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

摘要 前列腺癌(PCa)仍然是最常见的癌症和第二大致癌原因 美国男性的死亡率主要与转移性疾病有关。骨是远方的主要部位 前列腺癌的转移。虽然雄激素剥夺疗法(ADT)对激素幼稚的前列腺癌有效， 转移性去势耐药前列腺癌(MCRPC)的发病赋予雄激素耐药表型， 这是无法治愈的疾病的末期。因此，开发治疗mCRPC的新方法是 急需之物。众所周知，前列腺癌与骨微环境的相互作用导致了 独特的成骨反应，进一步促进了前列腺癌的进展。因此，我们假设双重目标 成骨细胞和PCa细胞有望成为治疗mCRPC的有效靶向治疗药物。 因此，我们建议探索酶引导的自组装(EISA)来靶向成骨细胞的mCRPC。 这项研究的目的是开发可以通过碱作用进行EISA的EISA衬底 并检测其在细胞检测中的作用。这 研究计划将集中在三个具体目标：目标1，设计和合成EISA衬底的ALPL和 ACPP；目的2，表征ALPL和ACPP的EISA底物并测定它们在共培养体系中的活性。 成骨细胞和mCRPC细胞的培养；以及目标3，检测EISA底物对抑制 MCRPC在临床相关动物模型中的应用。先前研究的严谨之处在于：(I)有充分的证据表明 ALPL的过度表达是成骨细胞转移的特征，ACPP的过度表达是骨转移的特征 PCA的特征和(II)我们的初步结果表明，ALPL催化的EISA选择性地抑制 ACPP催化的成骨模型细胞和EISA对CRPC细胞有选择性抑制作用。的成功之路 所提出的研究将有助于基于ALPL和ACPP的新型分子靶向剂的开发 MCRPC在骨转移过程中的过度表达，最终可能导致突破 在治疗mCRPC方面。

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.