) Members of the erbB receptor family are commonly amplified and/or overexpressed in various tumor cell lines and human malignancies, where it is believed that increased signaling is important in tumor etiology and progression. ErbB receptor family members are being investigated rigorously as biomarkers of cancer. Several studies demonstrate that cells produce """"""""soluble"""""""" ErbB analogs in addition to their holoreceptors. These sErbB proteins embody only the extracellular domain of the receptor; they are secreted or proteolytically released into the pericellular space and are present in body fluids. Recently, our laboratory has identified two alternate transcripts of the erbB1 proto-oncogene and several putative sErbB1 proteins in human sera. To further the biochemical characterization of sErbB1 proteins, and to understand better their potential role as markers of disease activity, we have generated monoclonal antibodies toward defined peptide epitopes of the ErbB1 extracellular domain. We have also developed an acridinium-linked immunosorbent assay (ALISA) to quantify sErbB1 molecules in patient body fluids. Studies with stage III/IV epithelial ovarian cancer patients indicate that sErbB1 levels are altered in the majority of these patients relative to normal subjects. However, 8 of the 59 ovarian cancer patients studied have sErbB1 levels comparable to those of disease-free subjects. Interestingly, the median survival time of this group of 8 patients is nearly double that of the 51 patients with altered sErbB1 levels, suggesting that sErbB1 levels may be potential prognostic biomarkers. These observations had lead us to hypothesize that sErbB1 molecules inhibit cellular growth normally, and that reduced levels of sErbB1 may unrestrain cell division in malignant tissues. We further hypothesize that sErbB1 analogs may be valuable prognostic tumor biomarkers.
The specific aims of this proposal are, therefore, to: 1) characterize biochemically sErbB1 analogs present in the sera of normal and ovarian cancer patients, 2) standardize, validate, improve, modify, and automate our current sErbB1 ALISA, and 3) expand our analysis of sErbB1 levels in stage III/IV epithelial ovarian cancer patients to a much larger population of ovarian cancer patients, to determine if sErbB1 level is associated with either patient survival or any known prognostic factors of this disease. The goals outlined, here, will further my training in the fields of epidemiology, biostatistics, clinical research and oncology, thus broadening my previous training in developmental biology, cell biology, and immunology. These goals will prepare me for an independent, academic career in the field of cancer prevention and control.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Academic/Teacher Award (ATA) (K07)
Project #
5K07CA076170-04
Application #
6376570
Study Section
Subcommittee G - Education (NCI)
Program Officer
Gorelic, Lester S
Project Start
1998-08-01
Project End
2003-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
4
Fiscal Year
2001
Total Cost
$77,971
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Lafky, Jacqueline M; Baron, Andre T; Maihle, Nita J (2006) Soluble epidermal growth factor receptor acridinium-linked immunosorbent assay. Methods Mol Biol 327:39-47
Lafky, Jacqueline M; Baron, Andre T; Cora, Elsa M et al. (2005) Serum soluble epidermal growth factor receptor concentrations decrease in postmenopausal metastatic breast cancer patients treated with letrozole. Cancer Res 65:3059-62
Baron, Andre T; Cora, Elsa M; Lafky, Jacqueline M et al. (2003) Soluble epidermal growth factor receptor (sEGFR/sErbB1) as a potential risk, screening, and diagnostic serum biomarker of epithelial ovarian cancer. Cancer Epidemiol Biomarkers Prev 12:103-13
Perez, E A; Geeraerts, L; Suman, V J et al. (2002) A randomized phase II study of sequential docetaxel and doxorubicin/cyclophosphamide in patients with metastatic breast cancer. Ann Oncol 13:1225-35
Christensen, Trace A; Reiter, Jill L; Baron, Andre T et al. (2002) Generation and characterization of polyclonal antibodies specific for human p110 sEGFR. Hybrid Hybridomics 21:183-9
Baron, A T; Lafky, J M; Suman, V J et al. (2001) A preliminary study of serum concentrations of soluble epidermal growth factor receptor (sErbB1), gonadotropins, and steroid hormones in healthy men and women. Cancer Epidemiol Biomarkers Prev 10:1175-85
Baron, A T; Lafky, J M; Connolly, D C et al. (1998) A sandwich type acridinium-linked immunosorbent assay (ALISA) detects soluble ErbB1 (sErbB1) in normal human sera. J Immunol Methods 219:23-43