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Development of New Folate-Based RadioImaging Agents and RadioTherapeutics

English title Development of New Folate-Based RadioImaging Agents and RadioTherapeutics
Applicant Müller Cristina
Number 156803
Funding scheme Project funding (Div. I-III)
Research institution Paul Scherrer Institut
Institution of higher education Paul Scherrer Institute - PSI
Main discipline Experimental Cancer Research
Start/End 01.04.2015 - 31.07.2018
Approved amount 419'100.00
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All Disciplines (2)

Discipline
Experimental Cancer Research
Radiobiology

Keywords (8)

ovarian cancer; folate; theragnostics; nuclear imaging; radionuclide therapy; lung cancer; folate receptor; tumor

Lay Summary (German)

Lead
Das Ziel neuer Therapie-Ansätze zur Behandlung von Krebs ist es, möglichst spezifisch das Krebsgewebe zu zerstören, ohne dass das gesunde Gewebe in Mitleidenschaft gezogen wird. Die Radionuklid-Therapie stellt einen solchen Ansatz dar.
Lay summary
 

Das Ziel neuer Therapie-Ansätze zur Behandlung von Krebs ist es, möglichst spezifisch das Krebsgewebe zu zerstören, ohne dass gesundes Gewebe in Mitleidenschaft gezogen wird. Die gezielte Radionuklidtherapie stellt einen solcher Ansatz dar, der in der Klinik bereits sehr erfolgreich umgesetzt wird. Der Folatrezeptor-α (FR-α) ist ein interessanter Tumormarker, weil er auf verschiedensten Krebsarten exprimiert wird. Der FR-β hingegen kommt auf aktivierten Makrophagen vor, welche bei Entzündungskrankheiten involviert sind. Die Folsäure wird als Transporter verwendet, um Radionuklide spezifisch in FR-exprimierende Tumorzellen zu befördern.

Für eine therapeutische Anwendung ist die relativ hohe Nierenanreicherung von Radiofolaten eine Herausforderung, da sie potentiell zu einer Nierenschädigung führen könnte. Kürzlich haben wir jedoch ein neuartiges Radiofolat synthetisiert, welches ein signifikant verbessertes Tumor-zu-Nieren Verhältnis zeigte, wodurch erstmals eine therapeutische Anwendung in der Maus möglich wurde. Die Resultate dieser Studie waren sehr vielversprechend.

Im vorliegenden Projekt wird die Entwicklung einer zweiten Generation von diagnostischen und therapeutischen Folat-Radiokonjugaten angestrebt, welche selektiv an den Tumor-assoziierten FR-α binden, nicht aber an den FR-β. Dieses Ziel soll erreicht werden, indem ein reduziertes Folat verwendet wird, das eine 50-fache Präferenz für den FR-α aufweist. Die Evaluation solcher Derivate erfolgt in präklinischen Experimenten an Mäusen. Ein weiteres Ziel ist es, die bisher entwickelte FR-gezielten Radionuklid-Therapie weiter zu optimieren, indem neue Albumin-bindende Folat Radiokonjugate mit verbesserter Pharmakokinetik entwickelt werden.

Die Entwicklung einer Tumor-spezifischen Folat-basierenden Radionuklid-Therapie und deren zukünftige Anwendung in der Klinik, würde erlauben, eine Grosszahl von krebskranken Menschen zu behandeln.

 

Direct link to Lay Summary Last update: 24.10.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Combining Albumin-Binding Properties and Interaction with Pemetrexed to Improve the Tissue Distribution of Radiofolates
Müller Cristina, Guzik Patrycja, Siwowska Klaudia, Cohrs Susan, Schmid Raffaella, Schibli Roger (2018), Combining Albumin-Binding Properties and Interaction with Pemetrexed to Improve the Tissue Distribution of Radiofolates, in Molecules, 23(6), 1465-1465.
Folate Receptor-Positive Gynecological Cancer Cells: In Vitro and In Vivo Characterization
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.
A Short-Term Biological Indicator for Long-Term Kidney Damage after Radionuclide Therapy in Mice
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.
Preclinical Comparison of Albumin-Binding Radiofolates: Impact of Linker Entities on the In Vitro and Vivo Properties
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.
Comparative Studies of Three Pairs of α- and γ‑Conjugated Folic Acid
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.
Diastereomerically Pure 6R- and 6S-3'-aza-2'-18F-Fluoro-5-Methyltetrahydrofolates Show Unprecedented High Uptake in Folate Receptor-positive KB Tumors
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.

Collaboration

Group / person Country
Types of collaboration
Merck & Cie, Schaffhausen Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Industry/business/other use-inspired collaboration
Prof. Andreas Türler and Dr. Nicholas van der Meulen, Radiochemistry Lab, Paul Scherrer Institute Switzerland (Europe)
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
30th Annual Congress of the European Association of Nuclear Medicine - EANM Talk given at a conference Therapeutic Potential of 47Sc in Comparison to 177Lu and 90Y: Preclinical Investigations 21.10.2017 Barcelona, Spain Schibli Roger; Müller Cristina;
22nd International Symposium on Radiopharmaceutical Sciences (ISRS) Talk given at a conference Radiosyntheses, in vitro and in vivo evaluation of 6S- and 6R-3'-aza-2'-[18F]Fluoro-5-Methlytetrahydrofolates for Tumor imaging with PET 14.05.2017 Dresden, Germany Boss Silvan David; Schibli Roger; Müller Cristina; Ametamey Simon M.;
23rd IRIST International Meeting Talk given at a conference Therapeutic Potential of 47Sc in Comparison to 177Lu and 90Y: Preclinical Investigations 27.05.2016 Lausanne, Switzerland Schibli Roger; Müller Cristina;
Jahrestagung der Arbeitsgemeinsachaft Radiochemie/Radiopharmazie (AGRR) Talk given at a conference Syntheses and biological characterization of three pairs of 18F-labeled alpha- and gamma-conjugated folate derivatives for tumor imaging 10.09.2015 Erlangen, Germany Boss Silvan David; Schibli Roger; Ametamey Simon M.; Müller Cristina;
Swiss Chemical Society SCS Fall Meeting Poster Comparison of 18F-labeled alpha- and gamma-conjugated folate derivatives for tumor imaging using positron emission tomography (PET) 04.09.2015 Lausanne, Switzerland Schibli Roger; Müller Cristina; Ametamey Simon M.; Boss Silvan David;
Swiss Congress of Radiology (SCR) Talk given at a conference Comparison of alpha- and gamma-conjugated folate derivatives for tumor imaging with PET 04.06.2015 Basel, Switzerland Boss Silvan David; Schibli Roger; Ametamey Simon M.; Müller Cristina;


Associated projects

Number Title Start Funding scheme
121772 Folate Receptor Targeting for Imaging and Potential Therapy of Cancerous and Inflammatory Diseases 01.02.2009 Ambizione
138834 Folate Receptor Targeting for Imaging and Potential Therapy of Cancerous and Inflammatory Diseases 01.02.2012 Ambizione
188978 Investigation of a New Class of Folate-Based RadioImaging Agents and RadioTherapeutics 01.02.2020 Project funding (Div. I-III)
189776 SAFIR - From the Prototype to the Full-Scale Scanner 01.09.2020 R'EQUIP

Abstract

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.
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