ovarian cancer; folate; theragnostics; nuclear imaging; radionuclide therapy; lung cancer; folate receptor; tumor
Umbricht Christoph A., Köster Ulli, Bernhardt Peter, Gracheva Nadezda, Johnston Karl, Schibli Roger, van der Meulen Nicholas P., Müller Cristina (2019), Alpha-PET for Prostate Cancer: Preclinical investigation using 149Tb-PSMA-617, in Scientific Reports
, 9(1), 17800-17800.
Müller Cristina, De Prado Leal Maria, Dominietto Marco D., Umbricht Christoph A., Safai Sairos, Perrin Rosalind L., Egloff Martina, Bernhardt Peter, van der Meulen Nicholas P., Weber Damien C., Schibli Roger, Lomax Antony J. (2019), Combination of Proton Therapy and Radionuclide Therapy in Mice: Preclinical Pilot Study at the Paul Scherrer Institute, in Pharmaceutics
, 11(9), 450-450.
Benešová Martina, Umbricht Christoph A., Schibli Roger, Müller Cristina (2018), Albumin-Binding PSMA Ligands: Optimization of the Tissue Distribution Profile, in Molecular Pharmaceutics
, 15(3), 934-946.
Siwowska Klaudia, Schmid Raffaella M., Cohrs Susan, Schibli Roger, Müller Cristina (2017), Folate Receptor-Positive Gynecological Cancer Cells: In Vitro and In Vivo Characterization, in Pharmaceuticals
, 10(3), 1-17.
Pellegrini Giovanni, Siwowska Klaudia, Haller Stephanie, Antoine Daniel J., Schibli Roger, Kipar Anja (2017), A Short-Term Biological Indicator for Long-Term Kidney Damage after Radionuclide Therapy in Mice, in Müller, Cristina
, 10, 57.
Siwowska Klaudia, Haller Stephanie, Bortoli Francesca, Benesova Martina, Groehn Viola, Bernhardt Peter, Schibli Roger, Muller Cristina (2017), Preclinical Comparison of Albumin-Binding Radiofolates: Impact of Linker Entities on the In Vitro and Vivo Properties, in Molecular Pharmaceutics
, 14(2), 523-532.
Boss Silvan D., Betzel Thomas, Müller Cristina, Fischer Cindy R., Haller Stephanie, Reber Josefine, Groehn Viola, Schibli Roger, Ametamey Simon M. (2015), Comparative Studies of Three Pairs of α- and γ‑Conjugated Folic Acid, in Bioconjugate Chemistry
, 27, 74-86.
Boss Silvan, Müller Cristina, Siwowska Klaudia, Schmid Raffaella, Groehn Viola, Schibli Roger, Ametamey Simon, Diastereomerically Pure 6R- and 6S-3'-aza-2'-18F-Fluoro-5-Methyltetrahydrofolates Show Unprecedented High Uptake in Folate Receptor-positive KB Tumors, in Journal of Nuclear Medicine
Background: The FR-alpha emerged as an attractive tumor target because of its expression in a variety of human tumor types (e.g. ovarian and lung cancer) whereas the FR-beta is expressed on activated macrophages involved in inflammatory diseases. Due to the high affinity of folic acid to these FRs this vitamin has been used as a targeting ligand for the selective delivery of attached imaging or therapeutic probes to diseased sites. Among FR-targeted therapeutics folate conjugates of highly toxic chemotherapeutics are successfully employed in clinical trials in the United States. As an imaging agent the SPECT tracer 99mTc-EC20 has been used for identification of patients with FR-positive malignancies.Status of Own Research: In the last decade we synthesized and evaluated a large number of folate radioconjugates for potential application in diagnostic nuclear medicine. For a therapeutic application, the high uptake of radioactivity in the kidneys is a major drawback as it comprises the risk of damage to the kidneys. Recently, we designed a novel folic acid radioconjugate (177Lu-cm09) with an albumin-binding entity to enhance the blood circulation time. It resulted in a significantly increased tumor uptake while retention in the kidneys was reduced. Thanks to this improved tumor-to-kidney ratio, it was possible for the first time to perform a preclinical study in mice in which folic acid was successfully employed for targeted radionuclide tumor therapy. The results were impressive with regard to the significant tumor growth delay and increased survival in treated mice compared to untreated controls. Goal of the Project: The goal of this project is the development of a second generation of theragnostic folate radioconjugates which are selective for the tumor-associated FR-alpha but which do not accumulate at sites of inflammation (FR-beta). This should be achieved by using reduced folates such as 5-methyl-tetrahydrofolate (5-Me-THF) instead of folic acid as a targeting ligand because of its known (50-fold increased) binding preference for the FR-alpha. For evaluation of these novel radioconjugates, new mouse models will be developed which combine cancer and inflammtion. The second goal of this project is the optimization of FR-targeted radionuclide therapy by designing novel albumin-binding folate radioconjugates with improved pharmacokinetics. Clinically more relevant tumor mouse models with “metastases-like” intraperitoneal tumors will be developed and used for testing the most promising candidate among the novel radioconjugates.Expected Value of the Proposal: The clinically implemented concept of peptide receptor targeted radionuclide therapy (e.g. 177Lu-DOTATATE) shows impressive results for the palliative treatment of cancer patients providing a significantly improved quality of life with long progression-free survival even in cases with advanced tumors. Application of a tumor-selective folate radioconjugate for nuclear imaging would allow unambiguous identification of patients with FR-positive malignancies who may undergo FR-targeted (radio)therapy. Due to the large number of patients who could benefit from a FR-targeted radionuclide therapy, it is of critical interest to optimize this concept. Clinical translation of FR-targeted nuclear imaging and radionuclide therapy is the long-term future goal of this project. Realization of this vision would comprise an enormous potential for a better management of cancer diseases such as ovarian cancer or lung cancer, the leading cause of cancer deaths in Switzerland and other Western countries.