Editorial: Targeted alpha particle therapy in oncology

COPYRIGHT © 2023 Bruland, Larsen, Baum and Juzeniene. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Editorial: Targeted alpha particle therapy in oncology


actinium-
, astatine-, lead-, radium-, radium-, thorium-, targeted alpha therapy (TAT), targeted radionuclide therapy (TRT) Editorial on the Research Topic Targeted alpha particle therapy in oncology Targeted radionuclide therapy (TRT), also known as molecular radiotherapy, targeted radiotherapy, or radiotheranostics, is a rapidly developing area with important recent breakthroughs (1)(2)(3). It aims to treat disseminated cancer, the main clinical challenge in oncology (4,5). TRT is based on personalized patient selection using molecular imaging to verify the presence of a biologic target either on the cancer cell surface or in vascular and/or stromal elements of metastases. The only approved alpha-emitting radiopharmaceutical is Xofigo ( 223 RaCl 2 , approved in 2013). The recent approval of beta-emitting 177 Lu-PSMA-617 (Pluctivo, approved in 2022) for the treatment of metastatic castration-resistant prostate cancer (mCRPC) expressing prostate-specific membrane antigen (PSMA), and of 177 Lu-DOTATATE (Lutathera, approved by EMA in 2018) for therapy of somatostatin receptor positive neuroendocrine tumors (NETs) will clearly shift TRT into the mainstream of cancer treatment. Nevertheless, some patients either do not respond, or, following initially good response, develop resistance to 177 Lu-based therapies, in spite of sufficient expression of target proteins on cancer cell surfaces (6,7). Many preclinical and clinical trials have demonstrated that alpha-particle-emitting radiopharmaceuticals, due to their physical properties, high linear energy transfer, and short range in tissue relative to beta-emissions, are emerging as a promising approach for cancer treatment (8)(9)(10)(11); they can also directly kill hypoxic or radio-and chemo-resistant cancer cells.
The goal of this Research Topic is to describe the development of novel alpha-emitting radiopharmaceuticals for different cancers, recent preclinical, completed, and ongoing clinical trials of targeted alpha-particle therapy (TAT) alone or in combination, dosimetry, safety, challenges related to supply and availability of suitable alpha-emitting radionuclides, as well as some future perspectives. This Research Topic includes 16 articles focusing on original research (four articles), reviews on different aspects of TAT (9 articles), ongoing clinical trials (one article), study protocols (one article), and hypotheses and theories (one article). Key opinion leaders, medical doctors, and scientists from Australia, Belgium, France, Germany, Poland, Norway, Singapore, Sweden, Switzerland, the United Kingdom, and the United States have contributed to this Research Topic. Bone-seeking 223 RaCl 2 is approved for patients with mCRPC and dominant osteoblastic skeletal metastases. Attempts to complex 223 Ra to cancer cell-targeting moieties have been unsuccessful. Some researchers and medical doctors speculate that 223 RaCl 2 will be less used after the approval of cancer cell- In TAT, radionuclides are delivered to cancer cells through a wide variety of formulations such as radiolabeled antibodies, peptides, or small molecules. A recent strategy incorporates 224 Ra into CaCO 3 microparticles (Radspherin R ), designed as a treatment of the remaining peritoneal micrometastasis in ovarian and colorectal cancer after complete cytroreductive surgery, as a means to decrease 224 Ra and its daughters' redistribution from the peritoneal cavity (12). The goal of the product is to generate an alpha particle radiation field on the surfaces and liquid volumes of the peritoneal cavity.  Kunikowska et al. provide an overview of strategies for the local treatment of primary and secondary glioblastomas using 213 Bi, 225 Ac, and 211 At. Antibodies targeting the extracellular matrix protein tenascin and substance P targeting the neurokinin type-1 receptor overexpressed in glioblastomas were discussed as targeting moieties for TAT.
It is crucial to select novel target molecules that are expressed in various types of cancers, and preferentially develop radiopharmaceuticals both for imaging and therapy, allowing a theranostic approach. However, not all targets are suitable for TAT; some are useful only for imaging. The biological effect of TAT depends on the absorbed dose, which is related to the "area under the curve"; the biological half-life at tumor sites and normal tissues, matched with the physical half-life of the given alpha emitter. Additionally, dosimetry calculations of TAT are challenging, since alpha particles have short ranges (<100 µm) that may provide heterogeneous irradiation and their daughters may have different pharmacokinetic profiles and chemical properties.
TAT is one of the most rapidly growing fields in the management of different types of cancer, and many radiopharmaceuticals are already in clinical trials. Commercial and business aspects of alpha radioligands have been discussed by Ostuni and Taylor.
We hope that this Research Topic on TAT will stimulate more research and clinical trials in this field.

Author contributions
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

Funding
This research was funded by the South-Eastern Norway Regional Health Authority (project number 2020028, Oslo, Norway).

Conflict of interest
ØB and RL hold ownership interest in Oncoinvent AS and ArtBio AS . RL is the owner of company Sciencons AS.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.