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Novel bisphosphonates for prostate cancer therapy

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 2R44CA121482-02
Agency Tracking Number: CA121482
Amount: $1,795,050.00
Phase: Phase II
Program: SBIR
Solicitation Topic Code: NCI
Solicitation Number: PHS2010-2
Timeline
Solicitation Year: 2010
Award Year: 2010
Award Start Date (Proposal Award Date): N/A
Award End Date (Contract End Date): N/A
Small Business Information
12635 E Montview Blvd Suite 100
Aurora, CO -
United States
DUNS: 074696415
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 ALEXANDER KARPEISKY
 (720) 859-4041
 ALKARP@MBCPHARMA.COM
Business Contact
Phone: (720) 859-4041
Email: alkarp@mbcpharma.com
Research Institution
N/A
Abstract

DESCRIPTION (provided by applicant): The goal of this project is to further develop novel bisphosphonate conjugate MBC-11 and other novel compounds as treatment for prostate cancer (PC) and PC-induced bone disease. MBC-11 is the anhydride formed between arabinocytidine (AraC)-59-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. We further hypothesis that this approach may use the skeleton as a drug depot from which drug release may provide systemic benefit. Encouraging results from our Phase I in vivo proof-of-concept studies demonstrated that MBC-11 preserves bone structure comparably or better than the standard of care zoledronate, and significantly reduced pain. The proposed studies will examine the effects of MBC-11 and a library of bone-targeted chemotherapic compounds in models of PC and PC-induced bone disease. The most promising compounds will be further investigated for dose response in treatment and preventative settings, mechanism of action (direct uptake into cancer cells) and be characterized in a number of pharmacokinetic/pharmacodynamic parameters. Recent evidence suggesting unique sensitivity to cytarabine for PC carrying ETS gene fusions warrants the testing of MBC-11 in this large subpopulation of prostate cancers. The specific aims of this Phase II project are: (1) To develop synthetic procedures for the preparation of novel bisphosphonate-chemotherapeutic conjugates and to synthesize sufficient amounts of required compounds for the proposed studies. (2) Screen the novel compounds for tumor burden reduction in NOD/SCID-hu-HAB models of prostate cancer induced bone disease (CIBD), assess dose response on select lead compounds in treatment and preventative forms of the CIBD models and assess the ability of novel leads to use the skeleton as a depot to address primary and non-osseous metastases in PC models. (3) Measure critical toxicology and pharmacokinetic (PK) parameters using the lead compound. 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. PUBLIC HEALTH RELEVANCE: Prostate cancer results in 30,000 deaths annually in the US; 85% die with metastatic bone cancer. One of the major clinical features is the development of cancer induced bone disease, characterized by progressive and devastating bone destruction, bone pain, pathological fractures and hypercalcemia. 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.

* Information listed above is at the time of submission. *

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