Novel bisphosphonates for prostate cancer therapy

用于前列腺癌治疗的新型双磷酸盐

• 批准号: 8742050
• 负责人: Alexander Karpeisky
• 金额: $ 7.79万
• 依托单位: MBC PHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-07 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8742050
• 关键词: Address; Anhydrides; Animal Model; Antimetabolites; Antineoplastic Agents; Azacitidine; Bone Diseases; Bone Pain; Cancer Patient; Canis familiaris; Cell Separation; Cessation of life; Clinical; Clofarabine; Cytarabine; DNA; Deterioration; Development; Disease; Disease model; Dose; Doxorubicin; Drug Kinetics; Drug Targeting; Gene Fusion; Generations; Goals; Growth; Hypercalcemia; Ibandronate; Intercalating Agents; Investigational Drugs; Lead; Lesion; Libraries; Licensing; Link; Localized Malignant Neoplasm; Malignant Neoplasms; Malignant neoplasm of prostate; Maximum Tolerated Dose; Measures; Metastatic Neoplasm to the Bone; Methods; Mus; Neoplasm Metastasis; New Drug Approvals; Paclitaxel; Pain; Pathological fracture; Patient Care; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phenotype; Plasma; Population; Preparation; Procedures; Prostate Cancer therapy; Quality of life; Recruitment Activity; Research Project Grants; Role; Safety; Sampling; Site; Skeleton; Small Business Innovation Research Grant; Source; Structure; Supporting Cell; Systemic disease; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Toxicology; Tumor Burden; Work; Zoledronate; anti-cancer therapeutic; base; bisphosphonate; bone; cancer cell; chemotherapeutic agent; chemotherapy; clinical application; conventional therapy; cytotoxic; design; drug candidate; effective therapy; gemcitabine; improved; in vivo; innovation; inorganic phosphate; mouse model; neoplastic cell; novel; pre-clinical; prevent; prostate cancer model; response; standard of care; success; targeted delivery; therapy design; tumor; tumor growth; uptake

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.

描述（由申请人提供）：本项目的目标是进一步开发新型双膦酸盐缀合物MBC-11和其他新型化合物，用于治疗前列腺癌（PC）和PC诱导的骨病。MBC-11是阿拉伯胞苷（AraC）-59-磷酸和依替膦酸盐之间形成的酸酐，是我们专有技术的主要产品，该技术采用已知化疗剂与骨靶向双膦酸盐的缀合物，以解决肿瘤诱导的骨疾病的常规疗法的局限性。这种靶向递送设计使得化疗剂能够在骨中浓缩，同时还保持低的全身水平。我们假设，这种共轭物将有一个更广泛的治疗范围比目前可用的疗法。作为一个额外的好处，这些药物还可以增强骨骼，并可能逆转与癌症相关的骨骼退化。我们进一步假设，这种方法可以使用骨骼作为药物仓库，药物释放可以提供全身益处。我们的I期体内概念验证研究的令人鼓舞的结果表明，MBC-11比标准的唑来膦酸盐更好地保留了骨结构，并显着减轻了疼痛。拟议的研究将检查MBC-11和骨靶向化疗化合物库在PC和PC诱导的骨病模型中的作用。将进一步研究最有前途的化合物在治疗和预防环境中的剂量反应、作用机制（直接摄取到癌细胞中），并在许多药代动力学/药效学参数中进行表征。最近的证据表明，携带ETS基因融合的PC对阿糖胞苷具有独特的敏感性，因此需要在这一大型前列腺癌亚群中检测MBC-11。该II期项目的具体目标是：（1）开发用于制备新型双膦酸盐-化疗剂缀合物的合成方法，并合成足够量的所需化合物用于拟议的研究。(2)在前列腺癌诱导的骨疾病（CIBD）的NOD/SCID-hu-HAB模型中筛选用于肿瘤负荷降低的新化合物，评估在CIBD模型的治疗和预防形式中对选择的先导化合物的剂量反应，并评估新先导化合物使用骨骼作为贮库以解决PC模型中的原发性和非骨转移的能力。(3)使用先导化合物测量关键毒理学和药代动力学（PK）参数。该II期项目的成功完成将指导这一有前途的概念的进一步发展，极大地帮助获得研究性新药批准，并导致最终的临床应用。预计这项技术将最终产生治疗剂，将显着改善癌症患者的护理，从而提高生活质量和生存。