Novel bisphosphonates for prostate cancer therapy

用于前列腺癌治疗的新型双磷酸盐

• 批准号: 8122337
• 负责人: Alexander Karpeisky
• 金额: $ 107.09万
• 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/8122337
• 关键词: Address; Anhydrides; Animal Model; Antimetabolites; Antineoplastic Agents; Azacitidine; Bone Diseases; Bone Pain; Cancer Model; Cancer Patient; Canis familiaris; Cell Separation; Cessation of life; Clinical; Clofarabine; Cytarabine; DNA; Deterioration; Development; Disease; Disease model; Dose; Doxorubicin; Drug Delivery Systems; Drug Kinetics; 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; Modeling; 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; public health relevance; 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. 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.

描述（由申请人提供）：该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 引起的骨病。 MBC-11 是阿拉伯胞苷 (AraC)-59-磷酸和依替膦酸之间形成的酸酐，是我们专有技术的主导产品，该技术采用已知化疗药物与骨靶向双磷酸盐的缀合物，以解决肿瘤诱导骨常规疗法的局限性疾病。这种靶向递送设计能够将化疗药物集中在骨骼中，同时保持较低的全身水平。我们假设这种缀合物将比目前可用的疗法具有更广泛的治疗范围。作为一个额外的好处，这些药物还可以强化骨骼，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架作为药物库，药物的释放可以提供全身益处。我们的 I 期体内概念验证研究取得了令人鼓舞的结果，表明 MBC-11 可以与标准护理唑来膦酸盐相比或更好地保留骨骼结构，并显着减轻疼痛。拟议的研究将检查 MBC-11 和骨靶向化疗化合物库在 PC 和 PC 诱导的骨疾病模型中的作用。最有前途的化合物将进一步研究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，因此需要在这一庞大的前列腺癌亚群中测试 MBC-11。该二期项目的具体目标是：（1）开发制备新型双膦酸盐-化疗缀合物的合成程序，并合成足够量的拟议研究所需的化合物。 (2) 在前列腺癌诱发的骨病（CIBD）的NOD/SCID-hu-HAB模型中筛选用于减少肿瘤负荷的新型化合物，评估选定的先导化合物在CIBD模型的治疗和预防形式中的剂量反应，并评估其能力的新颖导致使用骨骼作为储存库来解决 PC 模型中的原发性和非骨性转移。 (3) 使用先导化合物测量关键毒理学和药代动力学 (PK) 参数。该二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，极大地有助于获得研究性新药批准，并最终实现临床应用。预计这项技术最终将产生能够显着改善癌症患者护理的治疗剂，从而提高生活质量和生存率。 公共卫生相关性：在美国，前列腺癌每年导致 30,000 人死亡； 85% 死于转移性骨癌。主要临床特征之一是癌症诱发的骨病的发展，其特征是进行性和破坏性的骨破坏、骨痛、病理性骨折和高钙血症。因此，非常需要开发能够预防或减少癌症向骨扩散的药物。该研究项目的长期目标是开发更有效的疗法，旨在将抗癌药物输送到骨骼，同时为癌症引起的骨骼疾病提供有效的骨骼保护成分。