Stopping Cancer Early – The Best Possible Investment

Ovarian

The goal of the 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.

If ovarian cancer is caught early, the five-year survival rate for ovarian cancer patients is greater than 90 percent, yet less than 25 percent are found this early.

The Canary ovarian cancer team was formed in 2005 in response to the need for tools to detect lethal types of ovarian cancer at an early stage, with the highest curability. Since that time, the team has completed collaborative projects in biomarker discovery, validation, molecular imaging, and screening modeling, and the group has moved blood and imaging tests into clinical trials. The team has also served as a model for collaborative teamwork in the field of early detection.

Dr. McIntosh is involved in tumor immunology: using the body’s own immune response to detect forming tumors by imaging or blood biomarkers.

Imaging for Ovarian Cancer

There is a need for new imaging technologies that not only reliably visualize ovarian cancer with enhanced sensitivity and specificity but also differentiate between benign and malignant disease.

Ultrasound is a widely available imaging technology that lacks ionizing radiation, is relatively cost-effective, and allows a dynamic evaluation of the region of interest in real time. In current clinical practice, screening for ovarian cancer may include transvaginal ultrasound imaging of ovaries, combined with a blood test for the biomarker CA-125. However, these screening methods produce many false-positive results and unnecessary surgeries.

The ovarian cancer team will test a new technique, photoacoustic imaging (PAI), for its ability to meet these needs in ovarian cancer screening.

Another molecular imaging modality that holds promise for imaging ovarian cancer is enhanced ultrasound using targeted microbubble technology. Recent FDA approval for using targeted microbubbles in humans has opened the door to advance this study. Studies using targeted microbubbles in prostate cancer patients are underway at Stanford, with plans to expand to studies in additional cancer types, including ovarian cancer.

Photoacoustic Imaging for Ovarian Cancer

We are adapting traditional ultrasound imaging with an emerging non-ionizing photoacoustic imaging (PAI) technique that essentially lets us “hear” light.

PAI strategies allow deeper tissue penetration than optics alone while preserving the spatial and temporal resolution advantages of ultrasound.

Therefore, tissues within a human body can be more clearly visualized at a depth that is clinically relevant. Because hemoglobin is one of the primary molecules present naturally that produce a photoacoustic signal, PAI is especially suitable for detecting blood vessels associated with tumors, as well as monitoring changes in blood vessel growth that can accompany tumor formation and growth.

At Stanford, we have engineered a new PAI device that is being tested for visualization of prostate cancer. We are adapting this device for use in ovarian cancer imaging.

After development and pre-clinical testing of the device, we will move into the clinical setting to test in patients. Our goal is to reliably visualize cancer even from several centimeters deep inside ovarian tissue. We propose the following specific aims:

1. Refine and validate a combined transvaginal ultrasound and photoacoustic-imaging device by imaging models of ovarian tissue and surgically removed human ovaries. In this aim, we will adapt the current transrectal ultrasound and PAI system shown in figure 1, to develop the probe for transvaginal imaging of ovaries.

Figure 1. Photograph of the transrectal ultrasound and photoacoustic-imaging instrument currently used for prostate cancer imaging. The capacitive micromachined ultrasound transducer (CMUT) array is flip-chip bonded to a custom-designed integrated circuit that comprises the front-end circuitry for the transducer elements. The CMUT and integrated circuit are flip-chip bonded and placed on a PCB (printed circuit board). The PCB is rested in between two parallel fiber optic light guides that focus light 0.5 inches above the CMUT surface.

Figure 1. Photograph of the transrectal ultrasound and photoacoustic-imaging instrument currently used for prostate cancer imaging. The capacitive micromachined ultrasound transducer (CMUT) array is flip-chip bonded to a custom-designed integrated circuit that comprises the front-end circuitry for the transducer elements. The CMUT and integrated circuit are flip-chip bonded and placed on a PCB (printed circuit board). The PCB is rested in between two parallel fiber optic light guides that focus light 0.5 inches above the CMUT surface.

2. Conduct a pilot test of the combined transvaginal ultrasound and PAI instrument in patients undergoing ovarian cancer excision surgery. Fully optimized dual-modality transvaginal ultrasound and PAI with well-defined image metrics have the potential to further enhance the sensitivity and specificity of standard transvaginal ultrasound imaging of ovaries prior to surgery. In this study, we will test the efficacy of the combined device for clinical ovarian imaging. We anticipate that the combined procedure should not be more uncomfortable than a traditional transvaginal ultrasound procedure, since both are done with a hand-held transvaginal device of similar dimensions. The combined transvaginal ultrasound-PAI can be done at the time of traditional ultrasound, and in preclinical studies adds less than five to 10 minutes to each procedure.

The primary objective of this specific aim is to assess the combined instrument performance in a clinical setting, to understand the limitations of this instrumentation, to help improve the next-generation instrument design, and to understand how to integrate the combined transvaginal ultrasound and photoacoustic imaging into the standard clinical ultrasound workflow.

Modeling Window of Opportunity and Cost-Effectiveness

One of the challenging aspects of building a test for early detection of ovarian cancer is understanding the earliest stages of ovarian cancer growth.

Two key characteristics of ovarian cancer growth influence the development of an early detection test: the size at which a tumor progresses from early stage, treatable disease to incurable disease, and the amount of time the tumor spends as early stage, treatable disease, i.e. the window of opportunity for early detection. Canary research supported two modeling efforts to help address these critical pieces of knowledge.

The first comprised an analysis of tumors found in fallopian tubes and ovaries removed from healthy women at high risk for ovarian cancer. By comparing the size and stage of these previously undetected tumors with tumors from women diagnosed with ovarian cancer, the researchers were able to model both the size of early stage tumors and the length of time tumors spend in early stage before progressing.

The second effort modeled the mortality reduction and cost-effectiveness achievable by currently available screening tests using data on the natural history of ovarian cancer, survival after ovarian cancer diagnosis, and blood biomarker levels from clinical trials.

Team

The Canary Ovarian Cancer team includes physicians who focus on gynecologic diseases and ovarian cancer, molecular imaging experts, and those who focus on biomarker evaluation and molecular diagnostics.

Past and present members include:

  • Patrick Brown, M.D., Ph.D., Stanford University
  • Charles Drescher, M.D., University of Washington and Fred Hutchinson Cancer Research Center
  • Sanjiv Sam Gambhir, M.D., Ph.D., Stanford University
  • Peter Laird, Ph.D., Van Andel Research Institute
  • Martin McIntosh, Ph.D., Fred Hutchinson Cancer Research Center
  • Brad Nelson, Ph.D., British Columbia Cancer Agency
  • Muneesh Tewari, M.D., Ph.D., University of Michigan
  • Nicole Urban, Sc.D., Fred Hutchinson Cancer Research Center

Progress and Results/Clinical Studies

Novel Markers Trial (NMT)
The Novel Markers Trial (NMT) was launched in 2009 by the Pacific Ovarian Cancer Research Consortium (POCRC), a collaborative team of scientists led by Canary team member Dr. Nicole Urban who was awarded a five-year SPORE grant by the National Cancer Institute.

Previous clinical trials of ovarian cancer screening programs mostly involved a single biomarker (CA-125) as a blood test. The NMT incorporates a second blood-based biomarker (HE4) into the screening protocols for clinical decision-making. Furthermore, the trial uses a new computational algorithm to determine whether the biomarker signals the presence of cancer. The study is determining the predictive value for malignant ovarian cancer of a screening program that includes the two blood biomarkers, the new algorithm to decipher a cancer signature from blood biomarkers, and ultrasound as an imaging modality.

The five-year study has enrolled its goal of 1,200 women, divided into three risk groups depending on the mutation status of certain cancer risk genes, family history of ovarian cancer, and other factors that may influence a woman’s risk of ovarian cancer. The study has determined that HE4 is useful as a confirmatory screen when rising CA-125 is used alone as a primary screen. The screening protocol was found to be feasible and acceptable to women and physicians and did not result in excessive imaging, surgical consults or surgeries. Thousands of well-characterized samples, including blood and tissue specimens, are now stored in a central repository for use in future studies. The NMT is under consideration to be made available nationally through an NCI-funded cancer research cooperative group.

For more detailed information about this screening trial, please visit the POCRC website.

Where Canary Science is Happening

Canary Funded Ovarian Cancer Papers

Urban, N. et al. Identifying post-menopausal women at elevated risk for epithelial ovarian cancer. Gynecologic Oncology (2015)

Karlan, B.Y., et al. Use of CA125 and HE4 serum markers to predict ovarian cancer in elevated-risk women. Cancer Epidemiol Biomarkers Prev. (2014)

Lutz, A.M., et al. Ultrasound Molecular Imaging in a Human CD276 Expression-Modulated Murine Ovarian Cancer Model. Clin Cancer Res. (2014)

Urban, N., et al. Interpretation of single and serial measures of HE4 and CA125 in asymptomatic women at high risk for ovarian cancer. Cancer Epidemiol Biomarkers Prev. (2012)

Salzman, J., et al. Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. PLoS One (2012)

Hori, S.S. and Gambhir, S.S. Mathematical model identifies blood biomarker–based early cancer detection strategies and limitations. Sci Transl Med. (2011)

Salzman, J., et al. ESRRA-C11orf20 is a recurrent gene fusion in serous ovarian carcinoma. PLoS Biol. (2011)

Urban N., et al. Potential role of HE4 in multimodal screening for epithelial ovarian cancer. J Natl Cancer Inst. (2011)

Lutz, A.M., et al. Early diagnosis of ovarian carcinoma: is a solution in sight? Radiology (2011)

Houshdaran, S., et al. DNA methylation profiles of ovarian epithelial carcinoma tumors and cell lines. PloS One (2010)

Shaw, P.A., et al. Candidate serous cancer precursors in fallopian tube epithelium of BRCA1/2 mutation carriers. Mod Pathol. (2009)

Brown, P.O., et al. The Preclinical Natural History of Serous Ovarian Cancer: Defining the Target for Early Detection. PloS Med. (2009)

Köbel, M., et al. Ovarian carcinoma subtypes are different diseases: implications for biomarker studies. PLoS Medicine (2008)

Lutz, A.M., et al. Cancer screening: A mathematical model relating secreted blood biomarker levels to tumor sizes. PLoS Medicine (2008)

Martin, D.B., et al. MRMer: An interactive open-source and cross-platform system for data extraction and visualization of multiple reaction monitoring experiments. Mol. Cell. Proteomics (2008)

Palmer, C., et al. Systematic Evaluation of Candidate Blood Markers for Detecting Ovarian Cancer. PLoS One (2008)

Faca, V.M., et al.Proteomic analysis of ovarian cancer cells reveals dynamic processes of protein secretion and shedding of extra-cellular domains. PLoS One (2008)

Estep, A., et al. Mutation analysis of BRAF, MEK1 and MEK2 in 15 ovarian cancer cell lines: Implications for therapy. PLoS One (2007)

Scholler, N., et al. Development of a CA125-mesothelin cell adhesion assay as a screening tool for biologics discovery. Cancer Lett. (2007)

Thorpe, J.T., et al. Effects of blood collection conditions on ovarian cancer serum markers. PLoS One (2007)

Bergan, L., et al. Development and in vitro validation of anti-mesothelin biobodies that prevent CA125/Mesothelin-dependent cell attachment. Cancer Lett. (2007)

Scholler, N., et al. Method for generation of in vivo biotinylated recombinant antibodies by yeast mating. J. Immunol. Methods. (2006)

Scholler, N., et al. Bead-based ELISA for validation of ovarian cancer early detection markers. Clin. Cancer Res. (2006)