms. Ann Surg 251:937-45

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