Non-melanoma skin cancers (NMSC), comprising squamous cell (SCC) and basal cell carcinomas (BCC), have a significant impact upon the health care system because their overall incidence is higher than for all other cancers combined. Therefore, while not usually fatal, these skin carcinomas incur a very high cost for their management, e.g., 90% of the cost of treating breast cancer. The current standard of care is surgical excision with wide margins. Major morbidity stems from fibrosis, scarring, and loss of function after treatment. Photodynamic therapy (PDT) using 5-aminotevulinicacid (ALA) represents a non-disfiguring alternative to surgery, especially for patients with multiple tumors and for tumors in delicate sites. Currently, the efficacy of ALA-PDT is not adequate to realistically compete with surgery in the U.S.A. Based on one of the Program themes of Combination Photodynamic Biologic Therapy (CPBT), in Project 1, our overall hypothesis is that tumor-differentiating agents can be used to improve the efficacy of ALA-PDT so that PDT becomes a viable alternative to surgery for NMSC. Wewill build upon our discovery that two small molecules, methotrexate (MTX) and vitamin D (Vit D), can increase tumor cell differentiation and at the same time increase the levels of photosensitizer (PplX) within the cells, thus enhancing responsiveness to therapy. The project is translational in nature, with clinical and basic science components.
Aim 1 is preclinical, and uses mouse models of SCC and BCC to determine optimal dosing regimens for the systemic differentiating agent.
Aims 2 and 3 are clinical studies to determine the efficacy of topical Vit D and oral MTXas combination agents with ALA-PDT.
These Aims will also test new in vivo multimodal subsurface imaging devices for PplX detection, and evaluate C/EBP transcription factors ex vivo as prognostic markers of tumor response.
Aim 4 consists of mechanistic experiments that will examine regulatory functions and the prognostic value of the C/EBPs in terms of PplX accumulation, using the preclinical models and examining tissue-banked skin tumor specimens from the clinical studies.
Aim 4 is significant because those experiments will contribute to further improvements in the treatment design. The project involves significant collaborations with Project 4, Core B, and Core C of the Program. In summary, the potentialbenefits to public health will be the development of new rational combination approaches for PDT of skin cancer that include the manipulation of tumor cell physiology to increase endogenous levels of PplX. This will be coupled with individualized treatment planning based upon advanced PplX dosimetry and measurement of differentiation-responsive molecular markers, to optimize treatment response.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-GRB-P)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
O'Brien, Darragh P; Sandanayake, Neomal S; Jenkinson, Claire et al. (2015) Serum CA19-9 is significantly upregulated up to 2 years before diagnosis with pancreatic cancer: implications for early disease detection. Clin Cancer Res 21:622-31
Samkoe, Kimberley S; Tichauer, Kenneth M; Gunn, Jason R et al. (2014) Quantitative in vivo immunohistochemistry of epidermal growth factor receptor using a receptor concentration imaging approach. Cancer Res 74:7465-74
Skipworth, J R A; Keane, M G; Pereira, S P (2014) Update on the management of cholangiocarcinoma. Dig Dis 32:570-8
Huggett, Matthew T; Passant, Helen; Hurt, Chris et al. (2014) Outcome and patterns of care in advanced biliary tract carcinoma (ABC): experience from two tertiary institutions in the United Kingdom. Tumori 100:219-24
Jermyn, Michael; Davis, Scott C; Dehghani, Hamid et al. (2014) CT contrast predicts pancreatic cancer treatment response to verteporfin-based photodynamic therapy. Phys Med Biol 59:1911-21
Spring, Bryan Q; Abu-Yousif, Adnan O; Palanisami, Akilan et al. (2014) Selective treatment and monitoring of disseminated cancer micrometastases in vivo using dual-function, activatable immunoconjugates. Proc Natl Acad Sci U S A 111:E933-42
Spring, Bryan Q; Palanisami, Akilan; Hasan, Tayyaba (2014) Microscale receiver operating characteristic analysis of micrometastasis recognition using activatable fluorescent probes indicates leukocyte imaging as a critical factor to enhance accuracy. J Biomed Opt 19:066006
Kanick, Stephen Chad; Davis, Scott C; Zhao, Yan et al. (2014) Dual-channel red/blue fluorescence dosimetry with broadband reflectance spectroscopic correction measures protoporphyrin IX production during photodynamic therapy of actinic keratosis. J Biomed Opt 19:75002
Anand, Sanjay; Rollakanti, Kishore R; Horst, Ronald L et al. (2014) Combination of oral vitamin D3 with photodynamic therapy enhances tumor cell death in a murine model of cutaneous squamous cell carcinoma. Photochem Photobiol 90:1126-35
Keane, Margaret G; Bramis, Konstantinos; Pereira, Stephen P et al. (2014) Systematic review of novel ablative methods in locally advanced pancreatic cancer. World J Gastroenterol 20:2267-78

Showing the most recent 10 out of 101 publications