Novel Bone-Targeting Combination Therapy for Osteosarcoma Phase II

项目摘要/摘要： 该项目的总体目标是进一步开发新型吉西他滨-伊班磷酸钠结合物和/或AS 这是治疗骨肉瘤及其相关转移的综合疗法的一部分。共轭关系 由化学连接的抗癌抗代谢药吉西他滨和骨归巢双膦酸盐组成 伊班磷酸钠。这种新型结合物通过以下方式直接解决了传统骨肉瘤治疗的局限性 在骨骼损伤部位集中药物，在疗效和副作用方面提供潜在的改善 配置文件。这种靶向递送设计提供了有效浓度的化疗剂在骨中 同时保持较低的系统水平。在第1阶段中，我们已经演示了此共轭产品可提供与 多西他赛，可将吉西他滨的暴露剂量降低10倍，同时以类似的 水平。作为一个额外的好处，这种药物似乎可以增强骨骼，并可能逆转 与骨性恶性肿瘤相关的骨骼。该项目专门着眼于优化 吉西他滨-伊班磷酸钠结合物单独或联合多西紫杉醇治疗小鼠模型 骨肉瘤与游离吉西他滨联合多西他赛治疗的比较 犬自发性骨肉瘤的药物临床试验。 此二期项目的具体目标是评估新型骨靶向的组织分布和效果 联用和联合多西紫杉醇治疗局部肿瘤负荷、骨溶解和转移负荷 在原位骨肉瘤同基因小鼠模型和自发性犬骨肉瘤模型中。这个 该项目的成功完成将指导这一前景广阔的药物设计概念的进一步发展 并最终将产生显著改善癌症患者护理的治疗剂，从而导致 提高了生活质量和生存能力。

Project Summary/Abstract: The overall aim of this project is to further develop a novel gemcitabine-ibandronate conjugate alone and/or as part of a combination therapy for the treatment of osteosarcoma and associated metastases. The conjugate consists of chemically linked anticancer antimetabolite Gemcitabine and the bone-homing bisphosphonate Ibandronate. The novel conjugate directly addresses the limitations of conventional osteosarcoma therapies by concentrating drug at the site of bone lesions and offers potential improvements in efficacy and side-effect profiles. This targeted delivery design provides for an effective concentration of a chemotherapy agent in bone while maintaining low systemic levels. In Phase 1 we have demonstrated this conjugate offers synergies with Docetaxel and enables a 10-fold lower exposure to Gemcitabine while inhibiting cancer growth at a similar level. As an added benefit, the drug appears to strengthen the bones and may reverse the deterioration of bone associated with bony malignancies. This project looks specifically at optimizing the ability of the Gemcitabine-Ibandronate conjugate alone or in combination with Docetaxel to treat a mouse model of osteosarcoma as compared to treatment with free Gemcitabine in combination with Docetaxel and tests the drugs in spontaneous osteosarcoma in a canine clinical trial. The specific aims of this Phase II project assess the tissue distribution and effects of the novel bone targeting conjugate—alone and in combination with Docetaxel on local tumor burden, bone lysis and metastatic burden in an orthotopic osteosarcoma syngeneic murine model and spontaneous canine osteosarcoma. The successful completion of this project will guide the further development of this promising drug design concept and will ultimately result in therapeutic agents that will significantly improve cancer patient care, resulting in increased quality of life and survival.