Project: Photodynamic therapy of lung cancer

In the proposed project a proof of concept clinical study with lung cancer patients will be initiated by the pharma company APOCARE and performed at two university clinics (URUHR and VUMC) with a new tumor specific photosensitizer and a new developed LASER medical device. _x000D_The objectives of the clinical study are i) to determine safety and tolerability of a local photodynamic treatment using Chlorin e6 Trisodium Salt (Fotolon) as a photosensitizer in patients with endobronchial obstruction from progression or recurrence of NSCLC; ii) to determine the objective tumor response rate defined by improvement in bronchscopic luminal diameter, iii) to determine the clinical benefit based on symptoms like cough, hemoptysis, stridor, dyspnea, sputum production etc._x000D_Avantes a manufacturer of fiber optic spectroscopy instruments will develop a module for the analysis of flurorescence, from the photosensitizer in the tissue, in order to control the illumination of the LASER system, to optimise the therapeutic effect of the photodynamic therapy._x000D_Photodynamic therapy (PDT) is one of the most promising options in the treatment of malignant endobronchial lesions. PDT is based on the systemic or topical administration of a photosensitizer which preferably accumulates within the tumour tissue. When the tagged tumour cells are illuminated with light of an appropriate wavelength, the photosensitizer within the target cells is excited from its (singlet) ground state to a more energetic, metastable triplet state. As a consequence of an energy transfer to other molecules, photochemical reactions are induced which lead to necrosis and/or apoptosis of the tagged malignant cells._x000D_There are at least two mechanisms by which the triplet state photosensitizer can react with biomolecules; these are known as the Type I and Type II reactions. Type I involves electron/hydrogen transfer directly from the photosensitizer, producing ions, or electron/hydrogen abstraction from a substrate molecule to form free radicals. These radicals then react rapidly, usually with oxygen, resulting in the production of highly reactive oxygen species (ROS, e.g. superoxide and peroxide anions) which then attack several cellular targets. Type II reactions produce the electronically excited and highly reactive state of oxygen known as singlet oxygen. Direct interaction of the excited triplet state photosensitizer with molecular oxygen (which has a triplet ground state) results in the photosensitizer returning to its singlet ground state and the formation of singlet oxygen._x000D_The most important targets for ROS are membrane structures of target cells in close proximity. When such cells are damaged, repair mechanisms or cell death by necrosis and/or apoptosis are triggered, depending on the extent of damage (Gomer et al. 1988, Olcinick and Evans 1998, Moor 2000, Agostinis et al. 2000). The type of cellular damage also depends on the subcellular distribution of the photosensitizer in question. Thus, mitochondrial localisation leads to rapid induction of apoptosis whereas lysosomal localisation results in either a necrotic or an apoptotic response and accumulation in the plasma membrane in a mixture of both (Moor 2000). Close proximity is essential since singlet oxygen is only able to diffuse over distances of less than 10 nm due to its short lifetime. _x000D_In a synergistic manner, tumour blood vessels are damaged by coagulation within minutes after light application, a mechanism which is crucial for an extended in-depth effect of PDT. It has also been recognized that innate and adaptive immune responses including unspecific post-PDT inflammation contribute to the eradication of residual tumour cells (Gollnick et al. 2002, Korbelik 1996)._x000D_Fotolon as a Chlorin derivative has been developed by researchers in order to provide a third-generation photosensitizer for photodynamic therapy without the common disadvantages of established agents. Thus, an optimal accumulation of Fotolon in the target tissue is already achieved after approx. 3 hours which avoids hospitalisation for PDT treatment. Fotolon is also rapidly eliminated after photodynamic therapy. The method is based on the interaction between a photosensitive chemical substance and laser light whose wave length matches the absorption of the drug. In the presence of oxygen the interaction has a cytotoxic effect bringing about necrosis of the tissue possibly by the production of singlet of oxygen. In practice, the drug is administered to the patient and after a certain time when the concentration of the photosentisizer is relatively higher in tumor than in normal tissue, the neoplastic mass is then exposed to the laser light which initiates the necrotic process. _x000D_The clinical study will be performed at the Ruhrlandklinik, University Clinic Essen and the VU University Medical Center, Amsterdam, which have considerable experience in the treatment of lung cancer._x000D_

Acronym PHOTOCANCER (Reference Number: 7398)
Duration 01/06/2012 - 31/05/2014
Project Topic In the proposed project a proof of concept clinical study with lung cancer patients will be performed with a new tumor specific photosensitizer and a new developed LASER device. Fotolon has been developed by researchers in order to provide a third-generation photosensitizer for Photodynamic therapy.
Network Eurostars
Call Eurostars Cut-Off 8

Project partner

Number Name Role Country
4 VU University Medical Center Amsterdam Partner Netherlands
4 Ruhrlandklinik, Westdeutsches Lungenzentrum am Universitätsklinikum Essen Partner Germany
4 Avantes B.V. Partner Netherlands
4 APOCARE Pharma GmbH Coordinator Germany