Project

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Folate Receptor Targeting for Imaging and Potential Therapy of Cancerous and Inflammatory Diseases

English title Folate Receptor Targeting for Imaging and Potential Therapy of Cancerous and Inflammatory Diseases
Applicant Müller Cristina
Number 138834
Funding scheme Ambizione
Research institution Paul Scherrer Institut
Institution of higher education Paul Scherrer Institute - PSI
Main discipline Pharmacology, Pharmacy
Start/End 01.02.2012 - 31.01.2013
Approved amount 194'104.00
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Lay Summary (English)

Lead
Lay summary

Lead: Early diagnosis of cancer diseases and efficient therapy approaches are key components of modern medicine. Thus, there is an urgent need for the development of methods allowing non-invasive tumor diagnosis and therapy. Targeting the folate receptor (FR) with folate radioconjugates is a promising strategy to achieve this goal.

Background: The FR is overexpressed in a variety of tumor types (e.g. ovarian, endometrial, lung, colon carcinomas) but highly restricted in normal tissues and organs with the only exception of the kidneys. Therefore, folic acid can be used for selective delivery of diagnostic or therapeutic probes to cancer cells. Folate-based radioconjugates for imaging purposes have been successfully applied in preclinical and clinical studies. Recently, we developed a novel folic acid derivative with improved pharmacokinetics which allows for the first time also a therapeutic application using particle-emitting radioisotopes.

 

Goal: The goal of this project is to perform preclinical therapy studies using folate conjugates labeled with therapeutic radioisotopes. The effects of several radioisotopes with different decay properties, variable dosage and application protocols will be tested and compared. The antitumor effect of radiofolates will also be investigated in combination with chemotherapeutics (e.g. pemetrexed). Regarding a potential damage to the kidneys, the application of renoprotective agents such as e.g. amifostine will be assessed with the aim to improve the toxicity profile of this therapy approach. 

 

Expected Value: Over 50% of frequently occurring cancer types overexpress the FR which indicates the high relevance of this tumor target. Application of folic acid targeted radiopharmaceuticals to treat FR-positive cancer diseases is therefore of paramount interest. The development of an effective treatment protocol can help to face the rapidly growing problem of cancer in the western population.

 

 

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
A Unique Matched Quadruplet of Terbium Radioisotopes for PET and SPECT and for α- and β--Radionuclide Therapy: An In Vivo Proof-of-Concept Study with a New Receptor-Targeted Folate Derivative.
Müller Cristina, Zhernosekov Konstantin, Köster Ulli, Johnston Karl, Dorrer Holger, Hohn Alexander, van der Walt Nico T, Türler Andreas, Schibli Roger (2012), A Unique Matched Quadruplet of Terbium Radioisotopes for PET and SPECT and for α- and β--Radionuclide Therapy: An In Vivo Proof-of-Concept Study with a New Receptor-Targeted Folate Derivative., in Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 53(12), 1951-9.
PEGylation, increasing specific activity and multiple dosing as strategies to improve the risk-benefit profile of targeted radionuclide therapy with 177Lu-DOTA-bombesin analogues.
Däpp Simone, Müller Cristina, Garayoa Elisa García, Bläuenstein Peter, Maes Veronique, Brans Luc, Tourwé Dirk A, Schibli Roger (2012), PEGylation, increasing specific activity and multiple dosing as strategies to improve the risk-benefit profile of targeted radionuclide therapy with 177Lu-DOTA-bombesin analogues., in EJNMMI research, 2(1), 24-24.
Radioiodinated folic acid conjugates: evaluation of a valuable concept to improve tumor-to-background contrast.
Reber Josefine, Struthers Harriet, Betzel Thomas, Hohn Alexander, Schibli Roger, Müller Cristina (2012), Radioiodinated folic acid conjugates: evaluation of a valuable concept to improve tumor-to-background contrast., in Molecular pharmaceutics, 9(5), 1213-21.
[18F]fluoro-deoxy-glucose folate: a novel PET radiotracer with improved in vivo properties for folate receptor targeting.
Fischer Cindy R, Müller Cristina, Reber Josefine, Müller Adrienne, Krämer Stefanie D, Ametamey Simon M, Schibli Roger (2012), [18F]fluoro-deoxy-glucose folate: a novel PET radiotracer with improved in vivo properties for folate receptor targeting., in Bioconjugate chemistry, 23(4), 805-13.
5-(2-18F-fluoroethoxy)-L-tryptophan as a substrate of system L transport for tumor imaging by PET.
Krämer Stefanie D, Mu Linjing, Müller Adrienne, Keller Claudia, Kuznetsova Olga F, Schweinsberg Christian, Franck Dominic, Müller Cristina, Ross Tobias L, Schibli Roger, Ametamey Simon M (2012), 5-(2-18F-fluoroethoxy)-L-tryptophan as a substrate of system L transport for tumor imaging by PET., in Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 53(3), 434-42.
DOTA Conjugate with an Albumin-Binding Entity Enables the First Folic Acid-Targeted 177Lu-Radionuclide Tumor Therapy in Mice.
Müller Cristina, Struthers Harriet, Winiger Christian, Zhernosekov Konstantin, Schibli Roger, DOTA Conjugate with an Albumin-Binding Entity Enables the First Folic Acid-Targeted 177Lu-Radionuclide Tumor Therapy in Mice., in Journal of nuclear medicine : official publication, Society of Nuclear Medicine, in press, in press.
Single photon emission computed tomography tracer.
Müller Cristina, Schibli Roger, Single photon emission computed tomography tracer., 187.

Collaboration

Group / person Country
Types of collaboration
Dept. of Orthopedics, Erasmus Medical Center, Rotterdam Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Merck & Cie, Schaffhausen Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Industry/business/other use-inspired collaboration
Endocyte Inc., West Lafayette, Indiana United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
World Molecular Imaging Congress 05.09.2012 Dublin, Ireland
15th International Symposium on Pteridines and Folates 05.05.2012 Antalya, Turkey


Awards

Title Year
Galenus Support 2012 2012

Associated projects

Number Title Start Funding scheme
188978 Investigation of a New Class of Folate-Based RadioImaging Agents and RadioTherapeutics 01.02.2020 Project funding (Div. I-III)
156803 Development of New Folate-Based RadioImaging Agents and RadioTherapeutics 01.04.2015 Project funding (Div. I-III)
121772 Folate Receptor Targeting for Imaging and Potential Therapy of Cancerous and Inflammatory Diseases 01.02.2009 Ambizione

Abstract

Background: The vitamin folic acid has emerged as promising targeting ligand for selective delivery of attached probes to cancer cells that express the folate receptor (FR) including carcinomas of the ovaries, uterus, lungs, kidneys, colon, breast etc. In normal tissues and organs, however, the expression of the FR is highly limited to only a few tissues such as the kidneys. The utility of folic acid as a molecular “Trojan horse” has arisen from its high affinity to the FR (KD < 1 nM) also after conjugation to its diagnostic/therapeutic cargo and the fact that it is non-immunogenic and stable under a broad range of conditions. Status of Research: The potential of using folic acid radioconjugates for nuclear imaging (SPECT and PET) of cancer has been demonstrated by numerous examples of preclinical studies reported in the literature. The usefulness of FR-targeted nuclear imaging is generally accepted and currently not only a prevailing topic of our own research group but also of high interest by clinicians. In contrast, FR-targeted radionuclide therapy has not been envisaged yet because of the high uptake of folic acid radioconjugates in the kidneys which might be damaged by particle-emitting radiation. Previously, we observed that a pharmacological intervention with the antifolate pemetrexed reduces kidney accumulation of radifolates without affecting the tumor uptake. Currently, we are following a strategy that makes use of a chemical modification of the folic acid radioconjugate by installation of an additional entity that binds to serum albumin. Recent results showed that a prolonged circulation time of the folate radioconjugate could be achieved by this approach resulting in an increased tumor uptake of the radiofolate and concomitantly in a significantly reduced kidney accumulation of radioactivity. Goal of the Project: The therapeutic approach with folic acid conjugates of particle-emitting radioisotopes will be the topic of this project. First, we want to evaluate novel folic acid radioconjugates that are chemically modified by integration of an albumin binding entity. In addition, folate conjugates of “designed instability” (e.g. with a chemically cleavable bond) will be evaluated in vitro and in vivo. By these interventions we want to achieve a better tissue distribution of the radiofolates particularly with regard to its unfavorable accumulation in the kidneys. Second, we want to test folic acid conjugates radiolabeled with therapeutic radioisotopes that are potentially more suitable for FR-targeted radionuclide therapy than [177Lu]-lutetium (beta-emitter). Among those are beta-emitters with more favorable decay properties (161Tb, 47Sc; produced at PSI) and alpha-emitters (e.g. 211At, 213Bi, 225Ac) which might be superior over beta-emitters to effectively treat tumors. Also, the beneficial effect of renoprotective agents (e.g. amifostine) will be tested to prevent potential damage to the kidneys by particle-emitting radiofolats. Third, we want to investigate radioncuclide therapy in combination with chemotherapeutics, particularly with the antifolate pemetrexed. Pemetrexed was recently shown to act as a radiosensitizer in combination with radiofolates in vitro resulting in an increased inhibition of tumor cell growth. Such an approach would be particularly attractive for a therapeutic study in vivo because of pemetrexed’s favorable effect on the overall tissue distribution as mentioned before. Expected Value of the Proposal: Targeted radionuclide therapy emerges as a treatment modality that is effective in reducing tumor progression and improving quality of life and overall survival of cancer patients. So far this strategy is most successfully applied to somatostatin-receptor positive neuroendocrine tumor patients. However, since neuroendocrine tumors are relatively rare there is a pressing need for the identification of new targeting strategies. In this respect FR-targeting with folic acid radioconjugates is a highly promising approach. Of about 17’500 people that are diagnosed with frequent cancer diseases each year in Switzerland, about 56 % suffer from folate receptor-positive tumors. Taken these facts into account, clinical implementation of FR-targeted radionuclide therapy is of paramount interest because it comprises the potential of future treatment opportunities for a wide variety of frequently occurring cancer diseases and thus a better quality of life for a large number of patients.
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