Exploring enzyme-instructed self-assembly (EISA) for targeting osteoblastic metastasis of prostate cancer

探索酶指导自组装（EISA）以靶向前列腺癌的成骨细胞转移

基本信息

批准号：
10044030
负责人：
Jer-Tsong Hsieh
金额：
$ 43.05万
依托单位：
BRANDEIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10044030
关键词：
Acid Phosphatase Alkaline Phosphatase Androgens Animal Model Biochemical Reaction Biological Assay Cancer Etiology Cell model Cells Cellular Assay Cessation of life Coculture Techniques Development Disease Distant Metastasis Enzyme Inhibition Enzymes Hormones Image In Situ Lead Malignant Neoplasms Malignant neoplasm of prostate Medical center Metastatic Prostate Cancer Molecular Molecular Target NMR Spectroscopy Nanotechnology Neoplasm Metastasis Operative Surgical Procedures Osteoblasts Peptide Synthesis Peptides Phase Phenotype Process Prostate Cancer therapy Radiation Reaction Research Resistance Site Solid Structure Testing Therapeutic United States androgen deprivation therapy anti-cancer therapeutic base bone cancer cell cancer therapy castration resistant prostate cancer clinically relevant design end stage disease enzyme activity enzyme substrate improved outcome innovation male men mortality nanofibrillar nanoparticle new therapeutic target novel novel strategies overexpression programs prostate cancer cell prostate cancer metastasis prostate cancer progression self assembly small molecule success targeted agent targeted treatment tumor tumor microenvironment

项目摘要

Abstract Prostate cancer (PCa) remains as the most frequent cancer and the second leading cause of cancer mortality among U.S. males that are mainly associated with metastatic diseases. Bone is the major site of distant metastases of PCa. Although androgen deprivation therapy (ADT) is effective for treating hormone naive PCa, the onset of metastatic castration-resistant prostate cancer (mCRPC) confers androgen resistant phenotypes, which is the end stage of disease without cure. Thus, developing novel approaches for treating mCRPC is urgently needed. It is well known the reciprocal interaction between PCa and bone microenvironment resulted in unique osteoblastic reaction that further promotes PCa progression. Thus, we hypothesize that dual targeting osteoblast and PCa cells should lead to a novel single agent as an effective targeted therapy for mCRPC. Therefore, we propose to explore enzyme-instructed self-assembly (EISA) for targeting osteoblastic mCRPC. The proposed research is to develop the EISA substrates that can undergo EISA by the actions of alkaline phosphatase (ALPL) and acid phosphatase (ACPP) and to examine their efficacy in cell assays. This research program will focus on three specific aims: Aim 1, design and synthesis of EISA substrates of ALPL and ACPP; Aim 2, characterizing the EISA substrates of ALPL and ACPP and determining their activities in the co- culture of osteoblast and mCRPC cells; and Aim 3, examining the efficacy of the EISA substrates for inhibiting mCRPC in clinically relevant animal models. The rigor of prior research is that (i) it is well documented that overexpression of ALPL is the feature of osteoblastic metastases and overexpression of ACPP is the feature of PCa and (ii) our preliminary results show that EISA catalyzed by ALPL selectively inhibits osteoblast model cells and EISA catalyzed by ACPP selectively inhibit CRPC cells. The success of the proposed studies will contribute to the development of new molecular targeting agents based on ALPL and ACPP overexpressed during the process of metastasis of mCRPC in bone, which may ultimately lead to breakthrough in treating mCRPC.

抽象的前列腺癌 (PCa) 仍然是最常见的癌症，也是第二大癌症原因美国男性的死亡率主要与转移性疾病有关。骨是远距离的主要部位 PCa 转移。尽管雄激素剥夺疗法（ADT）对于治疗激素原发性 PCa 有效，转移性去势抵抗性前列腺癌（mCRPC）的发病赋予雄激素抵抗表型，这是疾病无法治愈的末期。因此，开发治疗 mCRPC 的新方法是迫切需要。众所周知，PCa 与骨微环境之间的相互作用导致独特的成骨细胞反应，进一步促进 PCa 进展。因此，我们假设双重靶向成骨细胞和 PCa 细胞应该会产生一种新型单一药物作为 mCRPC 的有效靶向治疗。因此，我们建议探索酶指导自组装（EISA）来靶向成骨细胞 mCRPC。拟议的研究是开发可通过碱性作用进行 EISA 的 EISA 基材磷酸酶（ALPL）和酸性磷酸酶（ACPP）并检查它们在细胞测定中的功效。这研究计划将重点关注三个具体目标：目标 1、ALPL 和 EISA 底物的设计和合成 ACPP；目标 2，表征 ALPL 和 ACPP 的 EISA 底物并确定它们在共-中的活性成骨细胞和 mCRPC 细胞的培养；目标 3，检查 EISA 底物抑制的功效临床相关动物模型中的 mCRPC。先前研究的严谨性在于 (i) 有充分证据表明 ALPL的过度表达是成骨细胞转移的特征，ACPP的过度表达是成骨细胞转移的特征。 PCa 的特征和 (ii) 我们的初步结果表明 ALPL 催化的 EISA 选择性抑制成骨细胞模型细胞和ACPP催化的EISA选择性抑制CRPC细胞。的成功拟议的研究将有助于开发基于 ALPL 和 ACPP 的新型分子靶向剂 mCRPC在骨转移过程中过度表达，最终可能导致突破在治疗 mCRPC 中。