Lymph Node Metastases Optical Molecular Diagnostic and Radiation Therapy
Abstract
Breast cancer metastases detection, imaging, and management is limited by a key technical problem fundamental to the nature of imaging, which is that micrometastases cannot be visualized at a relevant stage, largely because most imaging is based upon structures and not molecular functions. The one tool commonly used for metastases imaging is nuclear medicine. Positron emission tomography (PET) is used for whole body imaging of metastases, or Gamma probe imaging is used for sentinel lymph node detection. PET is extremely successful in clinical staging based upon detection of involvement in lymph nodes and secondary organs, but there are no tools to effectively sense early metastases. Gamma imaging of sentinel nodes is not a disease diagnostic, but rather just used to find the node and remove it for pathological inspection. As a result, we are in a situation where surgical node dissection procedures are the standard for detection and removal of metastases, but axillary node dissection has high morbidity and is only needed in about 25% of cases that it is done. Surgical dissection is the result of the fact that there is no molecular imaging tool today that can routinely sense the presence of cancer cells in lymph nodes or organs at the micrometastasis stage. The needed probe sensitivity would be in the uM to nM range with sub-mm spatial resolution throughout the body. This lack of high spatial resolution molecular imaging is a key factor inhibiting breast metastasis research and treatment. In this proposal, we plan to develop a completely unique hybrid modality that will have high resolution capability through several centimeters of tissue, and all the molecular specificity of standard optical luminescence tracers, with sensitivity down to the sub-uM level and spatial resolution below 1 mm. The new approach uses high energy x-rays from a linear accelerator, LINAC, used in radiation therapy, allowing metabolic imaging and treatment in the same setting. The LINAC radiation induces Cerenkov light in the tissue, and this light can excite luminescence for molecular imaging. This Cerenkov-excited luminescence scanned imaging approach is referred to as CELSI. We proposed to develop the two unique parts to this tool and test it as combined with multi-probe imaging, to quantify the molecular microenvironment of cancer tumors in vivo. The fascinating value of this new imaging modality is that it has many of the high resolution advantages of x-ray imaging and x-ray luminescence imaging, but with the key benefit of high molecular sensitivity of optical imaging using organic molecules. Additionally, it does not suffer from the high effective doses inherent in nuclear medicine methods where radionuclide clearance in excretory organs is known to limit use. CELSI could provide a fundamentally new way to diagnostically sense tumor microenvironments for cancer research and drug efficacy screening. This is a very early-stage concept imaging/treatment tool, but one which will be developed on a clinical treatment scanner, so has high potential for translation into a clinical trial. In this 3-year proposal, we will focus on system development and preclinical efficacy testing. The individual aims in this overall goal are: (1) to optimize the setup and design of a dedicated system to sense signals; (2) to design and build a dedicated system suitable for imaging signals from in small animals on the standard radiation therapy tools; (3) to evaluate the limits on structural, metabolic, and immunologic probes for molecular imaging; and (4) to complete studies on metastatic breast cancer with MeV photon imaging and treatment. CELSI has been demonstrated at the initial in vivo feasibility stage in a lymph node imaging study and should be evaluated as a fundamentally new molecular imaging modality. We anticipate that as the ability to sense molecular concentrations at low radiation dose gets established, human use possibilities will
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1610004
Entities
People
- Brian W Pogue
Organizations
- Dartmouth College
- United States Army