Exploring Targeted Thorium Conjugate and Small Molecule Combinations: New Effective Treatments for Cancer
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AbstractTargeted Thorium-227 Conjugates (TTCs) represent a novel class of cancer therapy currently in preclinical and clinical development. The TTCs consist of the alpha emitter thorium-227 (227Th) complexed to a 3,2-HOPO chelator conjugated to a tumor specific antibody. The high energy and short range of the alpha-particle induces a potent local irradiation of the tumor with limited damage to surrounding tissue, thus making them beneficial for treatment of cancer. This thesis describes the preclinical evaluation of TTCs in combination with small molecule DNA damage response (DDR) inhibitors. The overall aim with the combination therapy is to achieve an enhanced effect at lower doses and thereby an increased therapeutic window. The results presented in the thesis summarize in vitro and in vivo studies demonstrating synergistic effects achieved over a range of cancer indications, TTC targets and DDR inhibitors. In sum-mary, this supports the further exploration of combination therapy with TTCs and DDR inhibitors for treatment of dif-ferent cancer indications and investigation of defects in DDR genes as potential biomarkers for treatment with TTCs.
List of papers
|Paper I: “Synergistic Effect of a Mesothelin Targeted Thorium-227 Conjugate in Combination with DNA Damage Response Inhibitors in Ovarian Cancer Xenograft Models”. Authors: Katrine Wickstroem, Urs B Hagemann, Véronique Cruciani, Antje M Wengner, Alexander Kristian, Christine Ellingsen, Gerhard Siemeister, Roger M Bjerke, Jenny Karlsson, Olav B Ryan, Lars Linden, Dominik Mumberg, Karl Ziegelbauer and Alan S Cuthbertson. Published in Journal of Nuclear Medicine, March 8th 2019. DOI:10.2967/jnumed.118.223701. The paper is included in the thesis. The published version is available at https://doi.org/10.2967/jnumed.118.223701|
|Paper II: “Preclinical Combination Studies of an FGFR2 Targeted Thorium Conjugate and an ATR Inhibitor BAY 1895344”. Authors: Katrine Wickstroem, Urs B Hagemann, Alexander Kristian, Christine Ellingsen, Anette Sommer, Heidrun Ellinger-Ziegelbauer, Uta Wirnitzer, Else-Marie Hagelin, Aasmund Larsen, Roger Smeets, Roger M Bjerke, Jenny Karlsson, Olav B Ryan, Antje M Wengner, Lars Linden, Dominik Mumberg and Alan S Cuthbertson. Manuscript submitted to International Journal of Radiation Oncology, Biology, Physics. To be published. The paper is not available in DUO awaiting publishing.|
|Paper III: “Synergistic Effect of a HER2 Targeted Thorium-227 Conjugate in Combination with olaparib in a BRCA2 Deficient Xenograft Model”. Authors: Katrine Wickstroem, Jenny Karlsson, Urs B Hagemann, Véronique Cruciani, Alexander Kristian, Roger M Bjerke, Olav B Ryan, Lars Linden, Dominik Mumberg, Michael Brands and Alan S Cuthbertson. Manuscript submitted to Cancer Research. To be published. The paper is not available in DUO awaiting publishing.|