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

基本信息

批准号：
8444316
负责人：
Eric Oldfield
金额：
$ 29.71万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
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/8444316
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 Targeting 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

项目摘要

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.

描述（由申请人提供）：这项工作的目的是开发主要靶向类吸收类生物合成的新型抗癌药物。这项工作是基于该发现的基于最近的几项临床试验，即双膦酸盐药物唑来膦酸盐在乳腺癌中具有意想不到的积极作用（与芳香酶抑制剂联合治疗）在乳腺癌中具有意外的阳性作用，从而减少了36％的疾病再出现（在任何部位），此外还增加了前列腺癌患者的生存。可能的靶标是直接肿瘤细胞杀伤，抑制侵袭性和血管生成以及“表型切换”（34 T细胞激活和肿瘤相关巨噬细胞（TAM）从亲肿瘤，M2的转化为抗肿瘤，到抗肿瘤，M1，M1，表型）。在此处提出的工作中，我们将检验以下假设：新型的双膦酸盐称为“亲脂性双膦酸盐”（LBPS）（LBPS）将比肿瘤细胞杀死中的唑来膦酸盐更有效，并且在34 T细胞激活中，它们还将从M2-> M1转换巨噬细胞，从而从M2-> M1转换巨噬细胞，从而导致癌症化学疗法和癌症化学疗法，并从事癌症的疗法和癌症。我们还建议测试以下假设：通过使用高视野固态NMR和量热法来开发用于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骼结合的抗癌药物，从而意识到骨骼疾病的“魔术子弹”的目标是漫长的目标。在AIM 1中，我们将开发抑制两种蛋白酶合酶的化合物：Farnesyl二磷酸合酶（FPPS）（FPPS）和黄烷基凝血酶二磷酸合酶（GGPPS），这些合酶（GGPPS）与蛋白质（例如Ras，Rho，Rho，Rap1a）prenylation和Cell Cells and Semble and Survorce and Cynorke和Cells Survorce中有关。在AIM 2中，我们将对AIM 1中制造的化合物进行基于细胞的和体内测试。在AIM 3中，我们将开发“骨标签”或“魔术子弹”的概念，这些化合物可以将药物传递给骨骼。如果成功，我们将开发全新的癌症化学疗法和免疫疗法的方法，将来将对诊所产生重大影响。