1.    Introduction
The overall goal of our research group is to investigate the use of novel radiation qualities and applications for improving radiation therapy.
Radiation remains the most cost-efficient and effective method for detecting, imaging and treating cancer. The primary goal of any radiotherapy is to avoid damage to sensitive organs whilst applying the maximum dose to the tumor. However, even with most advanced radio-therapy techniques (e.g. highly conformal treatment planning), many patients develop irradiation induced acute and late reactions. However, it is known that certain tumors are quite resistant to photon irradiation.


2.    Physical and biological advantages of particle irradiation
Particle irradiation with protons or heavy ions offers the physical advantage of a focused energy deposition in a distinct peak (Bragg Peak). This enables a high precision irradiation by simultaneously sparing the surrounding healthy tissue. Due to the high precision of the particle beam, the surrounding healthy tissue can be spared.

                                           Dose distribution in tissue. Source: IRM

The biological advantage of heavy ions or alpha-particles is the high linear energy transfer (LET) that leads to multiple and complex DNA double strand breaks that are difficult to repair. In contrast, conventional photon radiation, which has a low LET, produces less DNA double strand breaks. Therefore, the relative biological effectiveness (RBE) of heavy ions or alpha-particles is higher compared to photon radiation.

Friedrich T, Ilicic K, Greubel C, Girst S, Reindl J, Sammer M, Schwarz B,Siebenwirth C, Walsh DWM, Schmid TE, Scholz M, Dollinger G. DNA damage interactions on both nanometer and micrometer scale determine overall cellular damage. Sci Rep. 2018 Oct 30;8(1):16063.
Ilicic K, Combs SE, Schmid TE. New insights in the relative radiobiological effectiveness of proton irradiation. Radiat Oncol. 2018 Jan 16;13(1):6.
Dehne S, Fritz C, Rieken S, Baris D, Brons S, Haberer T, Debus J, Weber KJ, Schmid TE, Combs SE, Habermehl D. Combination of Photon and Carbon Ion Irradiation with Targeted Therapy Substances Temsirolimus and Gemcitabine in Hepatocellular Carcinoma Cell Lines. Front Oncol. 2017 Mar 13;7:35.


3.    Microbeam radiation therapy (MRT) and proton minibeam radiotherapy (pMBRT)
A novel strategy for further reducing radiation damage in normal tissue is to spare parts of it from irradiation - a method called spatial fractionation. The treatment area is divided into several smaller regions which not all receive the same dose required for tumor control. Microbeam radiation therapy (MRT) and minibeam radiation therapy (pMBRT) use micrometer-sized (typically 20-200 µm) and sub-millimeter beams (500-700 µm) of planar or pencil beams with circular or regular polygonal cross-sections. Proton minibeam radiotherapy as well as microbeam radiotherapy (MRT) aims to minimize normal tissue damage, especially in the entrance channel. Our research includes defining on the basis of physiological and cellular analysis an innovative, optimized, safe, efficient and transferable proton minibeam and MRT irradiation scheme which is applicable to radiotherapy of tumors (e.g. in the human brain or lung).



                                         Principle of MRT and pMBRT. Source: IRM

Future in vivo experiments on the basis of physiological and cellular analysis will help to develop innovative treatment schemes for proton minibeam as well as MRT, which will be applicable and transferable to radiotherapy of tumors.

Meyer J, Eley J, Schmid TE, Combs SE, Dendale R, Prezado Y. Spatially fractionated proton minibeams. Br J Radiol. 2018 Nov 7:20180466.
Burger K, Ilicic K, Dierolf M, Günther B, Walsh DWM, Schmid E, Eggl E, Achterhold K, Gleich B, Combs SE, Molls M, Schmid TE, Pfeiffer F, Wilkens JJ. Increased cell survival and cytogenetic integrity by spatial dose redistribution  at a compact synchrotron X-ray source. PLoS One. 2017 Oct 19;12(10):e0186005.
Girst S, Greubel C, Reindl J, Siebenwirth C, Zlobinskaya O, Walsh DW, Ilicic K, Aichler M, Walch A, Wilkens JJ, Multhoff G, Dollinger G, Schmid TE. Proton Minibeam Radiation Therapy Reduces Side Effects in an In Vivo Mouse Ear Model. Int J Radiat Oncol Biol Phys. 2016 May 1;95(1):234-41.


4.    Development of innovative treatment options for glioblastoma and pancreatic cancer
Today, glioblastoma is the most aggressive and most common primary brain tumor in adults. The standard therapy is a multimodal treatment concept consisting of surgical resection, radiotherapy (with photons) and chemotherapy with temozolomide. Despite this multidisciplinary treatment modality, the prognosis for patients with glioblastoma remains poor with a 5-year survival rate less than 10%. The main obstacle is a general treatment resistance, independently of treatment type, e.g. chemotherapy, radiotherapy or other. Key factors contributing to this resistance include tumor cell proliferation, invasion, migration, as well as tumor neovascularization.
Another devastating tumor entity is the pancreatic cancer, which is one of the most lethal human cancers. It is the eighth leading cause of cancer-related deaths worldwide. The characteristics of pancreatic cancer are very aggressive tumor growth and a high incidence of metastasis.
The aim of our work group is to analyze the interaction of pathways and to establish innovative biomarkers which are involved in the radioresponse of glioblastoma and pancreatic cancer cells with different radiosensitivity.
Cancer research has shown that the molecular characteristics of tumors can vary significantly between patients, even in tumors from the same organ. However, these molecular characteristics determine the response to the treatment. Several approaches to establish prognostic biomarkers have been successful. Only recently, RT-related biomarkers have moved into focus since generally radiotherapy doses are specific by tumor type, but not by patient- and tumor-individual factors. Thus, biomarkers for radiotherapy response prediction are essential.

Wank M, Schilling D, Schmid TE, Meyer B, Gempt J, Barz M, Schlegel J, Liesche  F, Kessel KA, Wiestler B, Bette S, Zimmer C, Combs SE. Human Glioma Migration and Infiltration Properties as a Target for Personalized Radiation Medicine. Cancers  (Basel). 2018 Nov 20;10(11). pii: E456. Review.
Wank M, Schilling D, Reindl J, Meyer B, Gempt J, Motov S, Alexander F, Wilkens JJ, Schlegel J, Schmid TE, Combs SE. Evaluation of radiation-related invasion in  primary patient-derived glioma cells and validation with established cell lines:  impact of different radiation qualities with differing LET. J Neurooncol. 2018 Sep;139(3):583-590.