Photodynamic therapy (PDT) is a treatment modality that uses a photosensitizing agent and light to kill cells. In standard photodynamic reactions the simultaneous presence of oxygen is also required for tissue damage to occur. This project centers on a Phase I trial of PDT for pre-malignant mucosal lesions of the head and neck, with the primary goal of defining the toxicities of orally-administered ALA (Levulan)-PDT. Dysplasia of the head and neck is associated with subsequent risk of progression to invasive carcinoma in up to 30% of cases. Compared to alternative methods of treating pre-malignant head and neck cancer, PDT offers the possible advantages of being minimally invasive, less time consuming, organ preserving, selective for diseased tissue, and amenable to repeat treatment. A secondary aim of the clinical trial will be to evaluate photosensitizer and oxygen concentrations in the diseased and normal head and neck tissues of patients because the selectivity and efficacy of PDT depends in part on tissue photosensitizer and oxygen levels. In pre-clinical studies of rodent oral cancer and head and neck human tumor xenografts, the intra-tumor and inter-tumor relationships between photosensitizer and oxygen concentrations will be evaluated, and the effect of heterogeneities in oxygen and photosensitizer distributions on therapeutic outcome will be investigated. Studies will be conducted using noninvasive in vivo spectroscopy to measure tissue oxygen and photosensitizer content. Additionally, the microscopic distributions of these parameters will be measured in pre-clinical tissues using immunohistochemical and/or fluorescence microscopic techniques.
The aims of our proposal can be summarized as follows:
Aim 1 : To complete a Phase I trial of PDT with ALA (Levulan) for pre-malignant tumors of the head and neck. Question 1A: What are the toxicities and maximally tolerated dose of ALA-PDT? Aim 2: To measure pre- and post-PDT levels of oxygen and photosensitizer content in head and neck tissues from the Phase I trial. Question 2A: How does PDT affect tissue oxygen and photosensitizer levels in diseased vs. normal tissue? Aim 3: To define and evaluate the therapeutic relevance of macroscopic and microscopic heterogeneities in tissue photosensitizer and oxygen content in rodent tumor models. Question 3A: How do heterogeneities in oxygen and photosensitizer concentrations affect therapeutic outcome? Question 3B: Are macroscopic heterogeneities in oxygen and photosensitizer levels measures of underlying microscopic heterogeneities? Question 3C: How are distributions of oxygen and photosensitizer spatially related?

Public Health Relevance

Photodynamic therapy (PDT) is a local light- and drug-based treatment that offers significant potential as a method of treating superficial lesions of pre-malignant disease of the head and neck while causing little toxicity to normal tissues. Compared to the alternatives of surgery or ionizing radiation, PDT offers the possible advantages of being minimally invasive, less time consuming, organ preserving, selective for diseased tissue, and amenable to repeat treatment.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Radiation Therapeutics and Biology Study Section (RTB)
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Wong, Rosemary S
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University of Pennsylvania
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Ahn, Peter H; Finlay, Jarod C; Gallagher-Colombo, Shannon M et al. (2018) Lesion oxygenation associates with clinical outcomes in premalignant and early stage head and neck tumors treated on a phase 1 trial of photodynamic therapy. Photodiagnosis Photodyn Ther 21:28-35
Grossman, Craig E; Carter, Shirron L; Czupryna, Julie et al. (2016) Fluence Rate Differences in Photodynamic Therapy Efficacy and Activation of Epidermal Growth Factor Receptor after Treatment of the Tumor-Involved Murine Thoracic Cavity. Int J Mol Sci 17:
Ahn, Peter H; Quon, Harry; O'Malley, Bert W et al. (2016) Toxicities and early outcomes in a phase 1 trial of photodynamic therapy for premalignant and early stage head and neck tumors. Oral Oncol 55:37-42
Gallagher-Colombo, Shannon M; Miller, Joann; Cengel, Keith A et al. (2015) Erlotinib Pretreatment Improves Photodynamic Therapy of Non-Small Cell Lung Carcinoma Xenografts via Multiple Mechanisms. Cancer Res 75:3118-26
Gallagher-Colombo, Shannon M; Quon, Harry; Malloy, Kelly M et al. (2015) Measuring the Physiologic Properties of Oral Lesions Receiving Fractionated Photodynamic Therapy. Photochem Photobiol 91:1210-8
Han, Sung Wan; Mesquita, Rickson C; Busch, Theresa M et al. (2014) A Method for Choosing the Smoothing Parameter in a Semi-parametric Model for Detecting Change-points in Blood Flow. J Appl Stat 41:26-45
Maas, Amanda L; Carter, Shirron L; Wileyto, E Paul et al. (2012) Tumor vascular microenvironment determines responsiveness to photodynamic therapy. Cancer Res 72:2079-88
Gallagher-Colombo, Shannon M; Maas, Amanda L; Yuan, Min et al. (2012) Photodynamic therapy-induced angiogenic signaling: consequences and solutions to improve therapeutic response. Isr J Chem 52:681-690
Quon, Harry; Grossman, Craig E; Finlay, Jarod C et al. (2011) Photodynamic therapy in the management of pre-malignant head and neck mucosal dysplasia and microinvasive carcinoma. Photodiagnosis Photodyn Ther 8:75-85
Quon, Harry; Finlay, Jarod; Cengel, Keith et al. (2011) Transoral robotic photodynamic therapy for the oropharynx. Photodiagnosis Photodyn Ther 8:64-7

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