SBIR-STTR Award

Bisphosphonates are currently used as bone-specific palliative treatments for the tumor-induced bone diseases observed in breast cancer and multiple myeloma patients. However, bisphosphonate use has no proven impact on primary tumor burden and overall survival and only moderately reduces skeletal complications. Bisphosphonate conjugates were synthesized using proprietary technology that employs a unique chemical bridge between anti-cancer (nucleotide analogs) or vitamin B( moieties and a bisphosphonate backbone. The nucleotide-bisphosphonate conjugates were designed to deliver anti-cancer agents and bone-protecting bisphosphonates specifically to bone. The vitamin B6 conjugates were designed to increase the cellular uptake of bisphosphonates. Results from preliminary in vitro studies demonstrated increased anti-tumor efficacy of select conjugates compared to the anti-cancer or bisphosphonate compounds alone. The overall aim of this project is to further develop bisphosphonate conjugate technology and to determine the effects of these compounds on bone loss, tumor burden, and survival in an established animal model of multiple myeloma. Successful development of this new drug-design concept would provide a biologically and commercially superior approach for the treatment and prevention of skeletal-related complications of malignancy.

Thesaurus Terms:
antineoplastic, chemical conjugate, diphosphonate, drug design /synthesis /production, multiple myeloma, neoplasm /cancer chemotherapy, nucleotide bone density, chemical synthesis, disease /disorder model, drug screening /evaluation, metastasis, nonhuman therapy evaluation, pathologic bone resorption, tumor progression SCID mouse, high performance liquid chromatography

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 between 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 therapies 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 available 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 initial 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 parental 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 profile 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 the 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 model 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 accounts 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.

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