- Use of Novel Technologies to Identify and Investigate Molecular Markers for Ovarian Cancer Screening and Prevention - Paving the Way for the Pacific Ovarian Cancer Research Consortium
- Molecular Epidemiology of Ovarian Cancer - Australian Ovarian Cancer Study
- The Biological Basis for Chemoprevention of Ovarian Cancer - The International Ovarian Cancer Association Consortium
Use of Novel Technologies to Identify and Investigate Molecular Markers for Ovarian Cancer Screening and Prevention - Paving the Way for the Pacific Ovarian Cancer Research Consortium
Posted April 21, 2010
Nicole Urban, Sc.D., Fred Hutchinson Cancer Research Center, Seattle, Washington
Dr. Nicole Urban, one of the first grant recipients from the Department of Defense (DOD) Ovarian Cancer Research Program (OCRP) has worked extensively in the field of ovarian cancer early detection biomarker discovery and validation. Her goal since 1994 has been to identify a screening strategy to reduce mortality from ovarian cancer through early detection. Her current program in translational ovarian cancer research was built on work funded in 1998 by the OCRP, "Use of Novel Technologies to Identify and Investigate Molecular Markers for Ovarian Cancer Screening and Prevention." Working with Beth Karlan, M.D. at Cedars-Sinai and Leroy Hood, Ph.D., M.D. at the University of Washington, she identified novel ovarian cancer biomarkers including HE4, Mesothelin (MSLN), and SLPI using comparative hybridization methods (1), leading to funding in 1999 from the National Cancer Institute (NCI) for the Pacific Ovarian Cancer Research Consortium (POCRC) Specialized Program of Research Excellence (SPORE) in ovarian cancer. The DOD and NCI funding allowed her to develop resources for translational ovarian cancer research including collection, management, and allocation of tissue and blood samples from women with ovarian cancer, women with benign ovarian conditions, and women with healthy ovaries. The DOD grant provided the foundation for what is now a mature specimen repository that has accelerated the progress of scientists at many academic institutions and industry. Dr. Urban has provided specimens to 133 scientists from academic institutions and 9 industry collaborators, including over 60 from outside institutions. She received the SPORE program Leadership Award in 2005 in recognition of her collaborative approach, and her SPORE grant has been competitively renewed twice.
Building on the work funded by the DOD grant, Dr. Urban developed assays to measure both HE4 (2-4) and MSLN (4-6) in serum. HE4 is an epididymal gene that is consistently overexpressed in ovarian malignancy but not in normal or benign ovarian tissue. Mesothelin is a 40-kDa glycoprotein present on the surface of many different malignancies including the majority of mesotheliomas and ovarian cancers. Using a standard set of blood samples from her repository, Dr. Urban evaluated the diagnostic performance of these (2, 6) and other markers (7-10) and their contribution to a diagnostic marker panel (11). She searched extensively for additional markers that would contribute to a diagnostic panel, identifying MMP7 for which an assay was commercially available (11). The original plate-based HE4 and MSLN assays have been licensed to Fujirebio Diagnostics Inc. (FDI), a diagnostics company that has recently received U.S. Food and Drug Administration approval for HE4 as a recurrence monitoring marker. FDI markets MSLN (as MesoMark) in Australia as a diagnostic marker for mesothelioma. Using specimen-efficient bead-based assays, Dr. Urban has evaluated top markers in preclinical samples to learn which markers give early signal. Working with Garnet Anderson, Ph.D., she used serum samples from the CARET repository, measuring CA125, HE4, MSLN, B7H4, Spondin2, and DCR3 in preclinical specimens from 34 cases and 70 matched controls. A composite marker calculated as the maximum of CA125, HE4, and MSLN begins to separate cases from controls over four years prior to diagnosis (12). Dr. Urban is also leading an inter-institutional effort to introduce the best of the novel markers into a screening protocol. She is conducting the Novel Markers Trial, a prospective randomized Phase I screening trial in high-risk women, in collaboration with Beth Karlan, M.D. (Cedars-Sinai), Jonathan Berek, M.D. (Stanford), Melanie Palomares, M.D. (City of Hope), and Pam Paley, M.D. (Swedish Medical Center).
References:
Schummer M, Ng W, Bumgarner R, et al. 1999. Comparative hybridization of an array of 21,500 ovarian cDNAs for the discovery of genes overexpressed in ovarian carcinomas. Genetics 238(2):375-385.
Hellström I, Raycraft J, Hayden-Ledbetter M, et al. 2003. The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma. Cancer Research 63(13):3695-3700.
Scholler N, Crawford M, Sato A, et al. 2006. Bead-based ELISA for validation of ovarian cancer early detection markers. Clinical Cancer Research 12(7):2117-2124.
Scholler N, Lowe KA, Bergan LA, et al. 2008. Use of yeast-secreted in vivo biotinylated recombinant antibodies (biobodies) in bead-based ELISA. Clinical Cancer Research 14(9):2647-2655.
Scholler N, Fu N, Yang Y, et al. 1999. Soluble member(s) of the mesothelin/megakaryocyte potentiating factor family are detectable in sera from patients with ovarian carcinoma. Proceedings of the National Academy of Science U S A 96(20):11531-11536.
McIntosh M, Drescher C, Karlan B, et al. 2004. Combining CA 125 and SMR serum markers for diagnosis and early detection of ovarian carcinoma. Gynecology Oncology 95(1):9-15.
Goodell V, Salazar LG, Urban N, et al. 2006. Antibody immunity to the p53 oncogenic protein is a prognostic indicator in ovarian cancer. Journal of Clinical Oncology 24(5):762-768 [10.1200/JCO.2005.03.2813].
McIntosh MW, Liu Y, Drescher C, et al. 2007. Validation and characterization of human kallikrein 11 as a serum marker for diagnosis of ovarian carcinoma. Clinical Cancer Research 13(15 Pt 1):4422-4428.
Simon I, Liu Y, Krall KL, et al. 2007. Evaluation of the novel serum markers B7-H4, Spondin 2, and DcR3 for diagnosis and early detection of ovarian cancer. Gynecology Oncology 106(1):112-118.
Thorpe JD, Duan X, Forrest R, et al. 2007. Effects of blood collection conditions on ovarian cancer serum markers. PLoS ONE 2(12):e1281.
Palmer C, Duan X, Hawley S, et al. 2008. Systematic evaluation of candidate blood markers for detecting ovarian cancer. PLoS ONE 3(7):e2633.
Anderson GL, McIntosh MW, Wu L, et al. 2010. Assessing lead time of selected ovarian cancer biomarkers: A nested case-control study. Journal of the National Cancer Institute 102:26-38.
Link:
Molecular Epidemiology of Ovarian Cancer - Australian Ovarian Cancer Study
Posted April 15, 2010
Peter Bowtell, Ph.D., Peter MacCallum Cancer Centre, Melbourne, Australia
Dr. Peter Bowtell, from the Peter MacCallum Cancer Centre in Melbourne, Australia, was awarded a Fiscal Year 2000 Ovarian Cancer Research Program (OCRP) Program Project Award to study the molecular epidemiology of ovarian cancer. With funds from this award, he and his colleagues formed the Australian Ovarian Cancer Study (AOCS), a population-based cohort of over 2000 women with ovarian cancer, including over 1800 with invasive or borderline cancer. With a bank of over 1100 fresh-frozen tumors, hundreds of formalin-fixed, paraffin-embedded (FFPE) blocks, and very detailed clinical follow-up, AOCS has enabled over 60 projects since its inception, including international collaborative studies in the United States, United Kingdom, and Canada. AOCS has facilitated approximately 40 publications, including those of the founding investigators, most of which have been released in the past two years. Findings resulting from AOCS projects include the identification of:
- Differences in epidemiological risk factors between ovarian, fallopian and primary peritoneal cancer (International Journal of Cancer 2008)
- New ovarian cancer susceptibility loci (Nature Genetics 2009)
- Association between MDR1 genotype and progression-free survival in optimally debulked patients (Clinical Cancer Research 2008)
- Novel molecular subtypes of serous ovarian cancer associated with clinical outcome (Clinical Cancer Research 2008)
- Distinct mechanisms of primary treatment failure in serous ovarian cancer (Clinical Cancer Research 2009)
Since the initial OCRP award, AOCS has also been supported by Australian National Health and Medical Research Council (NHMRC), state-based Cancer Council, and Cancer Australia. AOCS was recently chosen by the NHMRC to contribute to the International Cancer Genome Consortium effort. In 2007, Dr. Peter Bowtell and Dr. Gillian Mitchell were awarded an OCRP Translational Research Partnership Award to examine the frequency of BRCA1 and BRCA2 mutations in the AOCS. Without award of the OCRP Program Project grant, this powerful enabling resource for ovarian cancer research would not have been created.
Clustering of expression data derived from serous and endometrioid tumors originating from the ovary, peritoneum, and fallopian tube. A, a series of 251 from 285 tumors were robustly clustered or classified into six k-means groups (C1-C6). Average linkage hierarchical clustering using a Pearson correlation metric was used to cluster genes based on relative expression across the 251 cancers. Per gene median normalization was used for visualization. B, differentially expressed genes identified by SAM analysis. Genes ordered to show relative position within the hierarchical cluster from A. Green, showing relative under expression; red, relative overexpression. C, differentially expressed genes identified by profiling LCM captured cells from tumor and stroma representing C1 tumor specimens. Genes are ordered based on relative position within the hierarchical cluster (A). Red, overexpressed in stroma; green, overexpressed in the tumor.
Publications:
Olsen CM, Nagle CM, Whiteman DC, et al. 2008. Body size and risk of epithelial ovarian and related cancers: A population-based case-control study. International Journal of Cancer 123:450-456.
Song H, Ramus SJ, Tyrer J, et al. 2009. A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2. Nature Genetics 41:996-1000.
Johnatty SE, Beesley J, Paul J, et al. 2008. ABCB1 (MDR 1) polymorphisms and progression-free survival among women with ovarian cancer following paclitaxel/carboplatin chemotherapy. Clinical Cancer Research 14:5594-5601.
Tothill RW, Tinker AV, George J, et al. 2008. Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome. Clinical Cancer Research 14:5198-5208.
Etemadmoghadam D, deFazio A, Beroukhim R, et al. 2009. Integrated genome-wide DNA copy number and expression analysis identifies distinct mechanisms of primary chemoresistance in ovarian carcinomas. Clinical Cancer Research 15:1417-1427.
Link:
Public and Technical Abstracts: Molecular Epidemiology of Ovarian Cancer
The Biological Basis for Chemoprevention of Ovarian Cancer - The International Ovarian Cancer Association Consortium
Posted April 6, 2010
Andrew Berchuck, M.D., Duke University, Durham, North Carolina
In 1997 Dr. Andrew Berchuck at Duke University, along with his colleagues, was awarded an Ovarian Cancer Research Program (OCRP) Program Project Award to investigate the biological basis for chemoprevention of ovarian cancer. In 2001, he received another Program Project Award to continue this research.
Although inherited BRCA1 and BRCA2 mutations are responsible for about 10% of ovarian cancer cases, these mutations are carried by less than 1% of the population. Other genetic factors likely exist that increase risk moderately, and by virtue of being more common, they may account for a significant fraction of cases. One of the aims of the Program Project was to perform an ovarian cancer genetic association study to identify common low penetrance risk alleles. Over 1,300 cases and an equal number of age- and race-matched control subjects were accrued to the North Carolina Ovarian Cancer Study.
Although Dr. Berchuck and his research group were thrilled by the enthusiasm with which their study was embraced locally, it became apparent that much larger studies would be needed. As the OCRP Program Project was ending in 2005, Dr. Berchuck and his colleague, Joellen Schildkraut, Ph.D., had the opportunity to help lead the formation of an international Ovarian Cancer Association Consortium (OCAC) that is now comprised of over 20 groups. The consortium meets biannually and is working together to identify and validate single nucleotide polymorphisms (SNPs) that affect disease risk through both candidate gene approaches and genome-wide association studies (GWAS). OCAC reported last year in Nature Genetics the results of the first ovarian cancer GWAS, which identified a SNP in the region of the BNC2 gene on chromosome 9 (Nature Genetics 2009, 41:996-1000.)
Dr. Berchuck and his colleagues envision a future in which reduction of ovarian cancer incidence and mortality will be accomplished by implementation of screening and prevention interventions in women at moderately increased risk. Such a focused approach may be more feasible than population-based approaches, given the relative rarity of ovarian cancer.
Publications:
Song H, Ramus SJ, Tyrer J, et al. 2009. A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2. Nature Genetics 41:996-1000.
Link:
Public and Technical Abstracts: Biological Basis for Chemoprevention of Ovarian Cancer
Public and Technical Abstracts: Biological Basis for Chemoprevention of Ovarian Cancer