Targeted Alpha Therapy: Current Clinical Applications

Abstract

a-Emitting radionuclides have been approved for cancer treatment since 2013, with increasing degrees of success. Despite this clinical utility, little is known regarding the mechanisms of action of a particles in this setting, and accurate assessments of the dosimetry underpinning their effectiveness are lacking. However, targeted alpha therapy (TAT) is gaining more attention as new targets, synthetic chemistry approaches, and a particle emitters are identified, constructed, developed, and realized. From a radiobiological perspective, a particles are more effective at killing cells compared to low linear energy transfer radiation. Also, from these direct effects, it is now evident from preclinical and clinical data that a emitters are capable of both producing effects in nonirradiated bystander cells and stimulating the immune system, extending the biological effects of TAT beyond the range of a particles. The short range of a particles makes them a potent tool to irradiate singlecell lesions or treat solid tumors by minimizing unwanted irradiation of normal tissue surrounding the cancer cells, assuming a high specificity of the radiopharmaceutical and good stability of its chemical bonds. Clinical approval of 223 RaCl 2 in 2013 was a major milestone in the widespread application of TAT as a safe and effective strategy for cancer treatment. In addition, 225 Ac-prostate specific membrane antigen treatment benefit in metastatic castrate-resistant prostate cancer patients, refractory to standard therapies, is another gamechanging piece in the short history of TAT clinical application. Clinical applications of TAT are growing with different radionuclides and combination therapies, and in different clinical settings. Despite the remarkable advances in TAT dosimetry and imaging, it has not yet been used to its full potential. Labeled 227 Th and 225 Ac appear to be promising candidates and could represent the next generation of agents able to extend patient survival in several clinical scenarios.

Low REST Expression Indicates a Biomarker of Poor Prognosis in Patients with Renal Cell Carcinoma

“…Although the significant progress had been made in diagnosis and treatment, the patient's prognosis is still worse. In recent years, with the further research in tumor molecular biology, targeted therapy has become a new diagnosis and treatment strategy in current clinical applications [8]. Therefore, the search for new molecular targets is extremely important for the clinical diagnosis, treatment, and prognostic monitoring of KIRC.…”

Preclinical and Clinical Status of PSMA-Targeted Alpha Therapy for Metastatic Castration-Resistant Prostate Cancer

“…The long half-life of 227 Th allows transportation and preparation of the radiopharmaceutical. Due to its chemical properties, 227 Th can be linked to a variety of antibodies and proteins [72,180]. Th-227 complexed with octadentate 3,2-hydroxypyridinone (3,2-HOPO) chelators that are conjugated to antibodies or other targeting moieties results in highly stable targeted 227 Th conjugates (TTCs) [104].…”

“…The detailed mechanisms of action of PSMA-TAT are far from fully understood [72]. Elucidating in vitro and in vivo molecular and cellular mechanisms related to targeted and bystander effects of PSMA-TAT are important.…”

“…Overview of α-emitting radionuclides used in PSMA-TAT[71][72][73][74][75]. Comparisons of prostate-specific membrane antigen (PSMA)-targeting small molecules, antibodies, and their fragments[55,[76][77][78][79][80].…”

Role of miRNAs in regulating responses to radiotherapy in human breast cancer

“…The common side effects of radiotherapy include local skin problems and cardiotoxicity . Recently, a newer form of radiation-based targeted therapy known as targeted alpha therapy (TAT) is gaining growing attention due to its potential to minimize radiation-associated toxicities to the normal cells surrounding target tumors (Guerra Liberal et al 2020). By linking a-emitting radionuclide to a specific molecule such as monoclonal antibody, TAT may deliver high-dose radiation specifically to targeted cancer cells (Guerra Liberal et al 2020).…”