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Translational molecular imaging of neuroendocrine tumours using innovative PET radionuclides

English title Translational molecular imaging of neuroendocrine tumours using innovative PET radionuclides
Applicant Schibli Roger
Number 156800
Funding scheme India
Research institution Zentrum für Radiopharmazeutische Wissenschaften ETH, PSI, USZ ETH Hönggerberg
Institution of higher education Paul Scherrer Institute - PSI
Main discipline Pharmacology, Pharmacy
Start/End 01.04.2015 - 31.03.2019
Approved amount 249'140.00
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All Disciplines (4)

Discipline
Pharmacology, Pharmacy
Experimental Cancer Research
Inorganic Chemistry
Nuclear Physics

Keywords (10)

DOTATATE; Automated radiotracer production; Clinical Phase I study; Good Manufacturing Practice; Molecular imaging; Scandium-43/44; Isotope production; Neuroendocrine tumors; Cancer diagnosis; Radiopharmacy

Lay Summary (German)

Lead
Für die Diagnose von Patienten, die an neuroendokrinen Tumoren (NET) leiden, werden heute radioaktiv markierte Somatostatin-Peptid-Analoga verwendet(z.B. 68Ga-DOTA-Tyr3-Octreotate). 68Ga-DOTA-Tyr3-Octreotate wird in Europa für die Positronenemissionstomographie (PET), wegen seiner exzellenten, disgnostischen Qualität oft eingesetzt. Die sehr kurze physikalische Halbwertszeit von 68Ga (T1/2 = 68 min) erschwert allerding den Transport an entfernte, nuklearmedizinische Zentren in der Schweiz und Indien. PET-Radionuklide mit längeren Halbwertszeiten bei gleichbleibend hoher Bildqualität wären ideal.
Lay summary

Ziel diese Indo-Swiss Forschungsprojekt ist es, translationale, biomedizinische Forschung zu betreiben, indem die langlebigen PET Radionuklide 44Sc (T1/2 = 3,97 h) und 43Sc (T1/2 = 3,9 h) hergestellt und zur Markierung von DOTA-Tyr3-Octreotate verwendet werden. Wir planten die Implementierung der Produktion dieser Radionuklide am Paul Scherrer Institut (PSI) und dem Institut für Nuklearmedizin&Allied Sciences (INMAS) in Neu-Delhi. Ferner werden wir DOTA-Tyr3-Octreotate unter sterilen  Bedingungen mit 44Sc oder 43Sc am PSI und INMAS radioaktiv markieren. Die Radiotracer sollen daraufhin am Universitätsspital Zürich (USZ), am INMAS, am die Postgraduate Institute of Medical Education & Research (PGIMER - Chandigarh) und am Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGI - Lucknow) klinisch auf ihre bildgebenden Eigenschaften, sowie ihre Gesamtstrahlungsdosis für den Patienten hin beurteilt werden.

Sollte das Projekt erfolgreich sein, werden mehr NET-Patienten in Indien und in der Schweiz Zugang zu präziser Diagnose ihres Kerbsleidens erhalten. Darüber hinaus werden in diesem Projekt junge Wissenschaftler in den Bereichen Radiochemie, radiopharmazeutischen Chemie und GMP-Produktion von Radiotracer geschult. Die Radionuklide und die entsprechenden Radiotracer haben das Potential, kommerzialisiert zu werden.

Direct link to Lay Summary Last update: 04.01.2015

Responsible applicant and co-applicants

Employees

Project partner

Publications

Publication
Terbium-161 for PSMA-targeted radionuclide therapy of prostate cancer
Müller Cristina, Umbricht Christoph A., Gracheva Nadezda, Tschan Viviane J., Pellegrini Giovanni, Bernhardt Peter, Zeevaart Jan Rijn, Köster Ulli, Schibli Roger, van der Meulen Nicholas P. (2019), Terbium-161 for PSMA-targeted radionuclide therapy of prostate cancer, in European Journal of Nuclear Medicine and Molecular Imaging, 46(9), 1919-1930.
44Sc-PSMA-617 for radiotheragnostics in tandem with 177Lu-PSMA-617—preclinical investigations in comparison with 68Ga-PSMA-11 and 68Ga-PSMA-617
Umbricht Christoph A., Benešová Martina, Schmid Raffaella M., Türler Andreas, Schibli Roger, van der Meulen Nicholas P., Müller Cristina (2017), 44Sc-PSMA-617 for radiotheragnostics in tandem with 177Lu-PSMA-617—preclinical investigations in comparison with 68Ga-PSMA-11 and 68Ga-PSMA-617, in EJNMMI Research, 7(1), 9-9.
44Sc for labeling of DOTA- and NODAGA-functionalized peptides: preclinical in vitro and in vivo investigations
Domnanich Katharina A., M?ller Cristina, Farkas Renata, Schmid Raffaella M., Ponsard Bernard, Schibli Roger, T?rler Andreas, van der Meulen Nicholas P. (2017), 44Sc for labeling of DOTA- and NODAGA-functionalized peptides: preclinical in vitro and in vivo investigations, in EJNMMI Radiopharmacy and Chemistry, 1(1), 8-8.
Evaluation of the first 44Sc-labeled Affibody molecule for imaging of HER2-expressing tumors
Honarvar H., Müller Cristina, Cohrs Susan, Haller Stephanie, Westerlund K., Karlstrom A. E., van der Meulen N. P., Schibli Roger, Tolmachev V. (2017), Evaluation of the first 44Sc-labeled Affibody molecule for imaging of HER2-expressing tumors, in Nuclear Medicine & Biology, 45, 15-21.
First-in-Human PET/CT Imaging of Metastatic Neuroendocrine Neoplasms with Cyclotron-Produced 44Sc-DOTATOC: A Proof-of-Concept Study
Singh A., van der Meulen N. P., Müller C., Klette I., Kulkarni H. R., Türler A., Schibli Roger, Baum Richard (2017), First-in-Human PET/CT Imaging of Metastatic Neuroendocrine Neoplasms with Cyclotron-Produced 44Sc-DOTATOC: A Proof-of-Concept Study, in Cancer Biother Radiopharm, 32(4), 124-132.

Collaboration

Group / person Country
Types of collaboration
Prof. Dr. med Richard Baum Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Susan Lapi United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Comecer Italy (Europe)
- Industry/business/other use-inspired collaboration
Mishra Anil Kumar, Inst. Nuclear Medicine and Allied Sciences, Delhi India (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Exchange of personnel
Prof. Saverio Branchini/University of Berne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
TERACHEM 2018 Poster 99mTechnetium site-specific labeling of S-alkylated homodimeric N-acetyl cysteine ethyl ester(NACET) DTPA derivative for neuro imaging 26.09.2018 Bressanone, Italy Mishra Anil Kumar;
TERACHEM 2018 Talk given at a conference The possibility of producing 43Sc from 44Ca via the (p,2n) nuclear reaction 26.09.2018 Bressanone, Italy Schibli Roger;
TERACHEM 2018 Talk given at a conference Medically interesting radiolanthanide terbium-161: from production towards clinical application 26.09.2018 Bressanone, Italy Schibli Roger; Gracheva Nadezda;
25. Arbeitstreffen der Gemeinschaft der Radiopharmazeuten und Radiochemiker der DGN Talk given at a conference Improved Chemical Separation Method To Obtain A Medically Interesting Radiolanthanide 05.10.2017 Starnberg, Germany Gracheva Nadezda; Schibli Roger;
ISRS 2017 Talk given at a conference 43Sc Production by the Cyclotron Irradiation of Enriched Ca and Ti 14.05.2017 Dresden, Germany Schibli Roger;
International Symposium Molecular Imaging Agents in Medicine Talk given at a conference Novel labels, tags and radionuclides:New radionuclides 13.02.2017 Groningen, Netherlands Schibli Roger;


Self-organised

Title Date Place
TERACHEM 26.09.2018 Bressanone, Italy

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Scientific workshop on isotope production and targetry Workshop 19.10.2015 Paul Scherrer Institute, Switzerland Haller Stephanie; Mishra Anil Kumar; Schibli Roger;


Communication with the public

Communication Title Media Place Year
New media (web, blogs, podcasts, news feeds etc.) Tb-161: Novel Radionuclide to be Tested Web International 2018
Talks/events/exhibitions Nicht-invasive Bildgebung in der personalisierten Medizin: Fact or Fiction ?“ German-speaking Switzerland 2017
Talks/events/exhibitions „Tracers for Life: Nicht-invasive Bildgebung in der personalisierten Medizin“ International 2016
New media (web, blogs, podcasts, news feeds etc.) Novel PET Radiochemistries: Improving understanding and detection of disease Webinar International 2016

Awards

Title Year
Marie Curie Award 2018 for the work entitled: Terbium-161 Application for PSMA-Targeted Radionuclide Therapy of Prostate Cancer Cristina Müller, Christoph A. Umbricht, Nadezda Gracheva, Peter Bernhardt, Roger Schibli, Nicholas P. van der Meulen. 2018
Springer Prize for Best Paper 2018: Christoph A. Umbricht, Martina Benešová, Raffaella Schmid, Andreas Türler, Roger Schibli, Nicholas P. van der Meulen, Cristina Müller. 44Sc-PSMA-617 for RadioTheragnostics in Tandem with 177Lu-PSMA-617 – Preclinical Investigations in Comparison with 68Ga-Based PSMA Ligands. EJNMMI Research 7 (2017), 9. 2018

Associated projects

Number Title Start Funding scheme
157763 MobiPET: A mobile, small animal PET scanner for molecular imaging 01.03.2015 R'EQUIP

Abstract

Background and Aims: Radiopharmaceuticals or radiotracers that comprise metallic radionuclides have proven to be valuable diagnostic and therapeutic tools in oncology. For the management of patients suffering from neuroendocrine tumours (NET) in particular, radiometal-labelled somatostatin analogues are readily used for both diagnosis and therapy. Radiosomatostatin analogues such as 111In-octreotide and 68Ga-DOTA-Tyr3-Octreotate (for diagnosis) and 90Y-DOTA-Tyr3-octreotide and 177Lu-DOTA-Tyr3-Octreotate (for therapy) represent the current bench-mark. It is apparent, however, that 111In-octreotide results in scintigrams or SPECT (Single Photon Emission Computed Tomography) of poor quality. The PET (Positron Emission Tomography) tracer 68Ga-DOTA-Tyr3-Octreotate has been clinically proven to be a better alternative to 111In-octreotide because of its better pharmacokinetics and, thus, image quality. 68Ga (T1/2 = 68 min), however, is not an ideal radionuclide for centralised tracer production and quality control - which is firmly believed to be the future of radiopharmacy - with distribution to the numerous nuclear medical centres in Switzerland and India, despite the availability of 68Ge/68Ga generators, being problematic. PET radionuclides with longer physical half-lives, but providing similar image quality, therefore, have to be evaluated. The aim of this Indo-Swiss Joint Research Project is to perform true translational biomedical research (bech-to-bedside) by developing and clinically assess a radiosomatostatin analogue with novel, longer-lived PET radionuclides. This will have a positive impact on the management of NET patients in India and Switzerland.Methods: It is aimed to develop the production of the positron-emitting radionuclide 44Sc (useful for Positron Emission Tomography, PET; T1/2 = 3.97 h; E?? = 1475 keV, 94.3%) and its diagnostic counterpart, 43Sc (T1/2 = 3.9 h; maxE?? = 1198 keV; E? = 372 keV) in quantities and quality useful for medical purposes in Switzerland (Paul Scherrer Institut) and India. It is planned to use these radionuclides to label the well-characterized somatostatin analogue DOTA-Tyr3-Octreotate under GMP conditions in India (Institute of Nuclear Medicine & Allied Sciences, INMAS - Delhi, Postgraduate Institute of Medical Education & Research, PGIMER - Chandigarh, Sanjay Gandhi Post Graduate Institute of Medical Sciences, SGPGI - Lucknow) and Switzerland (Paul Scherrer Institute - Villigen). The resulting 44Sc/43Sc-DOTA-Tyr3-Octreotate will be evaluated (and compared) in a clinical proof-of-concept study in a limited number of patients (typically 5-10 patients per centre and/or radionuclide) at the Nuclear Medical Departments of the abovementioned Indian institutes, as well as University Hospital Zurich. The tracers will be assessed with respect to their in vivo pharmacokinetic imaging capacity, as well as the total radiation dose to the patients in a head-to-head comparison with 68Ga-DOTA-Tyr3-Octreotate.Expected impact: Should this project be successful, two new radionuclides will be introduced to the portfolio of nuclear medicine. Due to their physical decay properties, they will be almost ideal for a centralised production and easy and economic distribution of their corresponding radiopharmaceuticals. 44Sc/43Sc-DOTA-Tyr3-Octreotate tracer availability for NET diagnosis will dramatically facilitate patient management for NTEs in India and Switzerland by making novel tracers available for a large number of nuclear medical centres. 44Sc-DOTA-Tyr3-Octreotate will serve as a prototype for other radiometal-based radiopharmaceuticals, especially novel peptide-based radiopharmaceuticals. Additionally, this project will cement Switzerland’s role in tracer and radionuclide development, while fostering India with regard to developing and bringing new, innovative radionuclides to the country’s nuclear medicine fraternity. The radionuclides and the corresponding radiotracers have the potential to be commercially exploited by industrial partners. Young scientists will also be trained in areas such as radiochemistry, radiopharmaceutical chemistry and GMP production of radiopharmaceuticals. Aside from the diagnostic power of 44/43Sc, this project possesses an inherent therapeutic component for the future by switching from 44/43Sc to the therapeutic match, 47Sc. This enhances the proposed project’s attraction for the scientific and medical community and may provide a long-term perspective for the project and the consortium as a whole. As a result, an additional dynamic impulse towards the development of new and effective radiodiagnostics and therapeutics for the management of cancerous diseases can also be expected. The studies mutually profit from capabilities of unique sites in India, as well as in Switzerland, and the know-how of local experts in the field of radiochemistry and radiopharmacy.
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