The foundations of specific radiobiological effects generated by laser-accelerated protons

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Current, mainstream Radiation Therapy (RT) predominantly utilizes X-rays that show unfavorable energy deposition patterns for deep-seated tumors. Energetic-charged-particle forms of IR offer major improvements in the energy deposition patterns in a tumor. Yet, the spreading of particle therapy is currently impeded by the high cost and resource footprint. Despite such limitations particle RT is emphatically pursued worldwide and Germany co-leads this development with several advanced proton and heavy ion therapy centers. In parallel, novel charged-particle acceleration technologies evolve promising particle generators at lower cost and smaller footprint, thus promising wide distribution and feasibility for clinical trials. The present application is designed to study the radiobiological effects of one such charged-particle acceleration technology: Laser-driven, plasma-acceleration, based on laser wake-field acceleration principles. The University of Düsseldorf has made large investments in this field and Professor O. Willi operates a 200 TW laser system dedicated to the production of laser-accelerated protons (LAP) that is the basis of the proposed research. The West German Proton Center Essen (WPE) at the University Clinics Essen under Prof. B. Timmermann provides the required reference proton beams (CAP). The radiobiology of LAP is at its infancy and relevant information is only now beginning to emerge. Our consortium under the leadership of Prof. G. Iliakis at the University Clinics Essen, has cooperated for several years to study the radiobiological effects of LAP and has made seminal discoveries underpinning the proposed studies. The proposal tests the hypothesis that LAP exhibit different radiobiology because each pulse is delivered in picosecond wave-trains and consists of a large, dense ion cluster with very short inter-particle distances. As a result dose rates in the order of 109 Gy/sec are reached that are up to 9-11 orders of magnitude greater than those achieved by a cyclotron. It follows that although LAP and CAP are similarly causing water radiolysis and generate short-lived primary radicals, their biochemical and biological consequences differ as indicated by our discovery of lower production of 3-nitrotyrosine through interaction with NO-dependent pathways. Prof. C. Suschek at the University of Düsseldorf elucidates the mechanistic underpinnings of such differences. Changes in the balance of radical production will modify the type of DNA damage generated by direct/indirect effects, as well cellular stress responses. These aspects of LAP are investigated in depth by Prof. F. Boege and Prof. G. Iliakis focusing on forms of DNA double strand breaks generated and the cellular responses to them. The proposed work addresses central questions of the biology of LAP, prepares their future application in the clinic and helps to enhance the clear edge of Germany in the field of particle therapy internationally.