Targeting Cell Surface Proteins in Molecular Photoacoustic Imaging to Detect Ovarian Cancer Early

PUBLIC ABSTRACT

New early diagnostic tests are urgently needed to achieve the promise of reducing ovarian cancer mortality through early detection of the disease. Ovarian cancer frequently is not diagnosed until it is well advanced, and there is significant opportunity to improve survival through early detection. Five-year survival is 95% in women with cancer confined to the ovaries, but only 25% when the disease has spread outside the ovary, and 70% of cases are diagnosed in this advanced stage. Currently available diagnostic tests have not proven adequate to detect early ovarian cancer.

Building on advances in molecular biology, nanotechnology, and imaging technology, molecular imaging methods have emerged as promising tools for biomedical imaging. Compared with traditional imaging methods that detect non-specific physical characteristics or anatomic change, a major advance in molecular imaging is the use of specific imaging probes to detect molecular events and processes. This provides an unprecedented opportunity to non-invasively detect and characterize a broad range of disease conditions at the molecular level. The approach is especially well suited for cancer early detection as molecular alterations typically precede anatomic change during cancer development.

Molecular photoacoustic imaging is an especially promising approach for high resolution ovarian cancer imaging in patients. The approach utilizes a laser light source and ultrasound transducer to generate high resolution images of disease processes. Sound waves induced in tissue by the absorbance of the laser light are detected at the tissue surface by ultrasound receivers and converted to a high resolution, three-dimensional image of tissue composition. The administration of specific contrast agents during the image procedure provides submillimeter resolution at tissue depths exceeding several centimeters. The relative ease of application and integration with conventional ultrasound technology make the approach especially appealing for ovarian cancer detection.

Recently, Dr. Sanjiv Gambhir's research team at Stanford showed for the first time successful molecular photoacoustic imaging of cancer in living mice using small particles (nanoparticles) as contrast agents. The nanoparticles used by Dr. Gambhir are coated with molecules allowing them to bind to cell surface protein receptors called integrins. While the approach is highly promising, integrins are abnormally expressed in a range of disease processes, and it is unlikely the nanoparticles used in these experiments will provide specific ovarian cancer detection required for clinical use. To achieve ovarian cancer-specific detection, it is necessary to identify proteins expressed only on the surface of ovarian cancer cells and generate nanoparticles targeting these proteins.

Our idea is to apply a series of novel techniques to identify the reagents needed to move molecular photoacoustic imaging technology forward into the clinic and realize the potential of this imaging method for ovarian cancer early detection. To address this challenge, we will identify proteins expressed on the surface of ovarian cancer cells and not on surface cells from healthy ovaries or other normal tissues, and generate antibodies against these proteins. Although outside the scope of this proposal, working with Dr. Gambhir, we will test nanoparticles surface-coated with the antibodies we produce in mouse ovarian cancer models. These small animal imaging experiments provide a pathway to ultimate testing in women. Our goal is to initiate a Phase I clinical trial of photoacoustic molecular imaging using ovarian cancer-specific contrast agents in high-risk women within 5 years.