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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.

摘要