Progress in Targeted Alpha-Particle-Emitting Radiopharmaceuticals as Treatments for Prostate Cancer Patients with Bone Metastases.

Chirayu M Patel,Yusuke Shiozawa,Thaddeus J Wadas

doi:10.3390/molecules26082162

Chirayu M Patel, Yusuke Shiozawa + Show 1 more

Open Access

https://doi.org/10.3390/molecules26082162

Copy DOI

Abstract

Bone metastasis remains a major cause of death in cancer patients, and current therapies for bone metastatic disease are mainly palliative. Bone metastases arise after cancer cells have colonized the bone and co-opted the normal bone remodeling process. In addition to bone-targeted therapies (e.g., bisphosphonate and denosumab), hormone therapy, chemotherapy, external beam radiation therapy, and surgical intervention, attempts have been made to use systemic radiotherapy as a means of delivering cytocidal radiation to every bone metastatic lesion. Initially, several bone-seeking beta-minus-particle-emitting radiopharmaceuticals were incorporated into the treatment for bone metastases, but they failed to extend the overall survival in patients. However, recent clinical trials indicate that radium-223 dichloride (223RaCl2), an alpha-particle-emitting radiopharmaceutical, improves the overall survival of prostate cancer patients with bone metastases. This success has renewed interest in targeted alpha-particle therapy development for visceral and bone metastasis. This review will discuss (i) the biology of bone metastasis, especially focusing on the vicious cycle of bone metastasis, (ii) how bone remodeling has been exploited to administer systemic radiotherapies, and (iii) targeted radiotherapy development and progress in the development of targeted alpha-particle therapy for the treatment of prostate cancer bone metastasis.

Highlights

As a result of improvements in cancer research, prevention, early diagnosis, and treatment, the survival time of cancer patients with localized disease has increased
external beam radiation therapy (EBRT), bisphosphonate, and denosumab can reduce the onset of the painful complications of bone metastasis [17,18,66,67,68,69,70,71], delivering EBRT to every bone metastatic lesion is not practical and bisphosphonate and denosumab fail to improve the overall survival of bone metastatic patients
Bone metastasis creates enormous physical, emotional, and financial burdens for cancer patients and society; it is a significant contributor to cancer mortality rates

Summary

Introduction

As a result of improvements in cancer research, prevention, early diagnosis, and treatment, the survival time of cancer patients with localized disease has increased. Bisphosphonate and denosumab, a human monoclonal anti-receptor activator of nuclear factor κB ligand (RANKL) antibody, which decreases osteoclastic activity, have been used as treatments for bone metastases [17,18] These treatments have been effective in reducing the painful complications of bone metastases but fail to improve the overall survival of cancer patients with bone metastases [17,18]. Recent clinical trials indicate that an alpha-particle-emitting radiopharmaceutical radium-223 dichloride (223RaCl2), which targets hydroxyapatite or osteoblastic bone metastatic lesions, improves the overall survival of prostate cancer patients with bone metastases. While many excellent reviews relating to targeted radiotherapy have been published [22,33,34,35], this review will highlight (i) the biology of bone metastases by emphasizing the vicious cycle of bone metastasis, (ii) the treatment strategies for bone metastasis by mainly focusing on radiopharmaceuticals, and (iii) the future directions for targeted alpha-particle-emitting radiopharmaceutical treatment strategies in bone metastasis

The Biology of the Vicious Cycle of Bone Metastases

Treatment of Bone Metastases

Radiopharmaceuticals for Bone Metastases

Targeted Radiopharmaceuticals for Bone Metastases

Findings

Conclusions