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）：该项目的目的是进一步开发新型的双膦酸盐结合MBC-11和其他新型化合物作为前列腺癌（PC）和PC诱导的骨病的治疗方法。 MBC-11是阿拉伯细胞替丁（ARAC）-59-磷酸和肠膦酸盐之间形成的赤道酸酯，是我们专有技术的主要产品，它采用了具有骨靶向双膦酸盐的已知化学治疗剂的共轭物来解决肿瘤诱导的骨骼骨骼疾病的常规疗法的限制。该目标递送设计使骨骼中化学疗法剂的浓度也使全身水平较低。我们假设这种结合物将具有比目前可用的疗法更大的治疗范围。为了额外的好处，这些药物还可以增强骨骼，并可能扭转与癌症相关的骨骼的恶化。我们进一步假设这种方法可以将骨骼用作药物释放可以提供系统性益处的药物库。 I阶段体内概念验证研究的令人鼓舞的结果表明，MBC-11可保留骨骼结构比护理标准差异齐隆的标准，并显着减轻疼痛。拟议的研究将研究MBC-11和PC诱导的骨骼疾病模型中MBC-11和骨靶向化学疗法化合物的影响。最有希望的化合物将进一步研究治疗和预防性环境中的剂量反应，作用机理（直接摄取癌细胞），并在许多药代动力学/药物动力学参数中进行表征。最近的证据表明，对携带ETS基因融合的PC的Cytarabine的独特敏感性值得对MBC-11的测试在这种大量的前列腺癌亚群中。该II期项目的具体目的是：（1）制定合成程序，以制备新型的双膦酸盐化学方法共轭物并合成足够量的所需化合物作为拟议的研究。 （2）筛选新的化合物，以减轻前列腺癌诱导的骨病（CIBD）的点头/SCID-HU-HAB模型，评估CIBD模型的治疗和预防性形式的精选铅化合物的剂量反应，并评估新型铅的能力，将铅铅作为skeleton用作PC模型中的skeleton来解决一级和非选择性代理。 （3）使用铅化合物测量关键的毒理学和药代动力学（PK）参数。该第二阶段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新药批准，并导致最终的临床应用。预计该技术最终会导致治疗剂，这些治疗剂将显着改善癌症患者护理，从而增加生活质量和生存。 公共卫生相关性：美国每年在美国每年30,000例死亡； 85％死于转移性骨癌。主要的临床特征之一是癌症引起的骨病的发展，其特征是进行性骨骼破坏，骨痛，病理骨折和高钙血症。因此，存在巨大的需求，以开发可以预防或减少癌症传播到骨骼的药物。该研究项目的长期目标是开发更有效的疗法，旨在为骨骼提供抗癌药物，同时还为癌症引起的骨骼疾病提供有效的骨骼保护成分。