Targeted Radionuclide Therapy: New Advances for Improvement of Patient Management and Response

Malcolm, Javian; Falzone, Nadia; Lee, Boon Quan; Vallis, Katherine A.

doi:10.3390/cancers11020268

Cited by 36 publications

(24 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The obtained data shows a steep drop in survival, which was expected due to the high-LET nature of Auger electrons. Comparison with EBIR allowed us to calculate the RBE, which corroborated the potential of Auger-emitting molecules for targeted radiotherapy, a fast-growing and promising field (41,42). This proved to be a significant improvement compared to a previously-published version of the molecule, 131 I-PARPi, where the RBE of the emitted electron is significantly lower.…”

Section: Discussionsupporting

confidence: 57%

Targeted Brain Tumor Radiotherapy Using an Auger Emitter

Pirovano

Jannetti

Carter

et al. 2020

Clinical Cancer Research

View full text Add to dashboard Cite

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. Experimental design 123 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. Results 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 123 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. In vitro and in vivo studies demonstrate high tumor uptake and a prolonged survival in mice treated with 123 I-MAPi when compared to vehicle controls. Different methods of drug delivery were investigated to develop this technology for clinical applications, including convection enhanced delivery (CED) and intrathecal injection. Conclusions Taken together, these results represent the first full characterization of an Augeremitting PARP inhibitor which demonstrate a survival benefit in mouse models of GBM and confirm the high potential of 123 I-MAPi for clinical translation.

show abstract

Section: Discussionsupporting

confidence: 57%

Targeted Brain Tumor Radiotherapy Using an Auger Emitter

Pirovano

Jannetti

Carter

et al. 2020

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…Several therapeutic agents that are currently under clinical trial are listed in Table 3. The clinical management of PCa is recently reviewed and updated in recent publications [194,195,196,197]. Several NEPC molecules that are thought to drive NEPC progression have been reported to date, and are being used in clinical trials for the better management of advanced PCa.…”

Section: Potential Therapeutic Strategies For Nepcmentioning

confidence: 99%

Neuroendocrine Differentiation of Prostate Cancer—An Intriguing Example of Tumor Evolution at Play

Patel

Chugh

Tripathi

2019

Cancers

View full text Add to dashboard Cite

Our understanding of neuroendocrine prostate cancer (NEPC) has assumed a new perspective in light of the recent advances in research. Although classical NEPC is rarely seen in the clinic, focal neuroendocrine trans-differentiation of prostate adenocarcinoma occurs in about 30% of advanced prostate cancer (PCa) cases, and represents a therapeutic challenge. Even though our knowledge of the mechanisms that mediate neuroendocrine differentiation (NED) is still evolving, the role of androgen deprivation therapy (ADT) as a key driver of this phenomenon is increasingly becoming evident. In this review, we discuss the molecular, cellular, and therapeutic mediators of NED, and emphasize the role of the tumor microenvironment (TME) in orchestrating the phenotype. Understanding the role of the TME in mediating NED could provide us with valuable insights into the plasticity associated with the phenotype, and reveal potential therapeutic targets against this aggressive form of PCa.

show abstract

“…Targeted radionuclide therapy (TRT) uses cancer-targeting molecules to shuttle cytotoxic radiation to the tumor. TRT is an excellent therapeutic option for inoperable or disseminated disease (Pouget et al 2015;Aghevlian et al 2017;Gill et al 2017;Malcolm et al 2019), however, curative potential can vary between and within patients. As such, novel approaches can improve the potential of this therapeutic strategy and reduce side effect toxicity.…”

Section: Introductionmentioning

confidence: 99%

Improved radiosynthesis of ¹²³I-MAPi, an auger theranostic agent

Wilson

Jannetti

Guru

et al. 2020

International Journal of Radiation Biology

View full text Add to dashboard Cite

Purpose: 123 I-MAPi, a novel PARP1-targeted Auger radiotherapeutic has shown promising results in pre-clinical glioma model. Currently, 123 I-MAPi is synthesized using multistep synthesis that results in modest yields and low molar activities (MA) that limits the ability to translate this technology for human studies where high doses are administered. Therefore, new methods are needed to synthesize 123 I-MAPi in high activity yields (AY) and improved MA to facilitate clinical translation and multicenter trials. Materials and methods: 123 I-MAPi was prepared in a single step via 123 I-iododetannylation of the corresponding tributylstannane precursor. In vitro internalization assay, subcellular fractionation and confocal microscopy where used to evaluate the performance of 123 I-MAPi in a small cell lung cancer model. Results: 123 I-MAPi was synthesized in a single step from the corresponding stannane precursor in AY of 45 ± 2% and MA of 11.8 ± 4.8 GBq mmol À1. In vitro in LX22 cells showed rapid internalization (5 min) with accumulation found predominantly in the membrane, nucleus and chromatin of the cell as determined by subcellular fractionation. Conclusions: Here, we have developed an improved radiosynthesis of 123 I-MAPi, an Auger theranostic agent. This process was achieved using a single step, 123 I-iododestannylation reaction from the corresponding stannane precursor in good AY and MA. 123 I-MAPi was evaluated in vitro in a small cell lung cancer model with high PARP expression, rapid internalization and high nuclear uptake shown.

show abstract

Targeted Radionuclide Therapy: New Advances for Improvement of Patient Management and Response

Cited by 36 publications

References 69 publications

Targeted Brain Tumor Radiotherapy Using an Auger Emitter

Targeted Brain Tumor Radiotherapy Using an Auger Emitter

Neuroendocrine Differentiation of Prostate Cancer—An Intriguing Example of Tumor Evolution at Play

Improved radiosynthesis of ¹²³I-MAPi, an auger theranostic agent

Contact Info

Product

Resources

About

Targeted Radionuclide Therapy: New Advances for Improvement of Patient Management and Response

Cited by 36 publications

References 69 publications

Targeted Brain Tumor Radiotherapy Using an Auger Emitter

Targeted Brain Tumor Radiotherapy Using an Auger Emitter

Neuroendocrine Differentiation of Prostate Cancer—An Intriguing Example of Tumor Evolution at Play

Improved radiosynthesis of 123I-MAPi, an auger theranostic agent

Contact Info

Product

Resources

About

Improved radiosynthesis of ¹²³I-MAPi, an auger theranostic agent