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：
10434241
负责人：
ANNA MOORE
金额：
$ 58.03万
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 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10434241
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，最终依靠姑息治疗代表未满足的临床需求。先前的研究表明microRNA在玩在包括乳腺癌（包括乳腺癌的转移）形成中起着重要作用。考虑到很少乳腺癌转移患者的选择，在此提案中，我们专注于靶向miR-10b 被证明是负责转移性传播的原因。虽然先前的研究表明miR-10b驱动入侵和癌细胞从原发性肿瘤的迁移，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，转移细胞的存活至关重要地取决于高水平的miR-10b表达。这一发现构成了我们针对的治疗策略的基石转移性肿瘤细胞的特异性根除。这将使用具有成像能力的模块化纳米果完成，分散到肺，肝脏，骨骼或脑转移。这些纳米果由磁性纳米颗粒组成携带锁定的核酸（LNA）寡核苷酸抑制microRNA-10B。定位部分共轭到纳米颗粒促进了它们在遥远转移部位的积累。以前我们已经证明了拟议方法的可行性。将纳米果递送到已经形成的淋巴结转移导致通过抑制肿瘤细胞增殖并引起转移性进展凋亡，这是一种以前没有描述的现象。当用纳米果处理是与低剂量的常规化学疗法（阿霉素）结合在一起，有消退和永久性消除淋巴结或肺转移，即使停止治疗后也没有复发。与众不同常规的化学疗法，该治疗方案与动物的发病率/死亡率无关。在我们建议将MIR10B抑制性纳米果与低剂量结合使用的当前应用化学疗法（如有必要）靶向遥远器官中的乳腺癌转移。无创成像将用于评估纳米果的传递。如果成功的话，这种方法可能是一种生活 - 为患有晚期转移性疾病的患者延长（可能是挽救生命的）替代方案打捞疗法是当前唯一的选择。