Novel bisphosphonates for multiple myeloma therapy

用于多发性骨髓瘤治疗的新型双磷酸盐

• 批准号: 7395192
• 负责人: Alexander Karpeisky
• 金额: $ 39.18万
• 依托单位: MBC PHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7395192
• 关键词: Accounting; Address; Adult; Affect; Anhydrides; Antineoplastic Agents; Apoptosis; Biodistribution; Blood; Bone Density; Bone Diseases; Bone Pain; Bone Tissue; Brain; C-terminal type I collagen telopeptide; Cancer Patient; Cell Separation; Cells; Cessation of life; Chronic; Clinical; Clinical Trials; Commit; Country; Daily; Deterioration; Development; Dose; Drug Kinetics; Femur; Frequencies; Goals; Harvest; Heart; Hematologic Neoplasms; Human; Hypercalcemia; Injection of therapeutic agent; Investigational Drugs; Kidney; Lead; Lesion; Liver; Lung; Lytic; Malignant Neoplasms; Marrow; Maxilla; Modeling; Monitor; Multiple Myeloma; Mus; Muscle; New Drug Approvals; Numbers; Osteocalcin; Osteoclasts; Osteolytic; Ovary; Parents; Pathological fracture; Patient Care; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phase II Clinical Trials; Preparation; Quality of life; Radiolabeled; Range; Rate; Rattus; Recruitment Activity; Research; Research Project Grants; Screening procedure; Serum; Serum Markers; Small Business Technology Transfer Research; Spleen; Staging; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Treatment Protocols; Tumor Burden; Zoledronate; base; bisphosphonate; bone; bone loss; bone turnover; cancer therapy; chemotherapeutic agent; chemotherapy; clinical application; concept; cytotoxic; day; design; improved; in vivo; inorganic phosphate; mecarzole; mouse model; neoplastic cell; novel; prevent; radiotracer; spine bone structure; subcutaneous; targeted delivery; tartrate-resistant acid phosphatase; therapy design; tumor; uptake

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：该项目的总体目标是进一步开发新型双膦酸盐缀合物 MBC-11，用于治疗肿瘤诱发的骨疾病，例如与多发性骨髓瘤相关的疾病。 MBC-11 是阿拉伯胞苷 (AraC)-5'-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，以解决肿瘤诱导的传统疗法的局限性骨骼疾病。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。我们的 I 期体内概念验证研究的令人鼓舞的结果表明，MBC-11 逆转了最初的骨质流失，并且与唑来膦酸盐相比，显着延长了受影响小鼠的生存期。 MBC-11 还维持了化合物诱导的骨矿物质密度增加。此外，缀合物的功效优于亲代成分的混合物，证明了缀合物增加骨组织中细胞毒性部分浓度的能力的价值。拟议的研究将检查 MBC-11 的作用机制，表征其药代动力学/药效学特征，以确定最佳剂量并验证其在基于 GFP 的多发性骨髓瘤小鼠模型中的疗效。该二期项目的具体目标是：（1）确定MBC-11在健康大鼠中的抗吸收效力和作用持续时间。确定给药后大鼠的破骨细胞是否表现出活性或数量减少，以及它们是否进入药物诱导的细胞凋亡； (2) 确定MBC-11在健康大鼠体内的药代动力学和生物分布曲线； (3) 在基于 GFP 的多发性骨髓瘤小鼠模型中展示功效。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。多发性骨髓瘤是第二常见的成人血液恶性肿瘤，约占西方国家所有癌症相关死亡的 1%。主要临床特征之一是形成一种独特的溶骨性骨病，其特征是进行性和破坏性的骨质破坏、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疾病（例如与多发性骨髓瘤相关的疾病）提供有效的骨保护成分。