KFO 120:  Selective Internal Radiotherapy: Mechanisms of Action and Clinical Efficacy for Hematological Neoplasms and Neuroendocrine Tumors

• Subject Area: Medicine
• Term: from 2004 to 2007
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5397141

Internal radiotherapy with adequate radiolabelled molecules is an attractive therapeutic approach in oncology. It combines selective tumor targeting, a high local deposition of energy, specific tumor cell kill and protection of normal tissue. Recently, we and others successfully established a radioimmunotherapy (RIT) for acute myeloid leukemia. Based on this approach and on peptide receptor mediated radiotherapy (PRRT) for neurendocrine tumors we want to improve therapeutic efficacy in these tumors. Furthermore, the spectrum of treatment options is to be enlarged and mechanisms of action are to be analysed on a molecular level. Ionizing particle-emitting radionuclides suitable for killing cell clusters and larger tissue masses (b-emitters) or single cells (a-emitters) as well as for induction of DNA double-strand breaks (Auger-electron emitters) will be utilized. For selective tumor targeting, substrates of tumor metabolism, specifically overexpressed cell membrane receptors or membrane proteins capable of peptide or antibody binding are to be used. Selective DNA targeting is to be evaluated in a model of recurrent acute myeloid leukemia. Thymidine analogs substituted with a fluoride ion at the 2¿- position and labelled with Auger-electron emitting radionuclides will be evaluated for bone marrow ablation and leukemic cell kill.Analysis of specific mechanisms of action regarding gene expression, DNA repair and signaling pathways of apoptosis will be performed. Extensive analyses of the toxicity of cytoreductive therapies will be evaluated using radiation sensitive and radiation resistant tumor bearing mice. Using these models we will be able to develop strategies for overcoming resistance of tumors to radiation therapy. The combination of advanced molecular genetic, radiopharmaceutic, physical and clinical expertise in combination with molecular imaging will help us to timely transfer novel molecular radiation treatment approaches from bench to bedside and ultimately into efficient clinical treatment protocols.

• DFG Programme: Clinical Research Units

Projects

• Derivatisierte Nukleoside zur Endo-Radio-Therapie (ERT) von Leukämien: Vom Diagnostikum [18F] Fluorthyymidin zu therapeutischen Analoga (Applicant Buck, Andreas )
• Endo-Radiotherapie-basierte Konzepte für neuroendokrine Tumoren (Applicant Karges, Wolfram )
• Koordination der Klinischen Forschungsgruppe 120 (Applicant Reske, Sven Norbert )
• PET-basierte Dosimetrie vor Therapie mit offenen Radionukliden: Modellierung der in vivo-Biokinetik und verallgemeinerte Toxizitätsanalyse (Applicant Glatting, Gerhard )
• Radioaktive Arzneimittel zur Diagnostik und Therapie (Applicant Neumaier, Bernd )
• Radioimmuntherapie refraktärer akuter myeloischer Leukämien (Applicant Bunjes, Donald )
• Untersuchungen der Resistenzmechanismen nach verschiedenen Bestrahlungsmodalitäten in Tumorzellen und Möglichkeiten der Sensitivierung (Applicant Friesen, Ph.D., Claudia )

• Spokesperson: Professor Dr. Sven Norbert Reske