Malignant melanoma is one of the fastest rising cancers in the US. While treatment for clinical stage I and II melanoma involves wide local excision of the primary tumor, with staging of the regional lymph nodes by sentinel lymph node (SLN) biopsy, SLN biopsy is fraught with false-negative results. Technology that would reliably detect nodal metastases, not just the first draining node, could improve the sensitivity of melanoma nodal staging. Therefore, our objective is to (1) develop, characterize, validate and compare (A) optoacoustic ultra-acidic pH-responsive acidic pH targeted dye, pHO dye, and (B) external cell membrane anchored, V7- pHO, for tumor detection by multispectral optoacoustic tomography (MSOT) and (2) provide real-time color maps of tissue pH to allow for identification of regions of tumor in lymph nodes. Based on our preliminary data, we reason that it is possible to use our targeting methodology to identify very small metastases, which would allow complete lymph node dissection to be performed only for the 15% to 20% of patients who actually have cancer in the non-sentinel nodes. We hypothesize that pHO and V7-pHO dyes will facilitate detection of melanoma within lymph nodes and differentiate it from non-malignant, fibrous, or inflammatory tissue with high sensitivity and specificity using multispectral optoacoustic tomography. To test our hypothesis, we propose the following aims: 1) characterize and validate pHO and V7-pHO dyes to target acidic pHe for detection of tumor cells in vitro and in tissue phantoms; 2) assess pHO and V7-pHO dyes to facilitate detection of melanoma from non-malignant tissue in vivo using multispectral optoacoustic tomography; and 3) develop ratiometric algorithms based upon the spectral modulation of the pHO and V7-pHO dyes to produce real-time pHe measurement color maps and bi-color maps of tumors. Successful identification of melanoma containing lymph nodes using pHO or V7-pHO dyes detected using MSOT has potential to stratify patients for treatment in the clinic. Identification of metastases in lymph nodes or elsewhere in melanoma patients has potential for game- changing clinical management of patients with melanoma.

Public Health Relevance

Identification of cancer within sentinel lymph nodes and non-sentinel lymph nodes is a criterion for staging of melanoma. Current methods of sentinel lymph node evaluation are prone to inaccurate results. This project will develop, characterize, and validate two novel contrast agents, pHO and V7-pHO dyes, to identify melanoma within lymph nodes using multispectral optoacoustic tomography. Identification of metastases in lymph nodes or elsewhere in melanoma patients has potential to impact clinical management of patients with melanoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA205941-03
Application #
9275936
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Zhang, Yantian
Project Start
2016-09-01
Project End
2022-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Biology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Bhutiani, N; Kimbrough, C W; Burton, N C et al. (2017) Detection of microspheres in vivo using multispectral optoacoustic tomography. Biotech Histochem 92:1-6
Bhutiani, Neal; Grizzle, William E; Galandiuk, Susan et al. (2017) Noninvasive Imaging of Colitis Using Multispectral Optoacoustic Tomography. J Nucl Med 58:1009-1012