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）：这项工作的目的是开发主要针对类异戊二烯生物合成的新型抗癌药物。这项工作基于最近几项临床试验的发现，即双膦酸盐药物唑来膦酸盐作为乳腺癌辅助剂（与芳香酶抑制剂联合治疗）具有意想不到的积极作用，除了提高前列腺癌患者的生存率外，还可以将疾病（在任何部位）的复发率降低 36%。可能的目标是直接杀死肿瘤细胞、抑制侵袭性和血管生成以及“表型转换”（34 T 细胞激活以及肿瘤相关巨噬细胞 (TAM) 从促肿瘤 M2 转化为抗肿瘤 M1 表型）。在此提出的工作中，我们将测试这样的假设：一种称为“亲脂性双磷酸盐”(LBP) 的新型双磷酸盐在肿瘤细胞杀伤和 34 T 细胞激活方面比唑来膦酸更有效，并且它们还将巨噬细胞从 M2 转换为 M1，从而为癌症化疗和免疫治疗带来新的线索。我们还建议测试这样一个假设：通过结合使用高场固态核磁共振和量热法来开发骨-配体相互作用的分子模型，我们可以非常有效地设计其他与骨结合的抗癌药物，实现人们长期以来追求的治疗骨疾病的“灵丹妙药”的目标。在目标 1 中，我们将开发抑制两种异戊二烯合酶的化合物：法尼基二磷酸合酶 (FPPS) 和香叶基香叶基二磷酸合酶 (GGPPS)，它们参与蛋白质（例如 Ras、Rho、Rap1A）异戊二烯化，对细胞信号传导和细胞生存途径具有重要意义。在目标 2 中，我们将对目标 1 中制备的化合物进行基于细胞和体内的测试。在目标 3 中，我们将开发“骨标签”或“魔弹”的概念，即能够将药物输送到骨骼的化合物。如果成功，我们将开发全新的癌症化疗和免疫治疗方法，这将在未来对临床产生重大影响。 公共健康相关性：该项目旨在开发治疗癌症的新线索。重点是新一代药物的开发；亲脂性双磷酸盐可杀死肿瘤细胞，并激活 34 个 T 细胞和巨噬细胞，从而杀死肿瘤细胞。