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Investigation of a New Class of Folate-Based RadioImaging Agents and RadioTherapeutics

English title Investigation of a New Class of Folate-Based RadioImaging Agents and RadioTherapeutics
Applicant Müller Cristina
Number 188978
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 01.02.2020 - 31.01.2024
Approved amount 705'928.00
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All Disciplines (2)

Discipline
Experimental Cancer Research
Radiobiology

Keywords (8)

folate receptor; gynecologic cancer; theragnostics; reduced folate; cancer detection; targeted radionuclide therapy; personalized medicine; PET imaging

Lay Summary (German)

Lead
Evaluation einer systemischen Radionuklidtherapie mit neuartigen Radiofolatkonjugaten für die Behandlung von metastasierten Krebserkrankungen
Lay summary

Die systemische Radionuklidtherapie basiert auf der Anwendung von radioaktiv markierten Molekülen, welche sich nach der Injektion in die Blutbahn im Körper verteilen und spezifisch an Oberflächenstrukturen der Tumorzellen binden. Dieses Therapiekonzept, welches auch als «Endoradiotherapie» bezeichnet wird, ermöglicht die direkte Bestrahlung der Tumorzellen und damit die Behandlung von metastasiertem Krebs. In der Klinik wird die systemische Radionuklidtherapie bei bestimmte Krebsarten (z.B. beim metastasierten Prostatakarzinom) bereits erfolgreich eingesetzt.

Der Folatrezeptor (FR) kommt auf verschiedenen Tumortypen (z.B. Eierstockkrebs und Lungenkrebs) vor und stellt somit eine vielversprechende Zielstruktur für die nukleare Bildgebung und Radionuklidtherapie mittels radioaktiver Folate dar. Anstelle der bisher verwendeten Folsäure Radiokonjugate, welche mit hoher Affinität an den FR binden, sollen nun 5-Methyl-Tetrahydrofolat-(5-MeTHF)-basierte Radiokonjugate evaluiert werden. Erste Pilotversuche im Forschungslabor haben gezeigt, dass die Gewebeverteilung der neuen Radiokonjugate gegenüber den Folsäurekonjugaten hinsichtlich der Anreicherung im Tumorgewebe und der raschen Ausscheidung über die Nieren vorteilhaft sind.

Das Ziel dieses Projektes ist es deshalb, die neu entwickelten 5-MeTHF Konjugate mit bekannten Therapienukliden (z.B. 177Lu) und neu entwickelten Radionukliden (z.B. 155Tb, 161Tb) zu markieren und präklinisch zu testen. Hierfür werden diverse in vitro Methoden sowie in vivo Modelle eingesetzt. Von zentralem Interesse ist die präklinische Evaluation der neuen Radiokonjugate im Hinblick auf die Entwicklung einer effektiven Radionuklidtherapie bei Eierstockkrebs. Eine klinische Translation des untersuchten Konzeptes wird im Erfolgsfall in Erwägung gezogen.

Direct link to Lay Summary Last update: 15.12.2019

Responsible applicant and co-applicants

Employees

Project partner

Associated projects

Number Title Start Funding scheme
138834 Folate Receptor Targeting for Imaging and Potential Therapy of Cancerous and Inflammatory Diseases 01.02.2012 Ambizione
121772 Folate Receptor Targeting for Imaging and Potential Therapy of Cancerous and Inflammatory Diseases 01.02.2009 Ambizione
156803 Development of New Folate-Based RadioImaging Agents and RadioTherapeutics 01.04.2015 Project funding (Div. I-III)

Abstract

Summary of the Research Plan:Background: The FR? is an attractive cell-surface exposed tumor target expressed in a variety of tumor types including ovarian and lung cancer, whereas the FR? is expressed on activated macrophages that are involved in inflammatory processes. Folic acid has been investigated for FR-targeted delivery of attached imaging and therapeutic probes to diseased cells. In spite of the large number of folate conjugates pre-clinically-developed over the past decades, only few have been translated to clinics and their application was of limited success. Status of Own Research: In the scope of a previous SNSF project, we have evaluated the feasibility of using the reduced folate, 5-methyl-tetrahydrofolate (5-MTHF), instead of folic acid as a FR-targeting ligand. Preliminary results showed an unprecedentedly high tumor accumulation of 5-MTHF-based 18F-radiotracers, but massive difference between the two isomers (6S vs. 6R) in terms of renal retention. For a therapeutic application, the commonly high renal retention of radiofolates has been a major drawback as it comprises the risk of damage to the kidneys when using therapeutic radiation. The design of folic acid radioconjugate with an albumin-binding entity resulted in significantly increased tumor-to-kidney ratios. The replacement of folic acid by 5-MTHF appeared to improve the concept even further, however, thorough investigations of this concept are urgently needed to estimate the potential of using them for therapeutic purposes.Goal of the Project: This project aims at addressing the shortcomings of existing FR-targeted imaging and therapy concepts by the development of FRa-targeted radiotheragnostics. The currently challenging selection of patients with FR-positive tumors should be faced by the implementation of a FRa-(i.e. tumor)-specific 18F-PET agent. This should be achieved by replacing folic acid with 5-MTHF as a targeting ligand because of its known (50-fold increased) binding preference for the FR?. Therewith, false negative results due to undesired accumulation of radiotracer at sites of inflammation (FRß) can be avoided. In terms of a therapeutic companion drug, 5-MTHF-based radioconjugates are also favorable due to their increased tumor uptake and reduced retention in the kidneys. Moreover, to face the disadvantage of the mostly heterogeneous expression of the FRa in tumor lesions and enable efficient treatment of micrometastases, we plan to investigate non-standard radionuclides (161Tb, 155Tb, 175Yb) and select the most suited candidate for a specific application, thereby addressing the concept of personalized medicine. Finally, it is essential to employ clinically relevant tumor mouse models with moderate FR-expression levels for testing the most promising candidates of the proposed radiotheragnostic concept.Expected Value of the Proposal: The clinically implemented concept of tumor-targeted radionuclide therapy using receptor-targeted peptides (e.g. 177Lu-DOTATATE (LutatheraTM) and prostate-specific membrane antigen (PSMA)-ligands (e.g. 177Lu-PSMA-617) have gained momentum in recent past. The pharmaceutical industry has realized the potential of this therapy modality for patients with metastasized disease as it can increase the survival rate but also improve the quality of life. The availability of a tumor-selective radiotracer to allow unambiguous identification of patients with FRa-positive malignancies is essential for a successful implementation of FR-targeted therapies. Due to the large number of patients suffering from FRa-positive tumors, it is of high interest to provide a viable therapy strategy. A clinical translation of the proposed concept is the long-term future goal of this project. Realization of this vision would comprise an enormous potential for the management of cancer diseases where efficient treatment option for late stage disease do not currently exist.
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