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

摘要 前列腺癌（Prostate cancer，PCa）是最常见的恶性肿瘤，也是第二大癌症病因 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的转移。虽然雄激素剥夺疗法（ADT）对治疗激素初始PCa有效， 转移性去势抵抗性前列腺癌（mCRPC）的发作赋予雄激素抵抗表型， 这是无法治愈的疾病的末期。因此，开发治疗mCRPC的新方法是 迫切需要。众所周知，PCa和骨微环境之间的相互作用导致了 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细胞应该导致一种新的单一药物作为mCRPC的有效靶向治疗。 因此，我们建议探索酶指导自组装（EISA）靶向成骨细胞mCRPC。 本研究的目的是开发一种能在碱性条件下进行EISA反应的EISA底物 本发明的目的在于检测磷酸酶（ALPL）和酸性磷酸酶（ACPP）的活性，并检查它们在细胞测定中的功效。这 研究计划将集中在三个具体目标：目标1，ALPL的EISA基板的设计和合成， ACPP;目的2，表征ALPL和ACPP的EISA底物，并确定它们在共沉淀中的活性。 目的3，检查EISA底物抑制成骨细胞和mCRPC细胞的功效。 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。 我们的初步结果表明，ALPL催化的EISA选择性抑制PCa的表达， 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 这些研究将有助于开发基于ALPL和ACPP的新型分子靶向药物 在mCRPC骨转移过程中过度表达，这可能最终导致突破性进展。 治疗mCRPC。

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.