Thora J. Jonasdottir

Radium-223: From Radiochemical Development to Clinical Applications in Targeted Cancer Therapy

The radiobiological and radiochemical properties of radium-223 (223Ra, T1/2 = 11.4 d) render this alpha-emitting radionuclide promising for targeted cancer therapy. Together with its short-lived daughters, each 223Ra decay produces four alpha-particle emissions which enhance therapy effectiveness at the cellular level. In this paper, we review the recently published data reported for pre-clinical and clinical use of 223Ra in cancer treatment. We have evaluated two distinct chemical forms of 223Ra in vivo: 1) cationic 223Ra as dissolved RaCl2, and 2) liposome-encapsulated 223Ra. Cationic 223Ra seeks metabolically active osteoblastic bone and tumor lesions with high uptake and strong binding affinity based on its similarities to calcium. Based on these properties, we have advanced the clinical use of 223Ra for treating bone metastases from breast and prostate cancer. The results show impressive anti-tumor activity and improved overall survival in hormone-refractory prostate cancer patients with bone metastases. In other studies, we have evaluated the biodistribution and tumor uptake of liposomally encapsulated 223Ra in mice with human osteosarcoma xenografts, and in dogs with spontaneous osteosarcoma and associated soft tissue metastases. Results indicate excellent biodistributions in both species. In dogs, we found considerable uptake of liposomal 223Ra in cancer metastases in multiple organs, resulting in favorable tumor- to-normal soft tissue ratios. Collectively, these findings show an outstanding potential for 223Ra as a therapeutic agent.

Age-period-cohort analysis of primary bone cancer incidence rates in the United States (1976-2005).

Background: Primary bone cancer comprises three major histologic types: osteosarcoma (OS), Ewing sarcoma (ES), and chondrosarcoma (CS). Given the limited knowledge about the etiology of primary bone cancer, we undertook an age-period-cohort (APC) analysis to determine whether incidence varied by birth cohort or calendar period. The purpose was to examine the temporal development of each bone cancer type and generate etiologic hypotheses via the observed birth cohort-related changes. Methods: An APC model was fitted to incidence data for U.S. whites for OS, ES, and CS obtained from nine registries of the Surveillance, Epidemiology, and End Results program, which covers about 10% of the U.S. population, 1976–2005. Results: The incidence of OS decreased between 1976 and 2005 among those aged over 60 years, a decline that occurred among patients with OS as their primary malignancy only. From 1986–1995 to 1996–2005, the incidence rate of CS among females of 20 to 69 years rose by about 50%, with rates increasing among consecutive cohorts born during 1935–1975. CS rates among males were stable, as were rates of ES. Conclusion: The risk reduction in OS as a primary malignancy at older ages could possibly be related to diminished exposure over time to bone-seeking radionuclides. The CS increase among females corresponds to birth cohorts with rising exposures to oral contraceptives and menopausal hormonal therapy. Impact: As the estrogen signaling pathway has been shown to stimulate proliferation of normal and malignant chondrocytes, estrogen exposure may increase the risk for CS. Further studies are warranted to clarify its possible etiological significance. Cancer Epidemiol Biomarkers Prev; 20(8); 1770–7. ©2011 AACR.

Evaluation of CD146 as Target for Radioimmunotherapy against Osteosarcoma

Background Osteosarcoma is a rare form of cancer but with a substantial need for new active drugs. There is a particular need for targeted therapies to combat metastatic disease. One possible approach is to use an antibody drug conjugate or an antibody radionuclide conjugate to target the osteosarcoma metastases and circulating tumor cells. Herein we have evaluated a radiolabeled monoclonal antibody targeting CD146 both in vitro and in vivo. Methods and Results A murine monoclonal anti-CD146 IgG1 isotype antibody, named OI-3, was developed along with recombinant chimeric versions with human IgG1 or human IgG3 Fc sequences. Using flow cytometry, selective binding of OI-3 to human osteosarcoma cell lines OHS, KPDX and Saos-2 was confirmed. The results confirm a higher expression level of CD146 on human osteosarcoma cells than HER2 and EGFR; antigens targeted by commercially available therapeutic antibodies. The biodistribution of 125I-labeled OI-3 antibody variants was compared with 125I-labeled chimeric anti-EGFR antibody cetuximab in nude mice with subcutaneous OHS osteosarcoma xenografts. OI-3 was able to target CD146 expressing tumors in vivo and showed improved tumor to tissue targeting ratios compared with cetuximab. Subsequently, the three OI-3 variants were conjugated with p-SCN-Bn-DOTA and labeled with a more therapeutically relevant radionuclide, 177Lu, and their biodistributions were studied in the nude mouse model. The 177Lu-labeled OI-3 variants were stable and had therapeutically relevant biodistribution profiles. Dosimetry estimates showed higher absorbed radiation dose to tumor than all other tissues after administration of the chimeric IgG1 OI-3 variant. Conclusion Our results indicate that CD146 can be targeted in vivo by the radiolabeled OI-3 antibodies.

Abstract 1822: Age-period-cohort (APC) analysis of primary bone cancer incidence rates in the United States (1976 – 2005)

BACKGROUND: Primary bone cancer comprises three major histological subtypes: osteosarcoma (OS), Ewing sarcoma (ES) and chondrosarcoma (CS). The most frequent subtype, OS, primarily occurs in adolescence, but has a second peak at the oldest ages, usually attributed to late effects of radiotherapy and chemotherapy, and Paget9s disease. The adolescent age distribution of ES resembles that of OS, suggesting a link between the onset of puberty and these subtypes of bone cancer. CS is rare in childhood, and incidence rates, unlike those of OS and ES, increase fairly uniformly with age. Given the limited knowledge about the etiology of primary bone cancer, and the unusual age-incidence distribution for OS and ES, we undertook an APC analysis to determine whether incidence varied by birth cohort or calendar period. For other cancers, such as testis and breast, the identification of cohort patterns has generated new hypotheses regarding environmental risk factors. METHODS: We fit an APC model to incidence data among U.S. whites for OS, ES and CS obtained from nine registries of the Surveillance, Epidemiology, and End Results (SEER) program, which covers about 10% of the U.S. population, 1976-2005. The purpose was to examine the temporal development of each bone cancer subtype, with an aim to providing etiologic clues as to the role of birth cohort-related changes. RESULTS: Incidence of OS decreased between 1976 and 2005 among those 60 years and older, and rates declined among cohorts born 1905-34. The risk of CS doubled among females 20-69 years, with rates increasing among consecutive birth cohorts born 1925-54, whereas those of males were unaltered. For both sexes, ES incidence rates tended to be stable. CONCLUSIONS: The risk reduction in OS at older ages was most likely due to improved radiotherapy and more effective chemotherapy. The CS risk increase in females corresponds to birth cohorts who were increasingly exposed to estrogens, both in terms of contraceptives (from 1960 onwards), and hormone replacement therapy (from 1950 onwards). In support of our hypothesis that estrogens are involved in the increase in CS among women over time, in vitro studies show that the estrogen signaling pathway stimulates proliferation of both normal and malignant chondrocytes. Further studies are warranted to pursue the possible etiological significance of estrogen exposure in CS risk. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1822.