SBIR-STTR Award

The overall aim of this project is to evaluate the feasibility of novel bisphosphonate conjugates as treatment for prostate cancer metastasis and tumor-induced bone pain. Current treatments including bisphosphonates are mainly palliative. Disadvantages such as low bioavailability, little or no proven clinical impact as adjuvant therapy, and moderate reduction of skeletal complications raise numerous pharmacoeconomic issues in bisphosphonate treatment and necessitate the development of more efficacious analogs. Our proprietary drug designs employ vitamin B6- and, nucleotide-bisphosphonate conjugates to address these limitations and offer potential improvements in efficacy and side-effect profiles. Our prior in vivo results in mouse models of metastatic breast cancer showed decreased tumor burden and incidence of bone metastases upon treatment with MBC compounds. In addition, restoration of bone mineral density loss and increased survival in a mouse model of multiple myeloma was demonstrated. We have shown that MBC bisphosphonate compounds have unique and distinct effects on osteoblasts in vitro. In this proposed work, our proprietary chemistry will be used to develop novel conjugates that include third generation bisphophonate scaffolds. The antiproliferative properties of these compounds will be tested in prostate cancer derived and human osteoblast cell lines; and their effects on osteoblast cell mineralization will be assessed. The most potent conjugates will be tested through a range of dose levels in a rat model of prostatic tumor induced bone pain. Successful development of bisphosphontate conjugates for the treatment of prostate cancer induced skeletal complications would address the currently unmet medical needs of the >200,000 new cases of prostate cancer anticipated every year in the US. Our novel bisphosphonate conjugates may not only be used as a therapy for the treatment of bone metastatises and its related pain, but may prove to be an effective prophylactic that prevents the appearance of bone metastases and their related skeletal complications. Thus, the development of these therapeutics may not only improve the quality of life for prostate cancer patients but may also prolong their lives

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.

Thesaurus Terms:
(1-Hydroxy-3-(Methylpentylamino)Propylidene)Bisphosphonate;(8s-Cis)-10-[(3-Amino-2,3,6-Trideoxy-Alpha-L-Lyxo-Hexopyranosyl)Oxy]-7,8,9,10-Tetrahydro-6,8,11-Trihydroxy-8-(Hydroacetyl)-1-Methoxy-5,12-Naphthacenedione;1-(2-Oxo-4-Amino-1,2-Dihydropyrimidin-1-Yl)-2-Deoxy-2,2-Difluororibose;1-.Beta.-D-Arabinofuranosyl-4-Amino-2(1h)Pyrimidinone;1-Hydroxy-3-(Methylpentylamino)Propylidenebisphosphonate;1.Beta.-D-Arabinofuranosylcytosine;14-Hydroxydaunomycin;2',2'-Dfdc;2',2'-Difluoro-2'-Deoxycytidine;2',2'-Difluorodeoxycytidine;2'-Deoxy-2'-Difluorocytidine;2'deoxy-2',2'-Difluorocytidine;2,2 Difluorodexoycytidine;2-Chloro-2'-Arabino-Fluoro-2'-Deoxyadenosine;2-Chloro-2'-Fluoroarabino-2'-Deoxyadenosine;2-Chloro-9-(2-Deoxy-2-Fluoro-Beta-D-Arbinofuranosyl)Adenine;2-Chloro-9-(2-Deoxy-2-Fluoroarabinofuranosyl)Adenine;4-Amino-1-Beta-D-Ribofuranosyl-1,3,5-Triazin-2(1h)-One;5 Azc;5,12-Naphthacenedione, 10-((3-Amino-2,3,6-Trideoxy-Alpha-L-Lyxo-Hexopyranosyl)Oxy)-7,8,9,10-Tetrahydro-6,8,11-Trihydroxy-8-(Hydroxyacetyl)-1-Methoxy-, (8s-Cis)-;5-Ac;5-Aza-Cytidine;5-Azacytidine;Ara-Cell;Azc;Address;Adriamycine;Alexan;Anhydrides;Animal Model;Animal Models And Related Studies;Anti-Cancer Agents;Anti-Tumor Agents;Anti-Tumor Drugs;Antimetabolites;Antineoplastic Agents;Antineoplastic Drugs;Antineoplastics;Antiproliferative Agents;Antiproliferative Drugs;Anzatax;Arabine;Arabinofuranosylcytosine;Arabinosylcytosine;Aracytidine;Aracytin;Aracytine;Asotax;Azacitidine;Azacytidine;Bisphosphonates;Blood Plasma;Bone;Bone Diseases;Bone Metastasis;Bone Pain;Bone Tumor;Bone And Bones;Bone Cancer Metastatic;Bone Neoplasms;Bones And Bone Tissue;Bony Metastasis;Bristaxol;Cancer Drug;Cancer Model;Cancer Patient;Cancer Of Prostate;Cancermodel;Cancers;Canine Species;Canis Familiaris;Cell Isolation;Cell Segregation;Cell Separation;Cell Separation Technology;Cessation Of Life;Chemotherapeutic Agents, Neoplastic Disease;Cl-F-Ara-A;Clinical;Clofarabine;Cytarabine;Cytarabinum;Cytarbel;Cytosar;Cytosar-U;Cytosaru;Cytosine Arabinoside;Cytosine-.Beta.-Arabinoside;Dna;Dna Intercalating Agent;Dox;Death;Deoxyribonucleic Acid;Deterioration;Development;Difluorodeoxycytidine;Disease;Disease Model;Disorder;Dogs;Dose;Doxorubicin;Doxorubicina;Drug Delivery;Drug Delivery Systems;Drug Kinetics;Drug Targeting;Drug Targetings;Drugs;Drugs, Investigational;Erpalfa;Fracture, Pathologic;Fractures, Spontaneous;Gene Fusion;Generalized Growth;Generations;Goals;Growth;Hydroxyl Daunorubicin;Hydroxyldaunorubicin;Hypercalcemia;Ibandronate;Intercalating Agents;Intercalating Ligands;Intercalative Compounds;Intercalators;Investigational Drugs;Investigational New Drugs;Lead;Lesion;Libraries;Licensing;Link;Local Cancer;Localized Cancer;Localized Malignancy;Localized Malignant Neoplasm;Malignant Cell;Malignant Neoplasms;Malignant Tumor;Malignant Tumor Of The Prostate;Malignant Neoplasm Of Prostate;Malignant Prostatic Tumor;Mammals, Dogs;Mammals, Mice;Maximal Tolerated Dose;Maximally Tolerated Dose;Maximum Tolerated Dose;Measures;Medication;Metastasis;Metastasis To Bone;Metastasize;Metastatic Cancer To The Bone;Metastatic Neoplasm;Metastatic Neoplasm To The Bone;Metastatic Tumor;Metastatic Tumor To The Bone;Metastatic Malignant Neoplasm To Bone;Methods;Mice;Modeling;Murine;Mus;Ndc-Zoledronate;Neoplasm Metastasis;New Drug Approvals;Novartis Brand Of Zoledronic Acid;Osseous Neoplasm;Osseous Tumor;Osseous Metastasis;Paclitaxel;Paclitaxel (Taxol);Pain;Painful;Pathological Fracture;Patient Care;Patient Care Delivery;Pb Element;Pharmaceutic Preparations;Pharmaceutical Preparations;Pharmacodynamics;Pharmacokinetics;Phase;Phenotype;Phosphates;Plasma;Population;Praxel;Preparation;Procedures;Prostate Ca;Prostate Ca Therapy;Prostate Cancer;Prostate Cancer Therapy;Prostatic Cancer;Qol;Quality Of Life;R01 Mechanism;R01 Program;Rpg;Recruitment Activity;Research Grants;Research Project Grants;Research Projects;Research Projects, R-Series;Reticuloendothelial System, Serum, Plasma;Role;Sbir;Sbirs (R43/44);Safety;Sampling;Secondary Neoplasm;Secondary Tumor;Secondary Cancer Of Bone;Secondary Malignancy Of Bone;Secondary Malignant Neoplasm Of Bone;Serum, Plasma;Site;Skeletal Metastasis;Skeleton;Small Business Innovation Research;Small Business Innovation Research Grant;Source;Structure;Supporting Cell;Systemic Disease;Tarabine Pfs;Taxol;Taxol (Old Nsc);Taxol A;Taxol Konzentrat;Technology;Testing;Therapeutic;Therapeutic Agents;Time;Tissue Growth;Toxicology;Tumor Burden;Tumor Cell;Tumor Cell Migration;Tumor Load;Tumor-Specific Treatment Agents;Udicil;Work;Zoledronate;Zometa;Anti-Cancer Therapeutic;Anticancer Agent;Anticancer Drug;Anticancer Therapeutic;Base;Biphosphonate;Bisphosphonate;Bone;Bone Disorder;Bone Neoplasm Secondary;Cancer Cell;Cancer Metastasis;Canine;Cell Sorting;Chemotherapeutic Agent;Chemotherapy;Clinical Applicability;Clinical Application;Conventional Therapy;Cytotoxic;Dfdc;Dfdcyd;Design;Designing;Diphosphonate;Disease/Disorder;Disorder Model;Domestic Dog;Drug Candidate;Drug/Agent;Effective Therapy;Gemcitabine;Heavy Metal Pb;Heavy Metal Lead;Improved;In Vivo;Innovate;Innovation;Innovative;Inorganic Phosphate;Intervention Design;Ladakamycin;Malignancy;Model Organism;Mouse Model;Neoplasm/Cancer;Neoplastic Cell;Novel;Ontogeny;Pre-Clinical;Preclinical;Prevent;Preventing;Public Health Relevance;Recruit;Response;Site Targeted Delivery;Social Role;Standard Of Care;Success;Targeted Delivery;Therapy Design;Treatment Design;Tumor;Tumor Growth;Uptake