Next generation bisphosphonates for chemo- and immuno-therapy

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。这项工作建立在最近几项临床试验的发现之上，即双膦酸盐药物唑来膦酸盐作为乳腺癌的辅助治疗（与芳香酶抑制剂联合治疗）具有意想不到的积极作用，除了增加前列腺癌患者的生存率外，还可将疾病（在任何部位）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”（34 T细胞激活和肿瘤相关巨噬细胞（tam）从促肿瘤的M2表型转化为抗肿瘤的M1表型）。在这里提出的工作中，我们将测试一个假设，即一种名为“亲脂性双膦酸盐”（lbp）的新型双膦酸盐在杀死肿瘤细胞和激活34 T细胞方面将比唑来膦酸盐更有效，它们还将使巨噬细胞从M2 -> M1转变为癌症化疗和免疫治疗的新途径。我们还提出，通过结合高场固体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，实现长期追求的骨病“灵丹妙药”的目标。在Aim 1中，我们将开发抑制两种戊烯基合成酶的化合物：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）戊烯化，在细胞信号传导和细胞存活途径中起重要作用。在Aim 2中，我们将对Aim 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，我们将发展“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，我们将因此开发出癌症化疗和免疫治疗的全新方法，未来将对临床产生重大影响。

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.