Project

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Focused Ultrasound-Mediated Delivery of Encapsulated MGMT Antagonists for the Treatment of Temozolomide-Resistant Glioblastoma

English title Focused Ultrasound-Mediated Delivery of Encapsulated MGMT Antagonists for the Treatment of Temozolomide-Resistant Glioblastoma
Applicant Leroux Jean-Christophe
Number 147651
Funding scheme Sinergia
Research institution Institut für Pharmazeutische Wissenschaften ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Experimental Cancer Research
Start/End 01.03.2014 - 31.05.2017
Approved amount 1'119'137.16
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All Disciplines (7)

Discipline
Experimental Cancer Research
Molecular Biology
Biochemistry
Biophysics
Pharmacology, Pharmacy
Organic Chemistry
Technical Physics

Keywords (13)

Blood Brain Barrier; Nanocarriers; Microbubbles; Glioblastoma; Liposomes; siRNA; Transfection; Calcium phosphate nanoparticles; MGMT; Focused Ultrasound; O6-Benzylguanine; Temozolomide; Drug Delivery

Lay Summary (French)

Lead
L'objectif de ce projet est de véhiculer des agents pharmacologiques permettant d'aumenter la réponse des gliobastomes à l'activité cytotoxique du témozolomide. Ces agents seront encapulés dans des nanovecteurs et leur déposition dans le cerveau facilité par l'entremise de d'ultrasons focalisés.
Lay summary

Le glioblastome est un cancer du cerveau caractérisé par une importante malignité. Le traitement standard comporte une résection chirurgicale, suivie d'une radiothérapie et d'une chimiothérapie au témozolomide. Les patients répondant le mieux à ce traitement sont ceux dont l'expression de l'enzyme O6-méthylguanine-ADN méthyltransférase (MGMT) est plus faible. Cette enzyme réduit l'efficacité de la chimiothérapie.

L'objectif de ce projet de recherche est de mettre au point une nouvelle approche visant à contrer la résistance au témozolomide. A cet effet, des nanovecteurs comportant des inhibiteurs de la MGMT seront administrés chez la souris et leur passage à travers la barrière hémoencéphalique sera assurée par l'entremise d'ultrasons focalisés de faible intensité. En plus d'améliorer l'activité anticancéreuse du témozolomide, cette approache devrait aussi permettre de diminuer les effets secondaires des inhibiteurs de la MGMT.

Il s'agit d'un projet multidisciplinaire combinant une expertise en science fondamentale (mise au point des vecteurs), translationelle (utilisation des ultrasons focalisés) et clinique (traitement des tumeurs) afin de traiter un des cancers les plus dévastateurs. Cette initiative pourrait aussi permettre à long terme d'améliorer le traitement d'autres pathologies cérébrales.

Direct link to Lay Summary Last update: 12.07.2013

Lay Summary (English)

Lead
The objective of this project is to deliver nanoparticle-encapsulated sensitizing agents to glioblastomas in order to improve the anticancer activity temozolomide. The brain delivery of the nanocarriers will be achieved through the use of low intensity focused ultrasounds.
Lay summary

Glioblastoma is the most malignant primary brain tumor. The current standard of care includes surgery followed by radiotherapy plus temozolomide chemotherapy. However, the benefit from this treatment is largely limited to a subgroup of patients (30-35%) with tumors exhibiting a decreased expression of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). MGMT reverses lethal damage induced by temozolomide and thus abrogates its therapeutic effects.

The aim of this research project is to develop a new approach to overcome MGMT-mediated resistance. Sensitization to temozolomide shall be achieved by developing nanocarriers for drugs that inactivates MGMT, or silencing nucleic acids targeting MGMT. This approach will reduce the systemic toxicity of the sensitizing drugs and will enable the tumor targeting. Since the blood brain barrier limits the passage of most neuropharmaceuticals from the circulation into the brain parenchyma, microbubble-enhanced low intensity focused ultrasounds will be used to locally and reversibly modulate the permeability of the blood brain barrier to facilitate the passage of the nanocarriers.

This interdisciplinary project aligns research efforts from basic science (nanocarrier formulation), translational science (non-invasive focused ultrasound interventions) and clinical science (tumor treatment) to propose a novel treatment approach for one of the most devastating cancers. Our initiative will also set the stage for similar approaches to silence the biological activity of further target genes thought to promote cancer progression and resistance to therapy and will established a platform for targeted therapeutic interventions in the brain.

Direct link to Lay Summary Last update: 12.07.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Chemotherapy sensitization of glioblastoma by focused ultrasound-mediated delivery of therapeutic liposomes
Papachristodoulou Alexandros, Signorell Rea Deborah, Werner Beat, Brambilla Davide, Luciani Paola, Cavusoglu Mustafa, Grandjean Joanes, Silginer Manuela, Rudin Markus, Martin Ernst, Weller Michael, Roth Patrick, Leroux Jean-Christophe (2019), Chemotherapy sensitization of glioblastoma by focused ultrasound-mediated delivery of therapeutic liposomes, in Journal of Controlled Release, 295, 130-139.
Closed-loop cavitation control for focused ultrasound-mediated blood-brain-barrier opening by long-circulating microbubbles
Cavusoglu Mustafa, Zhang Jia, Ielacqua Giovanna Diletta, Pellegrini Giovanni, Signorell Rea Deborah, Papachristodoulou Alexandros, Brambilla Davide, Roth Patrick, Weller Michael, Rudin Markus, Martin Ernst, Leroux Jean Christophe, Werner Beat (2018), Closed-loop cavitation control for focused ultrasound-mediated blood-brain-barrier opening by long-circulating microbubbles, in Physics in Medicine and Biology.
Pharmacokinetics of Lipid-Drug Conjugates Loaded into Liposomes
Signorell Rea, Luciani Paola, Brambilla Davide, Leroux Jean-Christophe (2018), Pharmacokinetics of Lipid-Drug Conjugates Loaded into Liposomes, in European Journal of Pharmaceutics and Biopharmaceutics, 128, 188-199.
Preparation of PEGylated liposomes incorporating lipophilic lomeguatrib derivatives for the sensitization of chemo-resistant gliomas.
Signorell Rea D, Papachristodoulou Alexandros, Xiao Jiawen, Arpagaus Bianca, Casalini Tommaso, Grandjean Joanes, Thamm Jana, Steiniger Frank, Luciani Paola, Brambilla Davide, Werner Beat, Martin Ernst, Weller Michael, Roth Patrick, Leroux Jean-Christophe (2017), Preparation of PEGylated liposomes incorporating lipophilic lomeguatrib derivatives for the sensitization of chemo-resistant gliomas., in International journal of pharmaceutics, (1), 388-396.

Collaboration

Group / person Country
Types of collaboration
Prof. M. Rudin, Animal Imaging Lab, UZH/ETHZ Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Prof. Paola Luciani Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Dr. Tommaso Casalini Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Jean-Francois Aubry France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Kim Butts Pauly United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
SF Nano, 5th Annual Meeting Talk given at a conference Vesicles - From treating cancer to liver diseases 03.12.2018 Montpellier, France Leroux Jean-Christophe;
19th International Pharmaceutical Technology Symposium Talk given at a conference Ultrasound-mediated delivery of drug-loaded liposomes for chemotherapy sensitization of glioblastomas 17.09.2018 Antalya, Turkey Leroux Jean-Christophe;
Biobarriers 2018 - 12th International Conference and Workshop on Biological Barriers Talk given at a conference Delivery of a liposomal O6-methylguanine-DNA methyltransferase inactivator to glioblastoma via ultrasound-supported blood-brain barrier opening 27.08.2018 Saarbrücken, Germany Leroux Jean-Christophe;
2018 ASCO Annual Meeting I Talk given at a conference Sensitization of glioblastoma to alkylating chemotherapy by ultrasound-mediated delivery of therapeutic liposomes 01.06.2018 Chicago, United States of America Papachristodoulou Alexandros; Martin-Fiori Ernst; Signorell Rea Deborah; Werner Beat; Weller Michael; Leroux Jean-Christophe;
2nd CNS Anticancer drug discovery/development conference Poster MRI-guided focused ultrasound-mediated delivery of liposomal MGMT antagonists for the treatment of temozolomide-resistant glioblastoma 16.05.2017 Scottsdale, Arizona, United States of America Papachristodoulou Alexandros;
Doktorandentag ETH Talk given at a conference Tackling Glioblastoma Therapy: Focused Ultrasound-Supported Liposomal Delivery of a PaTrin-2 Derivative to Defeat Temozolomide-Resistance 12.02.2017 ZURICH, Switzerland Signorell Rea Deborah;
Drug Discovery Network Zurich Symposium 2017 Poster Heading towards an Effective Glioblastoma Therapy: Focused Ultrasound-Supported Liposomal Delivery of PaTrin-2 Derivatives to Defeat Temozolomide-Resistance 10.02.2017 Zurich, Switzerland Signorell Rea Deborah;
SSCI Symposium 2016 Poster Heading towards an Effective Glioblastoma Therapy: Focused Ultrasound-Supported Liposomal Delivery of PaTrin-2 Derivatives to Defeat Temozolomide-Resistance 27.01.2017 Zurich, Switzerland Signorell Rea Deborah;
France Life Imaging – Imagerie Interventionelle Talk given at a conference High Intensity Focused Ultrasound in the Brain: Evolving a Promising Techology into Standard of Care 15.12.2016 France Life Imaging – Imagerie Interventionelle. Paris , France Werner Beat;
21st Annual Society for Neuro-Oncology Conference Poster MRI-guided focused ultrasound-mediated delivery of liposomal MGMT antagonists for the treatment of temozolomide-resistant glioblastoma 18.11.2016 Scottsdale, Arizona, United States of America Papachristodoulou Alexandros;
AAPS Annual Meeting and Exposition 2016 Poster Tackling Temozolomide-Resistant Glioblastoma Therapy with Focused Ultrasound-Supported Liposomal Delivery of PaTrin-2 Derivatives 13.11.2016 Denver, United States of America Signorell Rea Deborah;
NeuroSpin Centre CEA, Paris Individual talk Brain Focused Ultrasound: Current Status and Open Challenges 14.10.2016 Paris, France Werner Beat;
Swiss Galenik Joint Meeting 2016 Talk given at a conference Focused Ultrasound-Mediated Delivery of Liposomal MGMT Antagonists for the Treatment of Temozolomide-Resistant Glioblastoma 15.09.2016 Zurich, Switzerland Signorell Rea Deborah;
Biointerfaces International Conference 2016 Poster Focused Ultrasound-Mediated Delivery of Liposomal MGMT Antagonists for the Treatment of Temozolomide-Resistant Glioblastoma 23.08.2016 Zurich, Switzerland Signorell Rea Deborah;
1st Worldwide Exablate Nuero USser’s Forum Talk given at a conference Magnetic Resonance Guided Focused Ultrasound System for BBB opening in Rodents 18.06.2016 Chicago, United States of America Werner Beat;
6th Student Retreat of the Cancer Biology PhD Program Talk given at a conference Focused Ultrasound-Mediated Delivery of Encapsulated MGMT Antagonists for the Treatment of Temozolomide-Resistant Glioblastoma 30.03.2016 Davos, Switzerland Papachristodoulou Alexandros;
International Society of Therapeutic Ultrasound Talk given at a conference Magnetic Resonance Guided Focused Ultrasound System for BBB opening in Rodents 14.03.2016 Tel Aviv, Israel Çavusoglu Mustafa; Werner Beat;
SSCI Symposium 2016 Poster Focused Ultrasound-Mediated Delivery of Liposomal MGMT Antagonists for the Treatment of Temozolomide-Resistant Glioblastoma 22.01.2016 ETH, Hönggerberg, Zurich, Switzerland Signorell Rea Deborah; Brambilla Davide;
Kolloquium in angewandter Krebsforschung Poster Focused Ultrasound-Mediated Delivery of Encapsulated MGMT Antagonists for the Treatment of Temozolomide-Resistant Glioblastoma 11.11.2015 University Hospital Zurich, Switzerland Papachristodoulou Alexandros;
6th Cancer Network Zurich Retreat Poster Focused ultrasound-mediated delivery of encapsulated MGMT antagonists for the treatment of temozolomide-resistant glioblastoma 12.04.2015 Emmetten, Switzerland Papachristodoulou Alexandros; Weller Michael;
ZNZ Symposium 2014 Poster Magnetic Resonance Guided Focused Ultrasound System for BBB opening in Rodents 11.09.2014 Zürich, Switzerland Werner Beat; Li Ke;


Associated projects

Number Title Start Funding scheme
166697 Treating hyperammonemia with orally administered polymersomes 01.11.2016 Project funding (Div. I-III)
128791 NCCR CO-ME: Computer Aided and Image Guided Medical Interventions (phase III) 01.07.2009 National Centres of Competence in Research (NCCRs)
166634 Interferon type I-based immunotherapy targeting glioma stem cells 01.07.2016 Project funding (Div. I-III)
138342 Functional nanomedicines for improved anticancer chemotherapy 01.05.2012 Project funding (Div. I-III)

Abstract

Glioblastoma is the most malignant primary brain tumor. The current standard of care includes surgery followed by radiotherapy plus temozolomide chemotherapy. However, the benefit from chemotherapy is largely limited to a subgroup of patients (30-35%) with tumors exhibiting methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene. MGMT is a DNA repair protein that reverses lethal methylation damage induced by temozolomide and thus abrogates the therapeutic effects of alkylating agent chemotherapy. The aim of this research project is to develop a new approach to overcome MGMT-mediated resistance which severely limits the efficacy of temozolomide in the majority of glioblastoma patients.Sensitization to temozolomide shall be achieved by developing nanocarriers for O6-benzylguanine (and its main active metabolite), a pseudosubstrate MGMT-depleting agent, or siRNA targeting MGMT. Encapsulating the MGMT-depleting agents into nanocarriers serves the purpose to reduce their hematological toxicity while circulating systemically and to use ultrasound to target them towards tumor tissues where they shall deploy their payload in the local microenvironment.Since the blood brain barrier limits the passage of most neuropharmaceuticals from the circulation into the brain parenchyma, microbubble-enhanced low intensity focused ultrasound will be used to locally and reversibly modulate the permeability of the blood brain barrier to facilitate the passage of the nanocarriers. Intrainterventional Magnetic Resonance Imaging guidance will allow to deliver the nanocarriers preferentially to tumor-bearing brain regions, using infiltrative rodent glioma models.This interdisciplinary project aligns research efforts from basic science (drug nanocarrier formulation), translational science (non-invasive focused ultrasound interventions) and clinical science (tumor treatment) and builds on the highly specialized scientific expertise of the three participating research groups of the University of Zurich and ETH Zurich, to propose a novel treatment approach for one of the most devastating cancers. Since all key components of this research proposal are already actively investigated by the respective partners and preliminary feasibility data have been collected, the principal investigators are optimistic to reach the goals stated in this proposal and to be able to demonstrate proof of principle in relevant preclinical models of temozolomide-resistant glioblastoma. Although MGMT seems to be today the most relevant mediator of resistance to target, our initiative will set the stage for similar approaches to silence the biological activity of further target genes thought to promote cancer progression and resistance to therapy and will established a platform for targeted therapeutic interventions in the brain.
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