Overcoming Tumor Resistance with Enzyme-Instructed Nanoscale Assemblies and Immunotherapies

项目摘要/摘要 对化疗和分子靶向治疗的耐药性是面临的一个主要问题 目前的癌症研究。耐药性的发展可能会导致化疗失败和 肿瘤复发，导致存活率下降。此外，尽管取得了前所未有的成功， 在过去的几十年里，癌症免疫治疗取得了进展，肿瘤细胞的内在机制 耐药性导致患者的应答率低，这仍然是一个重大挑战。因此，它是 迫切需要开发新的治疗方法来解决这些问题。最近，我们实验室， 在我的发起人徐冰博士的带领下，开发了基于酶的抗癌纳米药物 自组装(EISA)。EISA能选择性抑制肿瘤而不损害正常组织 组织由于其精确的时空控制。此外，通过瞄准多个目标，EISA几乎 会导致获得性抗药性。最重要的是，联合疗法对肿瘤大有可为 预防和治疗。这个项目的总体目标是克服抗癌药物的耐药性 通过纳米技术的应用并与抗癌免疫疗法相结合。要实现 在这个目标上，我们提出了以下两个具体目标： 1)在F99阶段，我建议开发基于EISA的抗癌纳米药物，以 靶向功能丧失(下调)和内质网(ER)最小化癌细胞 耐药情况及副作用。我们设计了一种双酶控制的组装系统来靶向 通过酶调控的组装和拆卸相结合的下调，并测试了其 抗癌功效和选择性。我们还将研究EISA在靶向ER抑制癌症方面的作用。这个 将测试所设计分子的内质网靶向能力和动态分布。此外，我们 将阐明内质网靶向诱导癌细胞死亡的机制。 2)对于K00，我的博士后研究方向将集中在提高抗肿瘤方面 EISA纳米药物联合免疫治疗的反应。建议数 博士后培训将为我提供癌症免疫学方面的新见解和新技术。

Project Summary/Abstract Resistance to chemotherapy and molecularly targeted therapies is a major problem facing current cancer research. The development of drug resistance could lead to chemotherapy failure and tumor relapse, resulting in reduced survival rates. In addition, despite the unprecedented success achieved in cancer immunotherapy over the past decades, the cancer-cell-intrinsic mechanisms of resistance result in low response rates of patients which remains a major challenge. Therefore, it is urgently necessary to develop novel therapy to address these problems. Recently, our laboratory, headed by my sponsor Dr. Bing Xu, developed anticancer nanomedicine based on enzyme-instructed self-assembly (EISA). The EISA is capable of selective inhibition of tumor without harming normal tissues due to its precise spatiotemporal control. Additionally, by targeting multiple targets, EISA hardly induces acquired drug resistance. Most importantly, combination therapy holds great promise for tumor prevention and treatment. The overall goal of this project is to overcome cancer drug resistance through the application of nanotechnology and combination with anticancer immunotherapy. To achieve this goal, we proposed two following specific aims: 1) During the F99 phase, I propose to develop anticancer nanomedicines based on EISA to target loss-of-function (downregulation) and endoplasmic reticulum (ER) in cancer cells for minimizing the drug resistance and side effect. We designed a two enzyme controlled assembly system to target the downregulation via the combination of enzyme-instructed assembly and disassembly and tested its anticancer efficacy and selectivity. We will also study the EISA in targeting ER for cancer inhibition. The ER targeting ability and dynamic distribution of the designed molecules will be tested. Moreover, we will elucidate the mechanisms of cancer cell death induced by ER targeting. 2) For the K00, the direction of my postdoctoral research will focus on improving the anti-tumor response of immunotherapy through the combination with EISA based nanomedicines. The proposed postdoctoral training will provide me with new insight and techniques in cancer immunology.