- Affinity-Based Serum Proteomics for Ovarian Cancer Early Diagnosis
- Resveratrol and Autophagy: Inhibiting Glucose Metabolism to Overcome Chemoresistance
- Polymorphisms, Risk, and the Chemoprevention of Ovarian Cancer
With the goal of identifying biomarkers for the early detection of ovarian cancer, Dr. Martin McIntosh, a Fiscal Year 2005 Idea Development Award recipient, and colleagues Drs. Paul Lampe and Nathalie Scholler, of Fred Hutchinson Cancer Research Center, are taking advantage of the unique characteristics of phage and yeast recombinant antibody libraries and using them as the basis for serum biomarker discovery. The group has identified thousands of distinctive binding sequences that bind to peritoneal fluid from cancer in preference to control, and then identified those that also bind to case plasma in preference to controls. Forty putative biomarkers have been identified and are undergoing validation using ELISA assay or mass spectrometry-based methods.
One potential novel protein biomarker, PEBP1, identified via both mass spectrometry and microarray-based approaches was detected in 29 of 30 ascites samples and discriminated ovarian cancer sera from controls. PEBP1 is undergoing further evaluation as a protein biomarker for early detection of ovarian cancer. Two other markers have been measured in preclinical samples, those collected months and years before cancer diagnosis to determine which may elevate prior to disease. Although based on a small sample size, one marker may identify 25 percent of cases at 95 percent specificity one year early, and although it may not have higher sensitivity than the CA-125 marker at that time, may provide information pertaining to risk earlier. This marker is now being evaluated in additional preclinical samples prior to publication.
Scholler N, Gross JA, Garvik B, Wells L, Liu Y, Loch CM, Ramirez AB, McIntosh MW, Lampe PD, and Urban N. 2008. Use of cancer-specific yeast-secreted in vivo biotinylated recombinant antibodies for serum biomarker discovery. Journal of Translational Medicine 6:41.
May D, Liu Y, Law W, Fitzgibbon M, Wang H, Hanash S, and McIntosh M. 2008. Peptide sequence confidence in accurate mass and time analysis and its use in complex proteomics experiments. Journal of Proteome Research (Epub ahead of print).
Martin DB, Holzman T, May D, Peterson A, Eastham A, Eng J, and McIntosh M. 2008. MRMer: An interactive open-source and cross-platform system for data extraction and visualization of multiple reaction monitoring experiments. Molecular and Cellular Proteomics 7(11):2270-2278.
Loch CM, Ramirez AB, Liu Y, Sather CL, Delrow JJ, Scholler N, Garvik BM, Urban ND, McIntosh MW, and Lampe PD. 2007. Use of high density antibody arrays to validate and discover cancer serum biomarkers. Molecular Oncology 1(3):313-320.
Dr. Rebecca Liu of the University of Michigan is a recipient of an Idea Development Award through the Fiscal Year 2005 Ovarian Cancer Research Program. Dr. Liu has been studying the application of resveratrol, a phytoalexin found in grapes, as a potential treatment for recurrent ovarian cancer. Epithelial ovarian cancer is the leading cause of death in women with gynecological cancers, and, despite initial responses to chemotherapy, the majority of patients eventually develop drug-resistant tumors. Recurrent disease is due to tumor-acquired defects in the apoptosis pathway, ultimately resulting in the failure of cytotoxic drugs, such as cisplatin, to cause apoptotic cell death. To circumvent this problem, chemo-resistant tumor cells can be targeted through an alternative, non-apoptotic cell death pathway.
Ovarian cancer cells, among other types of cancer, have an increased level of glycolytic activity. This increase in glycolysis is proposed to occur as an adaptive response to either an oxygen-deprived tumor environment or to an increased carbon substrate demand for rapidly growing tumor cells. Dr. Liu has discovered that resveratrol can induce autophagy in glucose-sensitive ovarian cancer cell lines through the prevention of glucose uptake. By blocking glucose uptake, these cells are forced to use an alternative cell death pathway that can bypass any defects in apoptosis. Her current research addresses how resveratrol modulates the PI3K/Akt/mTOR pathway to regulate glucose uptake in ovarian cancer cells. Through the study of glucose uptake in these cells, new therapeutic agents, including resveratrol, can be developed that inhibit glucose metabolism, promote autophagy, and make a significant impact toward the treatment of recurrent ovarian cancer.
Kueck A, Opipari A, Griffith K, et al. 2007. Resveratrol inhibits glucose metabolism in human ovarian cancer cells. Gynecology Oncology 107(3):450-457.
Dr. Andrew Berchuck of the Duke University Medical Center has received two Ovarian Cancer Research (OCRP) Program Project Awards (1997 and 2001) focusing on the molecular epidemiologic study of genetic polymorphisms associated with an increased risk of ovarian cancer. The discovery and characterization of these polymorphisms could lead to the understanding of how gene-gene and gene-environmental interactions could contribute to the development of disease. The overall goal of this study was to define a method of stratification that could be used toward the identification of high-risk populations for early ovarian cancer screening and prevention. Such approaches are critical for the reduction of the high levels of mortality caused by this disease.
A population-based case-control study of women from North Carolina has accrued a collection of epidemiologic data, tissue, and blood samples from approximately 1,200 ovarian cancer cases and 1,200 age- and race-matched controls. Blood DNA samples have been genotyped for polymorphisms in pathway genes, such as those associated with hormonal action and DNA repair that are thought to be involved in the development of ovarian cancer: BCRA1/2, p53, HER-2/neu, cyclin E, BRAF, MMP1, and the progesterone, androgen, transforming growth factor beta-1 (TGFa-1), and vitamin D receptors.
Interestingly, +331G/A, a polymorphism in the progesterone receptor promoter region, appears to confer a significant degree of protection against clear cell and endometrial ovarian cancer subtypes, which constitute approximately 21% of invasive cases. This nucleotide change creates a unique transcription start site, which leads to production of the progesterone receptor B isoform (PR-B) over the A isoform (PR-A). It has been suggested that PR-B upregulation in carriers of +331A have an increased susceptibility to endometrial and breast cancers due to an increased proliferative response. However, the proposed model based on this study suggests that carriers of the rare allele of this polymorphism may be protected from developing endometriosis as well as clear cell and endometrioid ovarian cancers.
Dr. Berchuck, along with Dr. Georgia Chenevix-Trench, a 2005 OCRP Idea Development Award recipient, has formed an international consortium of investigators for the purpose of studying ovarian cancer susceptibility polymorphisms. The collaborative work of these investigators allows for the conformation of results and pooling of data to increase statistical power.
Pearce CL, Wu AH, Gayther SA, et al. 2008. Progesterone receptor variation and risk of ovarian cancer is limited to the invasive endometrioid subtype: Results from the ovarian cancer association consortium pooled analysis. British Journal of Cancer 98:282-288.
Schildkraut JM, Murphy SK, Palmieri RT, et al. 2007. Trinucleotide repeat polymorphisms in the androgen receptor gene and risk of ovarian cancer. Cancer Epidemiology, Biomarkers & Prevention 16:473-480.
Hoyo C, Berchuck A, Halabi S, et al. 2005. Anthropometric measurements and epithelial ovarian cancer risk in African American and white women. Cancer Causes & Control 16:955-963.
Kelemen L, Spurdle AB, Purdie DM, et al. 2005. RAD52 Y415X truncation polymorphism and epithelial ovarian cancer risk in Australian women. Cancer Letters 218:191-197.
Berchuck A, Schildkraut JM, Wenham RM, et al. 2004. Progesterone receptor promoter +331A polymorphism is associated with a reduced risk of endometrioid and clear cell ovarian cancers. Cancer Epidemiology, Biomarkers & Prevention 13(12):2141-2147.
Webb PM, Hopper JL, Newman B, et al. 2004. Double strand repair gene polymorphisms and risk of breast or ovarian cancer. Cancer Epidemiology, Biomarkers & Prevention 14:319-323.
Lancaster JM, Wenham RM, Halabi S, et al. 2003. No relationship between ovarian cancer risk and progesterone receptor gene polymorphism (PROGINS) in a population-based, case-control study in North Carolina. Cancer Epidemiology, Biomarkers & Prevention 12:226-227.
Wenham RM, Schildkraut JM, McLean K, et al. 2003. Polymorphisms in BRCA1 and BRCA2 and risk of epithelial ovarian cancer. Clinical Cancer Research 9:4396-4403.