Font: A | A | A
Ovarian Cancer Program

Motivation

Early detection of ovarian cancer promises to save the lives of thousands of women each year.

Over 230,000 women are diagnosed with ovarian cancer each year worldwide, including approximately 22,000 women in the United States.1 Unfortunately, the majority of these women ultimately die from this disease: ovarian cancer is responsible for an estimated 140,000 deaths per year worldwide, including over 15,000 deaths per year in the United States.1 The average lifetime risk of ovarian cancer for women in the US is approximately 1 in 70.1,2

Ovarian cancer is known as the 'silent killer' because most women are not diagnosed until the cancer has already spread, and chances of survival are poor (Figure 1). In contrast, if it is caught early enough, ovarian cancer can often be cured with current treatments (Figure 2). Thus, there exists a major opportunity to save lives through early detection of ovarian cancer. Ultimately, a major reduction in mortality due to ovarian cancer will require screening of the general population, as the vast majority of cases of ovarian cancer arise in women without a family history of cancer.3,4

Figure 1: Stage at Diagnosis Figure 2: Survival by Stage of Diagnosis

Research

Canary Foundation applies a collaborative approach towards biomarker discovery, validation, and translation into early detection tests.

The goal of our ovarian research program is to develop a strategy to accurately identify ovarian cancers that would otherwise be lethal at a stage when they are readily curable. Our vision is of a two-stage screening strategy, consisting of a simple blood test followed by a molecular imaging test. Development of blood and imaging tests follows a similar roadmap; both include biomarker discovery followed by validation, but they also involve different techniques and challenges.2

Blood-Based Biomarkers

The ideal blood biomarker is a protein or other biomolecule whose abundance in blood (or other fluids) is consistently higher (or lower) in women harboring very early stage ovarian cancers relative to women without cancer. We anticipate that no single biomarker will be a 'silver bullet' but rather that a diagnosis will be made based on measurements of several biomarkers at once (i.e. a 'biomarker panel').

Discovery

The first biomarker discovery projects undertaken by Canary's ovarian cancer team involved in-depth molecular characterization of ovarian cancer cell lines, ovarian cancer tumor tissues, and ascites-derived tumor cells. We subsequently added projects to discover novel protein biomarkers directly in the blood of women with pre-symptomatic ovarian cancer. Most recently, we have begun to investigate additional types of biomolecules, for example microRNAs, as potential blood biomarkers for ovarian cancer. We continue to augment and mine this remarkable resource of genomic, proteomic, and epigenomic profiles from this standardized set of ovarian biospecimens for increasingly deeper and more directed biomarker discovery.

Validation

  • Assay Development - For most novel biomarker candidates, the first step in validation is development of an assay to measure a biomarker in the blood or other fluids. Only then can the biomarker be either eliminated or advanced as a candidate for our early detection panel. To address this critical bottleneck, Canary Foundation supported the development of a dedicated biomarker validation team in Victoria, Canada. This team has built a system for efficient development of biomarker assays that is being highly leveraged by all Canary cancer programs.
  • Clinical Specimens - In order to be effective, our biomarker panel must definitively signal cancer in the tiny fraction of apparently healthy women in whom ovarian cancer has begun to develop. Access to clinical specimens, particularly from women prior to disease diagnosis, and from large numbers of non-diseased controls, is a critical part of biomarker validation. We are in the process of obtaining such clinical samples from a variety of sources and will use these precious specimens to test our leading biomarker candidates. Furthermore, our investigators are gearing up to test the most promising of our validated markers in a prospective clinical trial in women at high risk for ovarian cancer.

Imaging Biomarkers

Molecular imaging allows us to 'see' tumors based on specific and unique molecular characteristics. Our ideal biomarker for molecular imaging is a protein or other biomolecule that is highly abundant on the surface of tumor cells (or associated cells) but absent from the surface of healthy cells. Given a probe (labeled with an imaging agent) that specifically binds to this biomarker, we can visualize the tumor directly inside the woman being screened. We are pursuing two different molecular imaging approaches in our ovarian molecular imaging program: 1) PET imaging of proteins found on the cell surface of ovarian tumors and 2) targeted ultrasound imaging of proteins found on blood vessels associated with ovarian tumors using a novel microbubble-based approach.

Discovery

  • PET - Three leading candidate PET imaging protein biomarkers were identified through a combination of molecular data on ovarian tumors and literature review. We are in the process of developing them further as imaging targets.
  • Targeted Ultrasound - Through literature review, we have identified two promising candidate biomarkers for targeted ultrasound imaging. Both biomarkers have been successfully developed and tested in small animal models. We are actively engaged in discovery and development of other candidate biomarkers for imaging of tumor-associated blood vessels using targeted ultrasound.

Validation

  • PET - Antibodies have been used to evaluate our leading PET imaging cell-surface targets in our standardized set of ovarian cancer cell lines. Specific probes for PET-based imaging are being developed against each leading target to enable further validation in mouse models of ovarian cancer.
  • Targeted Ultrasound - Our two leading targeted ultrasound biomarkers have been validated in small animal models. Our investigators showed that ultrasound signal from tumors is enhanced with these markers, and that multi-target strategies may increase signal even further compared to single-target strategies. Our investigators are now working to move targeted ultrasound into a clinical trial. Other, newly identified biomarkers for targeted ultrasound will be validated on ovarian cancer tissue samples and, if successful, tested in small animal models.

Models of Ovarian Cancer Progression

One of the challenging aspects of building a test for early detection of ovarian cancer is that the earliest stages of ovarian cancer development are not well understood. To make a difference with early detection, we need to address how early and how small of a tumor we must detect. Furthermore, to isolate biomarkers that detect a tumor early, we asked what minimum tumor size a given biomarker can detect. We supported two modeling efforts to help address these critical knowledge gaps. The first comprised an in-depth pathological analysis of fallopian tubes from women at high risk for ovarian cancer as well as a literature-based meta-analysis of the characteristics of very early ovarian cancers. The second model relied on physiological information of known biomarkers secreted from tumors. Next, it will be applied to newly emerging biomarkers and combinations of biomarkers. In the future, we will integrate these and other modeling efforts to evaluate the effectiveness and economics of various cancer screening strategies, and to identify those best suited for early detection.

View Canary Funded Projects
2008 Ovarian Cancer Program Progress Report

Citations

  1. Cancer Facts & Figures 2008. American Cancer Society, Atlanta, GA, 2008.
  2. Surveillance, Epidemiology, and End Results (SEER) Program (http://seer.cancer.gov/) SEER*Stat Database: Incidence - SEER 9 Regs Limited-Use, Nov 2008 Sub (1973-2006) - Linked To County Attributes - Total U.S., 1969-2006 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2009, based on the November 2008 submission.
  3. Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Kwan E, Jack E, Vesprini DJ, Kuperstein G, Abrahamson JL, Fan I, Wong B, Narod SA. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet. 2001 Mar;68(3):700-10. Epub 2001 Feb 15.
  4. Schildkraut JM, Thompson WD. Familial ovarian cancer: a population-based case-control study. Am J Epidemiol. 1988 Sep;128(3):456-66.