Skin cancers are the most frequent cancers in the United States and are a significant public health problem. Basal cell carcinomas (BCCs), squamous cell carcinomas (SCCs) and malignant melanomas (MMs) are respectively, the most common types of skin cancer. The most efficacious treatment for cutaneous BCCs, SCCs and MMs is surgical excisions of tumors coupled with histological techniques to demarcate the tumor margins. However, histology for demarcation of tumor margins can be ambiguous. Furthermore, metastasis of cancer cells to distant sites are not detected. Optical imaging in concert with fluorescent probes that bind tumors may aid physicians in: a) demarcating skin tumor margins for surgical treatment, and b) identifying metastatic spread at an early and potentially curable stage of disease. Hyaluronan (HA) is a glycosaminoglycan expressed in high concentrations by nearly all BCCs, SCCs and MMs. Thus, HA may be a new molecular marker for these skin cancers. Recently, we have developed an HA-binding peptide (termed """"""""Pep-1"""""""") that binds strongly to HA polymers associated with cutaneous melanoma tumors but weakly to HA in adjacent non-lesional skin. Based on these results we propose to test the utility of fluorescently labeled Pep-1 in concert with near-infrared multi-photon microscopy to image cutaneous BCCs, SCCs and MMs in murine models (Aim 1). Briefly, we will determine the optimal Pep-1 concentrations and post injection time intervals for near-infrared microscopic imaging using human tumor xenograft models. Next, we will examine the utility of optimized Pep-1 concentrations and post injection time intervals to demarcate tumor margins in mice that spontaneously develop BCC tumors or mice that develop skin lesions after photocarcinogenesis (SCC and MM models). Because metastasis of MMs and SCCs can result in death early detection of disseminated disease for therapeutic intervention can save lives. Thus, we will also assess the potential utility of fluorescently labeled Pep-1 in concert with near-infrared wavelengths and a CCD (charge coupled device) camera to detect metastatic disease (Aim 2). Again, we will determine the optimal concentrations for Pep-1 and the post injection time interval for detecting systemic disease using human tumor xenograft models. Once we have determined the optimal Pep-1 concentrations and time-to-imaging we will examine the utility of Pep-1 to detect spontaneous MM metastasis in mice. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR048840-06
Application #
7394351
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Baker, Carl
Project Start
2002-08-01
Project End
2010-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
6
Fiscal Year
2008
Total Cost
$330,799
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Dermatology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Fudala, Rafal; Mummert, Mark E; Gryczynski, Zygmunt et al. (2012) Lifetime-based sensing of the hyaluronidase using fluorescein labeled hyaluronic acid. J Photochem Photobiol B 106:69-73
Fudala, Rafal; Mummert, Mark E; Gryczynski, Zygmunt et al. (2011) Fluorescence detection of hyaluronidase. J Photochem Photobiol B 104:473-7
Zhang, L-S; Ma, H-W; Greyner, H J et al. (2010) Inhibition of cell proliferation by CD44: Akt is inactivated and EGR-1 is down-regulated. Cell Prolif 43:385-95
Zhang, Li-Shu; Greyner, Henry J; Mummert, Mark E et al. (2009) Development of a hyaluronan bioconjugate for the topical treatment of melanoma. J Dermatol Sci 55:56-9
Zhang, Li-Shu; Mummert, Mark E (2008) Development of a fluorescent substrate to measure hyaluronidase activity. Anal Biochem 379:80-5
Rudrabhatla, S R; Petroll, W Matthew; Mahaffey, Christie L et al. (2008) Development of a hyaluronan targeted contrast reagent for the demarcation of melanoma margins in vivo. J Invest Dermatol 128:740-2
Mahaffey, Christie L; Mummert, Mark E (2007) Hyaluronan synthesis is required for IL-2-mediated T cell proliferation. J Immunol 179:8191-9
Rudrabhatla, Sri Rajalakshmi; Mahaffey, Christie L; Mummert, Mark E (2006) Tumor microenvironment modulates hyaluronan expression: the lactate effect. J Invest Dermatol 126:1378-87
Mummert, Mark E (2005) Immunologic roles of hyaluronan. Immunol Res 31:189-206
Zmolik, Jessica M; Mummert, Mark E (2005) Pep-1 as a novel probe for the in situ detection of hyaluronan. J Histochem Cytochem 53:745-51