Pyropheophorbide-based compounds have been developed as second generation photosensitizers (PS) that have low phototoxicity but high efficacy in photodynamic therapy (PDT) of various cancer forms, such as of the lung and aerodigestive tract. The goal of this project is to elucidate the cellular and molecular mechanisms by which these PS initiate signaling in epithelial tumor cells that leads to stress reactions and decision over cell death or survival. In the current funding period, diagnostic markers were identified that correlate in a dose-dependent fashion with the immediate cellular response to PDT. These markers include oxidative crosslinking of signal-transducing proteins, inactivation of cytokine and growth factor receptor functions, reduced cellular protein phosphorylation and activation of stress protein kinases. These changes are transient in PDT-surviving cells and, after a period of arrest, cells recover the capability to signal in response to inflammatory cytokines and resume proliferation. We have used these markers to identify newly designed derivatives of PS with enhanced uptake, altered subcellular distribution, increased singlet oxygen production and improved tumor control. We hypothesize that conjugation of PS with carbohydrates and metals alters PS uptake and subcellular accumulation resulting in enhanced cellular activity;that alterations in plasma membrane receptors and intracellular signaling play a major role in tumor cell survival following PDT;and that identification of regulatory mechanisms at multi-cellular level helps in devising combination therapies suppressing tumor, which survive the PDT reaction. Following specific aims are proposed to test these predictions: 1) To identify in mouse and human epithelial cells the mechanisms by which carbohydrate- and metal-conjugated PS achieve their cell type-specific action by determining uptake, cell organelle-preferred accumulation, and the relative contribution of ATP-binding cassette transporter-G2 to the steady state level of PS;2) to define the peri- and post-PDT reactions within epithelial tumor cells that determine survival, recovery from stress, reestablishment of homeostasis, and resumption of proliferation; and 3) to develop a reconstituted three-dimensional co-culture system of epithelial, stromal or endothelial cells, which will permit the identification of the regulatory pathways that lead to the release of inflammatory mediators in response to PDT-treated tumor cells. The findings regarding PDT effect made in the tissue culture will be verified in tumors of preclinical animal models and in patients undergoing PDT treatment for skin and head/neck cancers as part of this program.

Public Health Relevance

The biochemical and molecular understanding of tumor cell survival after PDT is crucial to the ability to optimize this treatment for clinical use in the eradication of cancer. Studies in Project II will identify regulatory pathways that are relevant in determining survival of tumor cells and assess the impact of therapeutic interference with these pathways in controlling recurrence of tumor cell growth.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA055791-20
Application #
8462214
Study Section
Special Emphasis Panel (ZCA1-GRB-P)
Project Start
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
20
Fiscal Year
2013
Total Cost
$230,310
Indirect Cost
$92,615
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
824771034
City
Buffalo
State
NY
Country
United States
Zip Code
14263
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 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
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
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
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