The overall aim of this project is to evaluate the feasibility of using 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. As such, we hypothesize that this conjugate will have a wider therapeutic range and offer the potential for synergies with other drugs as compared to currently available therapies. As an added benefit, the drug is anticipated to strengthen the bones and may reverse the deterioration of bone associated with bony malignancies. This project looks specifically at the ability of the Gemcitabine-Ibandronate conjugate alone or in combination with Docetaxel to demonstrate improved benefits in treating a mouse model of osteosarcoma as compared to treatment with free Gemcitabine in combination with Docetaxel. The specific aims of this Phase I project is to assess the 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. 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.
Public Health Relevance Statement: Public Health Relevance: Osteosarcoma, the most common malignant bone tumor is highly metastatic; great need exists to develop drugs for patients who present with metastatic disease or develop recurrent disease that leads to very poor prognoses. The long-term goal of this research project is to further develop a promising drug specifically designed to deliver an anti-cancer drug to bone, while synergizing with standard of use drugs to improve patient outcomes such as survival and quality of life, and reduce the numbers of amputations.
Project Terms: Address; Adolescent and Young Adult; Adverse effects; Amputation; Antimetabolites; Antineoplastic Agents; base; bisphosphonate; bone; Bone Diseases; Bone Surface; Cancer Patient; Canis familiaris; Carcinoma; Central Osteosarcoma; chemotherapy; Child; Childhood; Clinical; Clinical Research; Combined Modality Therapy; Cytarabine; Cytolysis; Data; design; Deterioration; Development; Diagnosis; Disease; docetaxel; Dose; Doxorubicin; Drug Combinations; Drug Design; Drug Targeting; Drug toxicity; Drug usage; Evaluation Studies; experience; Future; gemcitabine; Generations; Goals; Homing; Human; Ibandronate; Image; improved; in vivo; Individual; innovation; Investigation; Investments; Lead; Lesion; Link; Malignant Bone Neoplasm; malignant breast neoplasm; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant Neoplasms; Modality; mouse model; Neoplasm Metastasis; novel; novel therapeutics; Nucleosides; osteosarcoma; outcome forecast; Pancreas; Patient Care; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase; Platinum; Population; pre-clinical; public health relevance; Quality of life; Recurrence; Recurrent disease; Refractory; Regimen; Reporting; Research Project Grants; research study; Rodent Model; sarcoma; Site; Solid Neoplasm; standard of care; success; Sum; systemic toxicity; targeted delivery; Testing; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Tumor Burden; Xenograft procedure
