The Overall Goal of this PPG is to develop a novel treatment option for head and neck squamous cell carcinoma (HNSCC) that results in treatment responses that are as effective as current treatment modalities, but that preserve organ function. During the last funding period we demonstrated that HPPH-PDT of HNSCC resulted in complete responses in 82% of patients. In the ancillary studies that accompanied this trial we used noninvasive fluorescence spectroscopy to measure HPPH levels within the lesion. Although preliminary, these studies suggested that non-responding lesions retained low HPPH levels. Simultaneous studies were carried out in this Project using an innovative 3-demensional co-culture system that incorporates patient-derived primary epithelial lung tumor cells and tumor-associated stromal cells from the same patient. The results of this study showed that some tumor cells fail to retain HPPH and were resistant to PDT killing. Subsequent studies showed that HPPH binding to the cell surface, mode of cellular uptake, intracellular localization, subcellular redistribution, exocytosis, and retention was critically dependent upon the structure of the HPPH macrocycle. The long-range goal of this Project is to develop HNSCC-specific photosensitizers that are selectively retained in tumor cells and result in increased efficacy of clinical PDT. To accomplish this goal the following hypotheses will be tested: 1) Photosensitizer (PS) retention characteristics are tumor-dependent and are reflected in the response to HPPH-PDT; 2) Tumor cell properties can be identified that are responsible for PS retention 3) Structural modifications of HPPH can be identified that will enhance PS retention in tumor cells; 3) Targeting of PS to cell surface addresses, such as integrins or epidermal growth factor receptor (EGFR), will further enhance the therapeutic PS differential between non-tumor and tumor epithelial cells. To test these hypotheses we will take advantage of the novel and unique tools developed in the current funding period: a) a compound ?library? of macrocycle-modified HPPH analogs and b) a 3D culture system for primary human HNSCC that has revealed different retention characteristics for individual tumors. The studies proposed in this project are compelling in that they have the potential to enhance our understanding of PS retention and ultimately lead to the generation of HNSCC-specific PS that result in increased efficacy and selectivity of PDT against this disease. The studies are critical to the PPG as they lay the foundation for our long term goal of achieving 100% efficacy in the treatment of early stage HNSCC.

Public Health Relevance

The studies proposed in Project 2 have the potential to eventually lead to the generation of head and neck squamous cell carcinoma (HNSCC)-specific photosensitizers that result in increased overall PDT efficacy and selectivity for this disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA055791-25
Application #
9619552
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
25
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
824771034
City
Buffalo
State
NY
Country
United States
Zip Code
14263
Shafirstein, Gal; Bellnier, David A; Oakley, Emily et al. (2018) Irradiance controls photodynamic efficacy and tissue heating in experimental tumours: implication for interstitial PDT of locally advanced cancer. Br J Cancer 119:1191-1199
Tracy, Erin C; Bowman, Mary-Jo; Pandey, Ravendra K et al. (2018) Cell-specific Retention and Action of Pheophorbide-based Photosensitizers in Human Lung Cancer Cells. Photochem Photobiol :
Shafirstein, Gal; Bellnier, David; Oakley, Emily et al. (2017) Interstitial Photodynamic Therapy-A Focused Review. Cancers (Basel) 9:
Saenz, Courtney; Cheruku, Ravindra R; Ohulchanskyy, Tymish Y et al. (2017) Structural and Epimeric Isomers of HPPH [3-Devinyl 3-{1-(1-hexyloxy) ethyl}pyropheophorbide-a]: Effects on Uptake and Photodynamic Therapy of Cancer. ACS Chem Biol 12:933-946
Oakley, Emily; Bellnier, David A; Hutson, Alan et al. (2017) Surface markers for guiding cylindrical diffuser fiber insertion in interstitial photodynamic therapy of head and neck cancer. Lasers Surg Med 49:599-608
Egan, Shawn M; Karasik, Ellen; Ellis, Leigh et al. (2017) miR-30e* is overexpressed in prostate cancer and promotes NF-?B-mediated proliferation and tumor growth. Oncotarget 8:67626-67638
Harris, Kassem; Oakley, Emily; Bellnier, David et al. (2017) Endobronchial ultrasound-guidance for interstitial photodynamic therapy of locally advanced lung cancer-a new interventional concept. J Thorac Dis 9:2613-2618
Hall, Brandon M; Balan, Vitaly; Gleiberman, Anatoli S et al. (2017) p16(Ink4a) and senescence-associated ?-galactosidase can be induced in macrophages as part of a reversible response to physiological stimuli. Aging (Albany NY) 9:1867-1884
Mimikos, Christina; Shafirstein, Gal; Arshad, Hassan (2016) Current state and future of photodynamic therapy for the treatment of head and neck squamous cell carcinoma. World J Otorhinolaryngol Head Neck Surg 2:126-129
Patel, Nayan; Pera, Paula; Joshi, Penny et al. (2016) Highly Effective Dual-Function Near-Infrared (NIR) Photosensitizer for Fluorescence Imaging and Photodynamic Therapy (PDT) of Cancer. J Med Chem 59:9774-9787

Showing the most recent 10 out of 167 publications