Next generation bisphosphonates for chemo- and immuno-therapy

用于化疗和免疫治疗的下一代双膦酸盐

• 批准号: 8085202
• 负责人: Eric Oldfield
• 金额: $ 31.64万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8085202
• 关键词: Adjuvant; Affinity; Anabolism; Antineoplastic Agents; Aromatase Inhibitors; Binding; Biological Assay; Bone Diseases; Bone Surface; Calorimetry; Cancer Center; Cancer Model; Cancer Patient; Cell Survival; Cells; Charge; Chemotherapy-Oncologic Procedure; Clinic; Clinical Trials; Combined Modality Therapy; Crystallography; Development; Disease; Docking; Drug Delivery Systems; Drug or chemical Tissue Distribution; Enzymes; Future; Generations; Geranyltranstransferase; Goals; Grant; Human; Immunotherapy; Ligands; Magic; Malignant Bone Neoplasm; Malignant Neoplasms; Malignant neoplasm of prostate; Methods; Minerals; Modeling; Molecular Models; Pathway interactions; Pharmaceutical Preparations; Phenotype; Proteins; Quantitative Structure-Activity Relationship; Site; Structure; T-Cell Activation; T-Lymphocyte; Testing; Tetracyclines; Time; Titrations; Work; Zoledronate; analog; angiogenesis; base; bisphosphonate; bone; cancer immunotherapy; cancer therapy; cell killing; chemotherapy; design; farnesyltranstransferase; in vivo; inhibitor/antagonist; intercellular communication; isoprenoid; killings; macrophage; malignant breast neoplasm; matrigel; molecular modeling; neoplastic cell; next generation; novel; novel strategies; prenyl; prenylation; professor; rho; scaffold; soft tissue; solid state nuclear magnetic resonance; success; tumor

DESCRIPTION (provided by applicant): The objective of this work is to develop novel anti-cancer drugs that target, primarily, isoprenoid biosynthesis. The work builds on the discovery in several recent clinical trials that the bisphosphonate drug zoledronate has unexpected positive effects as an adjuvant (in combination therapy with aromatase inhibitors) in breast cancer, reducing the re-occurrence of disease (at any site) by 36%, in addition to increasing the survival of prostate cancer patients. Likely targets are direct tumor cell killing, inhibition of invasiveness and angiogenesis, and "phenotype switching" (34 T cell activation and conversion of tumor associated macrophages (TAMs) from a pro-tumor, M2, to an anti-tumor, M1, phenotype). In the work proposed here we will test the hypothesis that a new class of bisphosphonates called "lipophilic bisphosphonates" (LBPs) will be far more effective than zoledronate in tumor cell killing and in 34 T cell activation and that they will also switch macrophages from M2 -> M1, resulting in new leads for cancer chemotherapy and immunotherapy. We also propose to test the hypothesis that by using a combination of high-field solid-state NMR and calorimetry to develop molecular models for bone-ligand interactions, we can very effectively design other anti-cancer drugs that bind to bone, realizing the long sought after goal of "magic bullets" for bone diseases. In Aim 1, we will develop compounds that inhibit two prenyl synthase enzymes: farnesyl diphosphate synthase (FPPS) and geranylgeranyl diphosphate synthase (GGPPS), that are involved in protein (e.g. Ras, Rho, Rap1A) prenylation, of importance in cell signaling and cell survival pathways. In Aim 2, we will carry out cell-based and in vivo testing of the compounds made in Aim 1. In Aim 3, we will develop the concept of "bone-tags" or "magic bullets", compounds which enable the delivery of drugs to bone. If successful, we will thus develop completely new approaches to cancer chemotherapy and immunotherapy that, in the future, will have a major impact in the clinic. PUBLIC HEALTH RELEVANCE: The project is aimed at developing new leads for treating cancer. Focus is on the development of a new generation of drugs; lipophilic bisphosphonates that kill tumor cells, as well as activate 34 T cells and macrophages, to kill tumor cells.

描述(由申请人提供)：这项工作的目标是开发新的抗癌药物，主要针对异戊二烯类生物合成。这项工作建立在最近几项临床试验的发现基础上，即双膦酸类药物唑来膦酸盐作为乳腺癌的辅助药物(与芳香酶抑制剂联合治疗)具有意想不到的积极效果，除了提高前列腺癌患者的存活率外，还将疾病(任何部位)的复发率降低36%。可能的目标是直接杀伤肿瘤细胞，抑制侵袭性和血管生成，以及“表型转换”(34T细胞激活和肿瘤相关巨噬细胞(TAMs)从亲肿瘤的M2表型转化为抗肿瘤的M1表型)。在这里提出的工作中，我们将测试这样一种假设，即一种新的双膦酸类被称为“脂亲双膦酸盐”(LBPS)在杀死肿瘤细胞和激活34T细胞方面将比唑来膦酸盐有效得多，并且它们还会将巨噬细胞从M2-GT；M1切换到巨噬细胞，从而为癌症化疗和免疫治疗带来新的线索。我们还建议检验这一假设，即通过使用高场固态核磁共振和量热技术相结合的方法来开发骨-配体相互作用的分子模型，我们可以非常有效地设计出与骨结合的其他抗癌药物，实现人们长期以来追求的治疗骨骼疾病的“神奇子弹”的目标。在目标1中，我们将开发抑制两种戊烯基合酶的化合物：法尼基二磷酸合成酶(FPPS)和香叶基二磷酸合成酶(GGPPS)，这两种酶参与蛋白质(如RAS、Rho、Rap1A)的戊烯基化，在细胞信号转导和细胞生存途径中具有重要作用。在目标2中，我们将对目标1中合成的化合物进行基于细胞的体内测试。在目标3中，我们将开发“骨标签”或“神奇子弹”的概念，即能够将药物输送到骨骼中的化合物。如果成功，我们将因此开发出癌症化疗和免疫治疗的全新方法，这将在未来对临床产生重大影响。 与公共卫生相关：该项目旨在开发治疗癌症的新线索。重点是开发新一代药物：亲脂性双膦酸盐，它可以杀死肿瘤细胞，也可以激活34T细胞和巨噬细胞来杀死肿瘤细胞。