Targeted Brain Tumor Radiotherapy Using an Auger Emitter
Glioblastoma multiforme is a highly aggressive form of brain cancer whose location, tendency to infiltrate healthy surrounding tissue, and heterogeneity significantly limit survival, with scant progress having been made in recent decades. I-MAPi (Iodine-123 Meitner-Auger PARP1 inhibitor) is a precis...
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| Veröffentlicht in: | Clinical cancer research Jg. 26; H. 12; S. 2871 |
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| Sprache: | Englisch |
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15.06.2020
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| ISSN: | 1557-3265, 1557-3265 |
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| Abstract | Glioblastoma multiforme is a highly aggressive form of brain cancer whose location, tendency to infiltrate healthy surrounding tissue, and heterogeneity significantly limit survival, with scant progress having been made in recent decades.
I-MAPi (Iodine-123 Meitner-Auger PARP1 inhibitor) is a precise therapeutic tool composed of a PARP1 inhibitor radiolabeled with an Auger- and gamma-emitting iodine isotope. Here, the PARP inhibitor, which binds to the DNA repair enzyme PARP1, specifically targets cancer cells, sparing healthy tissue, and carries a radioactive payload within reach of the cancer cells' DNA.
The high relative biological efficacy of Auger electrons within their short range of action is leveraged to inflict DNA damage and cell death with high precision. The gamma ray emission of
I-MAPi allows for the imaging of tumor progression and therapy response, and for patient dosimetry calculation. Here we demonstrated the efficacy and specificity of this small-molecule radiotheranostic in a complex preclinical model.
and
studies demonstrate high tumor uptake and a prolonged survival in mice treated with
I-MAPi when compared with vehicle controls. Different methods of drug delivery were investigated to develop this technology for clinical applications, including convection enhanced delivery and intrathecal injection.
Taken together, these results represent the first full characterization of an Auger-emitting PARP inhibitor which demonstrate a survival benefit in mouse models of GBM and confirm the high potential of
I-MAPi for clinical translation. |
|---|---|
| AbstractList | Glioblastoma multiforme is a highly aggressive form of brain cancer whose location, tendency to infiltrate healthy surrounding tissue, and heterogeneity significantly limit survival, with scant progress having been made in recent decades.
I-MAPi (Iodine-123 Meitner-Auger PARP1 inhibitor) is a precise therapeutic tool composed of a PARP1 inhibitor radiolabeled with an Auger- and gamma-emitting iodine isotope. Here, the PARP inhibitor, which binds to the DNA repair enzyme PARP1, specifically targets cancer cells, sparing healthy tissue, and carries a radioactive payload within reach of the cancer cells' DNA.
The high relative biological efficacy of Auger electrons within their short range of action is leveraged to inflict DNA damage and cell death with high precision. The gamma ray emission of
I-MAPi allows for the imaging of tumor progression and therapy response, and for patient dosimetry calculation. Here we demonstrated the efficacy and specificity of this small-molecule radiotheranostic in a complex preclinical model.
and
studies demonstrate high tumor uptake and a prolonged survival in mice treated with
I-MAPi when compared with vehicle controls. Different methods of drug delivery were investigated to develop this technology for clinical applications, including convection enhanced delivery and intrathecal injection.
Taken together, these results represent the first full characterization of an Auger-emitting PARP inhibitor which demonstrate a survival benefit in mouse models of GBM and confirm the high potential of
I-MAPi for clinical translation. Glioblastoma multiforme is a highly aggressive form of brain cancer whose location, tendency to infiltrate healthy surrounding tissue, and heterogeneity significantly limit survival, with scant progress having been made in recent decades.PURPOSEGlioblastoma multiforme is a highly aggressive form of brain cancer whose location, tendency to infiltrate healthy surrounding tissue, and heterogeneity significantly limit survival, with scant progress having been made in recent decades.123I-MAPi (Iodine-123 Meitner-Auger PARP1 inhibitor) is a precise therapeutic tool composed of a PARP1 inhibitor radiolabeled with an Auger- and gamma-emitting iodine isotope. Here, the PARP inhibitor, which binds to the DNA repair enzyme PARP1, specifically targets cancer cells, sparing healthy tissue, and carries a radioactive payload within reach of the cancer cells' DNA.EXPERIMENTAL DESIGN123I-MAPi (Iodine-123 Meitner-Auger PARP1 inhibitor) is a precise therapeutic tool composed of a PARP1 inhibitor radiolabeled with an Auger- and gamma-emitting iodine isotope. Here, the PARP inhibitor, which binds to the DNA repair enzyme PARP1, specifically targets cancer cells, sparing healthy tissue, and carries a radioactive payload within reach of the cancer cells' DNA.The high relative biological efficacy of Auger electrons within their short range of action is leveraged to inflict DNA damage and cell death with high precision. The gamma ray emission of 123I-MAPi allows for the imaging of tumor progression and therapy response, and for patient dosimetry calculation. Here we demonstrated the efficacy and specificity of this small-molecule radiotheranostic in a complex preclinical model. In vitro and in vivo studies demonstrate high tumor uptake and a prolonged survival in mice treated with 123I-MAPi when compared with vehicle controls. Different methods of drug delivery were investigated to develop this technology for clinical applications, including convection enhanced delivery and intrathecal injection.RESULTSThe high relative biological efficacy of Auger electrons within their short range of action is leveraged to inflict DNA damage and cell death with high precision. The gamma ray emission of 123I-MAPi allows for the imaging of tumor progression and therapy response, and for patient dosimetry calculation. Here we demonstrated the efficacy and specificity of this small-molecule radiotheranostic in a complex preclinical model. In vitro and in vivo studies demonstrate high tumor uptake and a prolonged survival in mice treated with 123I-MAPi when compared with vehicle controls. Different methods of drug delivery were investigated to develop this technology for clinical applications, including convection enhanced delivery and intrathecal injection.Taken together, these results represent the first full characterization of an Auger-emitting PARP inhibitor which demonstrate a survival benefit in mouse models of GBM and confirm the high potential of 123I-MAPi for clinical translation.CONCLUSIONSTaken together, these results represent the first full characterization of an Auger-emitting PARP inhibitor which demonstrate a survival benefit in mouse models of GBM and confirm the high potential of 123I-MAPi for clinical translation. |
| Author | Demétrio De Souza França, Paula Maeda, Masatomo Pirovano, Giacomo Jannetti, Stephen A Carter, Lukas M Guru, Navjot Kossatz, Susanne Humm, John L Sadique, Ahmad Reiner, Thomas Lewis, Jason S Zeglis, Brian M |
| Author_xml | – sequence: 1 givenname: Giacomo orcidid: 0000-0001-8862-3613 surname: Pirovano fullname: Pirovano, Giacomo organization: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York – sequence: 2 givenname: Stephen A orcidid: 0000-0003-0847-8028 surname: Jannetti fullname: Jannetti, Stephen A organization: PhD Program in Biochemistry, The Graduate Center, The City University of New York (CUNY), New York, New York – sequence: 3 givenname: Lukas M orcidid: 0000-0003-4848-4190 surname: Carter fullname: Carter, Lukas M organization: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York – sequence: 4 givenname: Ahmad surname: Sadique fullname: Sadique, Ahmad organization: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York – sequence: 5 givenname: Susanne surname: Kossatz fullname: Kossatz, Susanne organization: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York – sequence: 6 givenname: Navjot surname: Guru fullname: Guru, Navjot organization: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York – sequence: 7 givenname: Paula orcidid: 0000-0003-4316-8834 surname: Demétrio De Souza França fullname: Demétrio De Souza França, Paula organization: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York – sequence: 8 givenname: Masatomo surname: Maeda fullname: Maeda, Masatomo organization: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York – sequence: 9 givenname: Brian M surname: Zeglis fullname: Zeglis, Brian M organization: PhD Program in Chemistry, The Graduate Center, The City University of New York (CUNY), New York, New York – sequence: 10 givenname: Jason S orcidid: 0000-0001-7065-4534 surname: Lewis fullname: Lewis, Jason S organization: Department of Pharmacology, Weill Cornell Medical College, New York, New York – sequence: 11 givenname: John L surname: Humm fullname: Humm, John L organization: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York – sequence: 12 givenname: Thomas surname: Reiner fullname: Reiner, Thomas email: reinert@mskcc.org organization: Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York |
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| SubjectTerms | Animals Apoptosis Brain Neoplasms - drug therapy Brain Neoplasms - pathology Brain Neoplasms - radiotherapy Cell Proliferation Female Glioblastoma - drug therapy Glioblastoma - pathology Glioblastoma - radiotherapy Humans Iodine Radioisotopes - therapeutic use Mice Mice, Nude Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors Poly(ADP-ribose) Polymerase Inhibitors - pharmacology Radiotherapy - methods Tumor Cells, Cultured Xenograft Model Antitumor Assays |
| Title | Targeted Brain Tumor Radiotherapy Using an Auger Emitter |
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