Therapy for Metastatic breast cancer based on micro RNA silencing

基于微小RNA沉默的转移性乳腺癌治疗

基本信息

批准号：
10489811
负责人：
ANNA MOORE
金额：
$ 55.53万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10489811
关键词：
Aftercare Anatomy Animal Behavior Apoptosis Biological Availability Body Weight Brain Breast Adenocarcinoma Breast Cancer Cell Breast cancer metastasis Cancer Patient Cell Proliferation Cell Survival Cells Clinical Development Disease Disseminated Malignant Neoplasm Distant Distant Metastasis Dose Doxorubicin Drug Kinetics Enzymes Evaluation Fluorescence Microscopy Goals Gonadotropin-Releasing Hormone Receptor Histology Histopathology Human Image Inflammatory Interferon-alpha Interleukin-6 Life Liver Lung Magnetic Resonance Imaging Magnetic nanoparticles Mediating Membrane Metastatic Neoplasm to the Bone Metastatic Neoplasm to the Liver Metastatic Neoplasm to the Lung Metastatic breast cancer Metastatic malignant neoplasm to brain Metastatic to MicroRNAs Molecular Neoplasm Metastasis Oligonucleotides Oncogenic Organ Palliative Care Patients Peptides Physiological Play Primary Neoplasm Protocols documentation RNA Interference Relapse Research Role Salvage Therapy Savings Site Specificity Survival Analysis TNF gene Therapeutic Therapeutic Effect Time Toxic effect Treatment Efficacy activating transcription factor animal morbidity base bioluminescence imaging bone cancer cell chemotherapy cytokine effectiveness evaluation efficacy evaluation in vitro testing in vivo in vivo imaging locked nucleic acid lymph nodes malignant breast neoplasm migration mortality mouse model nanodrug nanoparticle nanotherapy neoplastic cell non-invasive imaging novel strategies therapeutic target therapy outcome treatment response uptake

项目摘要

Treatment options for patients with metastatic breast cancer are severely limited and ultimately rely on palliative care representing an unmet clinical need. Previous studies have demonstrated that microRNAs play a significant role in the formation of metastasis including those from breast cancer. Considering the paucity of options for patients with metastasis from breast cancer, in this proposal we focused on targeting miR-10b proven to be responsible for metastatic spread. While previous studies showed that miR-10b drives invasion and migration of cancer cells from primary tumors, our recent discovery demonstrated that in metastatic cells it is also responsible for cell viability and proliferation and that survival of metastatic cells crucially depends on the high level of miR-10b expression. This discovery formed a cornerstone of our therapeutic strategy aimed at specific eradication of metastatic tumor cells. This will be done using imaging-capable modular nanodrugs, which distribute to lung, liver, bone, or brain metastases. These nanodrugs consist of magnetic nanoparticles that carry locked-nucleic acid (LNA) oligonucleotides inhibiting microRNA-10b. Targeting moieties conjugated to the nanoparticles facilitate their accumulation at distant metastatic sites. Previously we have demonstrated the feasibility of the proposed approach. Delivery of the nanodrug to lymph nodes with already formed metastases resulted in arrest of metastatic progression by inhibiting tumor cell proliferation and causing apoptosis, which is a phenomenon that has not been described before. When treatment with the nanodrug was combined with a low-dose of conventional chemotherapy (doxorubicin), there was regression and permanent elimination of lymph node or lung metastases without relapse even after treatment was discontinued. Unlike conventional chemotherapies, this therapeutic protocol was not associated with animal morbidity/mortality. In the current application we propose to use the miR10b-inhibitory nanodrug in combination with low-dose chemotherapy (where necessary) for targeting breast cancer metastases in distant organs. Noninvasive imaging will be used to evaluate the delivery of the nanodrug. If successful, this approach could be a life- extending (and possibly, life saving) alternative for patients with advanced metastatic disease for whom salvage therapy is the only current option.

转移性乳腺癌患者的治疗选择受到严重限制，最终依赖于姑息治疗代表了未满足的临床需求。先前的研究表明 microRNA 发挥着在包括乳腺癌在内的转移形成中发挥重要作用。考虑到数量稀少乳腺癌转移患者的选择，在本提案中，我们重点关注靶向 miR-10b 已被证明是导致转移扩散的原因。虽然之前的研究表明 miR-10b 驱动入侵以及癌细胞从原发肿瘤的迁移，我们最近的发现表明，在转移细胞中还负责细胞活力和增殖，转移细胞的存活关键取决于高水平的 miR-10b 表达。这一发现构成了我们的治疗策略的基石，旨在特异性根除转移性肿瘤细胞。这将使用具有成像功能的模块化纳米药物来完成，分布至肺、肝、骨或脑转移。这些纳米药物由磁性纳米颗粒组成携带抑制 microRNA-10b 的锁核酸 (LNA) 寡核苷酸。缀合的靶向部分纳米颗粒有助于它们在远处转移部位的积累。之前我们已经演示过所提议方法的可行性。将纳米药物递送至已形成的淋巴结转移通过抑制肿瘤细胞增殖并导致转移进展停滞细胞凋亡，这是一种以前从未描述过的现象。当使用纳米药物治疗时与低剂量常规化疗（阿霉素）相结合，出现消退和永久性消除淋巴结或肺转移，即使治疗停止后也不会复发。不像与传统化疗相比，该治疗方案与动物发病率/死亡率无关。在目前的应用我们建议使用抑制miR10b的纳米药物与低剂量的药物相结合针对远处器官的乳腺癌转移进行化疗（必要时）。无创成像将用于评估纳米药物的输送。如果成功的话，这种方法可能会成为一种生活—— 为患有晚期转移性疾病的患者提供扩展（并且可能挽救生命）的替代方案挽救治疗是目前唯一的选择。