Ovarian cancer is often a silent disease, showing no obvious signs until late in its development. The 5-year survival rate for advanced disease is only 15-20%, as most tumors ultimately become resistant to treatment. With early diagnosis and treatment, the survival rate increases dramatically to 90%, supporting the notion that prevention and early detection represent our best hope to overcome this disease. The strongest single biomarker of ovarian cancer, CA 125, has a sensitivity (SN) of only 50-60% for early stage disease in postmenopausal women at 99% specificity (SP). Recently, several laboratories have launched investigations focused on identifying a multi-biomarker panel capable of detecting ovarian cancer with high power. However, the sensitivity achieved at 98% SP for all appropriately validated studies fell below 80%. We have utilized a multiplex approach to identify serum biomarker panels (CA 125, Cyfra 21-1, Eotaxin, and VCAM-1) with a SN of 86% at 98% SP for stages I-II ovarian cancer, and 92% SN at 98% SP for stages III-IV. Differences in urine biomarker levels may be more readily detectable than those in serum given the increased biomarker stability and decreased matrix interference observed in urine. We therefore hypothesize that a urine multimarker test will have higher sensitivity and specificity than a similar serum test for early detection of ovarian cancer. In support of this hypothesis, our preliminary data demonstrate that a set of three biomarkers, HE4, CA 125, and Cyfra 21-1 demonstrated 96% SN at 99% SP for discriminating a mixed stage (I-IV) set of ovarian cancer cases from healthy controls. The combination of urine CEA and Cyfra 21-1 with serum CA 125 resulted in 98% SN at 100% SP in this set. Our goal is to develop a reliable urine-based assay for early detection of ovarian cancer. The following Specific Aims are proposed: 1. Analyze additional ovarian cancer associated biomarkers in urine samples in a small case control set. Select optimal biomarker combinations with high diagnostic power. 2. Validate the results in large training and validation sets representing early and late stages of ovarian cancer. Compare the performance of urine and serum biomarkers and if necessary generate and identify a combined urine/serum test with the highest diagnostic value. 3. Perform preliminary validation of the performance of an optimized test in a small retrospective cohort. At the completion of this study, we expect to create a urine or urine/serum based diagnostic test for screening and early detection of ovarian cancer with superb classification power for early and late stage disease.

Public Health Relevance

At the completion of this study, we expect to create a urine or urine/serum based diagnostic test for screening and early detection of ovarian cancer with superb classification power for early and late stage disease. Early detection holds a promise of substantially decreasing mortality from this deadly cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA143736-02
Application #
8011217
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Patriotis, Christos F
Project Start
2010-01-01
Project End
2011-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
2
Fiscal Year
2011
Total Cost
$191,776
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; Lomakin, Aleksey; Marrangoni, Adele et al. (2015) Urinary protein biomarkers in the early detection of lung cancer. Cancer Prev Res (Phila) 8:111-9
Lokshin, Anna E (2012) The quest for ovarian cancer screening biomarkers: are we on the right road? Int J Gynecol Cancer 22 Suppl 1:S35-40
Nolen, Brian M; Lokshin, Anna E (2012) Protein biomarkers of ovarian cancer: the forest and the trees. Future Oncol 8:55-71
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
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
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
Nolen, Brian M; Lokshin, Anna E (2010) Autoantibodies for cancer detection: still cause for excitement? Cancer Biomark 6:229-45
Nolen, Brian M; Lokshin, Anna E (2010) Screening for ovarian cancer: old tools, new lessons. Cancer Biomark 8:177-86
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
Nolen, Brian M; Lokshin, Anna E (2010) Targeting CCL11 in the treatment of ovarian cancer. Expert Opin Ther Targets 14:157-67

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