Novel bisphosphonates for multiple myeloma therapy

DESCRIPTION (provided by applicant): The overall goal of this project is to further develop novel bisphosphonate conjugate MBC-11 as treatment for tumor-induced bone diseases such as those associated with multiple myeloma. MBC-11 is the anhydride formed be tween arabinocytidine (AraC)-5'-phosphate and etidronate and is the lead product of our proprietary technology which employs conjugates of known chemotherapeutic agents with bone targeting bisphosphonates to address the limitations of conventional therapie s for tumor-induced bone diseases. This targeted delivery design enables the concentration of a chemotherapy agent in bone while also maintaining low systemic levels. We hypothesize that such conjugates will have a wider therapeutic range than currently av ailable therapies. As an added benefit, the drugs also strengthen the bones and may reverse the deterioration of bone associated with cancer. Encouraging results from our Phase I in vivo proof-of-concept studies demonstrated that MBC-11 reversed the initia l bone loss and in contrast to zoledronate, significantly prolonged survival of affected mice. MBC-11 also sustained the compound induced gain in bone mineral density. Furthermore, the efficacy of the conjugate outperformed that of the mixture of the paren tal components, demonstrating the value of the conjugates ability to increase the concentration of the cytotoxic moiety in the bone tissue. The proposed studies will examine MBC-11 mechanism of action, characterize its pharmacokinetic/pharmacodynamic profi le to establish optimal dosing and validate its efficacy in GFP-based mouse model of multiple myeloma. The specific aims of this Phase II project are: (1) Identify the antiresorptive potency and duration of effect of MBC-11 in healthy rats. Determine if th e osteoclasts from post-dosed rats show reduced activity or numbers and if they are entering drug induced apoptosis; (2) Determine the pharmacokinetics and biodistribution profiles of MBC-11 in healthy rats; (3) Demonstrate efficacy in GFP-based mouse mode l of multiple myeloma. The successful completion of this Phase II project will guide the further development of this promising concept, greatly aid in obtaining investigational new drug approval, and lead to eventual clinical application. It is anticipated that this technology will ultimately result in therapeutic agents that will significantly improve cancer patient care resulting in increased quality of life and survival. Multiple myeloma is the second most common adult hematological malignancy, which acc ounts for approximately 1% of all cancer-related deaths in Western countries. One of the major clinical features is the development of a unique osteolytic bone disease, characterized by progressive and devastating bone destruction, bone pain, pathological fractures and hypercalcaemia. Therefore, a great need exists to develop drugs that can prevent or reduce the spread of cancer to bone. The long-term goal of this research project is to develop more effective therapies, designed to deliver anti-cancer drugs to bone while also providing a potent bone-protecting ingredient, for cancer-induced bone diseases, such as those associated with multiple myeloma.