Primary bone cancers and bone metastases derived from advanced cancers have low survival rates. To answer medical need to treat tumors localized in bone environment, we have developed bone-targeted drugs through covalent binding to hydroxybisphosphonates known for their high affinity to bone. Objectives were improvement of efficacy and reduction of systemic toxicity.
Preclinical proof of concept of lead compound 12b80, an HBP-bound doxorubicin, was carried out on rodents and dogs. 12b80 was administered by IV injection every 3 weeks. Antitumor effects were investigated on various rodent models of bone cancer (orthotopic xenograft models of osteosarcoma or Ewing’s sarcoma, models of osteosarcoma-derived lung metastases and models of bone invasion by prostate or mammary adenocarcinoma) and on spontaneous osteosarcoma bearing dogs. Biodistribution was examined by radiolabeling and fluorescence analyses. Toxicity was evaluated by biological and clinical monitoring and histopathological analysis of organs.
12b80 displayed rapid and sustained targeting of bone tissue and tumor-associated heterotopic bone, and permitted a higher doxorubicin payload in tumor bone environment. Doxorubicin release from 12b80 was dependent on acidic pH associated with active bone tumor environment. 12b80 showed a much lower and reversible toxicity compared with doxorubicin: mild medullar toxicity was recovered within two weeks and no sign of cardiotoxicity or osteonecrosis were observed in rodents and dogs. 12b80 promoted strong antitumor effects on rodent primary bone sarcoma (orthotopic osteosarcoma and Ewing sarcoma), osteosarcoma-derived lung metastasis and on prostate or breast adenocarcinoma bone invasion. 12b80 displayed a dose-response therapeutic effect and was more potent than combination of doxorubicin and zoledronate. First cases of tumor response were also reported in dogs currently under veterinary trial.
HBP-bound doxorubicin 12b80 demonstrated a proof of concept of preclinical bone-targeted doxorubicin delivery. The next step is to complete regulatory phase before starting 12b80 clinical trial (phase I/IIa) as an orphan drug in osteosarcoma salvage therapy.
Clinical trial identification
Legal entity responsible for the study
E. David, S. Cagnol, J-Y. Goujon, M. Egorov, R. Le Bot: Employment: Atlanthera.