Imaging tumor bioenergetics

Harnessing the power of light to see and treat breast cancer (DoD) 

Principal Investigator: Nimmi Ramanujam
9/01/09 -- 08/31/2015
$2,854,824 total costs

My goal is to design and develop novel optical strategies to make current treatments for breast cancer faster and more effective, thereby reducing over- or under-treatment and the time and cost burden associated with it. To achieve this, I will leverage optically detectable biomarkers that report on the physiological, metabolic, molecular and morphological state of the cancer, with novel technologies being developed by our team. These tools will have the flexibility to be implemented during surgery (lumpectomies) or at the time of image-guided percutaneous biopsy. In the context of intra-operative margin assessment, optical bands of light will rapidly image the micro-environment in tumor margins. If a margin(s) is found to be positive, the surgeon can go back and take additional shavings to ensure that the tumor has been completely removed, or otherwise complete the procedure, obviating the need for a more invasive repeat surgery. In the context of image-guided percutaneous biopsy, a thin optical fiber that fits into a fine needle aspiration needle for example, which when in contact with the tumor inside the breast can diagnose cancer, assist in prognosis or predict the most effective therapy.

Objective/Hypothesis:  Our objective is to exploit the wealth of physiological, metabolic, morphological and molecular sources of optical contrast to develop novel strategies that focus on two breast cancer applications: tumor margin assessment and prediction of response to neo-adjuvant therapy. The specific aims are:

Aim 1: Optical imaging of margin morphology on breast lumpectomy specimens: To evaluate the role of wide-field imaging (coverage) and high-resolution interrogation (localization) of breast margin morphology to guide surgical resection intra-operatively and pathologic assessment of the tumor margin post-operatively.

Aim 2: Optical quantitative biology of different sub-types of breast cancer: To investigate biomarkers of oxygenation, carotenoids (-carotene) and ECM proteins (collagen) in human breast cancer stratified by tumor sub-type and receptor status and their association with neo-adjuvant chemotherapy response.

Aim 3: Optical quantitative biology to assess therapy response in different sub-types of breast cancer: To investigate biomarkers of oxygenation and ECM proteins (collagen and αvβ3 expression) in rodent breast cancer stratified by tumor sub-type, receptor status and metastatic potential in response to targeted and chemotherapies.

Light-based technologies will potentially advance our understanding of cancer in a non-destructive manner, which will not only benefit the development of effective detection strategies, but it can help elucidate the biology of this very heterogeneous and complex disease in its native micro-environment, i.e., the breast. According to the American Cancer Society, the mortality from breast cancer is decreasing due to earlier detection with improved imaging techniques and due to the use of targeted neo-adjuvant agents. Surgical excision is becoming a key element in the treatment of this disease and it is only through an effective primary excision that the surgeon can contribute to a reduction in recurrence. As the use of neo-adjuvant therapies increases, the number of women eligible for BCS will also increase.  An intra-operative tool to assure complete excision of the residual tumor, including DCIS is essential to prevent re-excision in women undergoing surgery for their primary tumor and those who have just completed their therapy. On average, a staggering four out of ten women return for a re-excision surgery. We believe that the optical strategies we have proposed, in particular a combination of wide-field and high-resolution imaging will maximally exploit differences reflected in the tumor micro-environment to assure complete removal of the tumor margins at the time of the first surgery, thereby making a significant impact on current re-excision rates.

We believe that being able to rapidly and quantitatively assess biomarkers of oxygenation as well as other optical biomarkers of tumor biology within its native micro-environment at the time of diagnosis could have a tremendous impact on breast cancer prognosis since it is generally agreed that tumor hypoxia is an independent and adverse indicator of breast tumor prognosis.  Given the strong inverse association between oxygenation and therapy outcome, the optically based approach may prove to be a valuable predictive tool for choosing the most effective cancer therapies. With these tools, clinicians and clinical researchers can get a better understanding of this disease and how it might react to a drug. Understanding how these parameters are modulated by therapy in drug-resistant and metastatic tumors will directly benefit basic science researchers who could use it as an informed approach to study tumor biology and to assay the effect of novel therapeutic agents in vivo.

 

Two-photon imaging was used to observe 2-NBDG uptake in 4T1-RFP murine cancer cells at several timepoints after hypoxic stress. Each image features an area 500 x 500 microns.

Hyperspectral window chamber imaging of tumor RFP expression, hemoglobin saturation in blood vessels and 2-NBDG uptake at 20 minutes after injection. All images were acquired post-stress.