Aptamer-siRNA Chimeras Targeting HER2-Positive Breast Cancers

靶向 HER2 阳性乳腺癌的适体-siRNA 嵌合体

• 批准号: 8462456
• 负责人: Paloma Hoban Giangrande
• 金额: $ 29.59万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-10 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8462456
• 关键词: Adverse effects; Animal Model; Antibodies; Apoptotic; Binding; Breast; Breast Cancer Cell; Breast Cancer Treatment; Breast Carcinoma; Cancer Patient; Cell Death; Cell surface; Cells; Cessation of life; Chimera organism; Clinical Trials; Combined Modality Therapy; Complex; Country; Data; Development; Disease; Disease Resistance; ERBB2 gene; ERBB3 gene; Engineering; Epidermal Growth Factor Receptor; Epithelial Cells; Exhibits; Family; Future; Gene Silencing; Genes; Goals; Growth; Growth Factor Receptors; Human; Knowledge; Laboratories; Lead; Ligands; Malignant Epithelial Cell; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Methods; Modality; Mouse Mammary Tumor Virus; Mus; Nature; Neoplasm Metastasis; Patients; Phenotype; Property; Protein Tyrosine Kinase; RNA; Rattus; Reagent; Refractory Disease; Research; Resistance; Resistance development; Rodent Model; Safety; Small Interfering RNA; Specificity; Techniques; Technology; Testing; Therapeutic; Toxic effect; Transgenic Mice; Transgenic Organisms; Treatment Efficacy; Treatment outcome; Woman; Work; Xenograft Model; advanced disease; anticancer research; aptamer; base; cancer cell; cell type; cytotoxic; effective therapy; expectation; fighting; human disease; improved; in vivo; inhibitor/antagonist; killings; malignant breast neoplasm; member; mouse model; novel; novel therapeutics; outcome forecast; public health relevance; response; therapeutic target; therapy resistant; tumor xenograft

DESCRIPTION (provided by applicant): The recognition that one out of 4 breast cancers exhibits elevated levels of the epidermal growth factor receptor type 2 (HER2) is one of the most significant recent discoveries in breast cancer research. HER2 is associated with advanced disease and typifies cancers that are fast growing, highly metastatic, and resistant to treatment. As such, patients with HER2-positive breast cancers have a worse prognosis compared to patients with HER2-negative breast cancers. Despite recent advances in treatments, the outcome for HER2-positive breast cancer patients with advanced disease is death. Several reasons have been proposed for this. One reason is insensitivity or resistance to treatment resulting from the complex nature of the disease. The second reason is toxicity associated with the non-specific nature of the treatments themselves. Therefore, there is an increasing need for developing safer, more effective treatments for HER2-positive breast tumors. We propose to develop a novel reagent that is specific and circumvents many of the adaptive responses of HER2-positive breast cancers that lead to resistance. These properties will be achieved by engineering a multifunctional inhibitor composed of a targeting moiety (an RNA aptamer that binds to HER2) and a therapeutic moiety (a cytotoxic siRNA to breast cancer specific pro-survival factors). Upon binding to HER2 on the cell-surface, the reagent will deliver its therapeutic cargo into the cells resulting in cancer cell death. In addition to inhibiting pro-survival factors, this reagent has the potential to antagonize the activity of HER2 itself by promoting its degradation (combination therapy). During the five-year project we propose to validate this approach in proof-of-concept studies using rodent models of breast cancer. The knowledge derived from this work will be used to develop a human-specific therapeutic modality with emphasis on safety and therapeutic efficacy. Our specific aims are to (1) apply cutting-edge RNA technologies to inhibit pro-survival factors in HER2-positive breast cancer cells, (2) determine efficacy and safety of this reagent in rodent models of breast cancer, and (3) develop human-specific reagents and evaluate efficacy in human breast cancer cells and in mouse models of human breast cancer. At the completion of these studies, it is our expectation that we will have identified reagents for targeting HER2-positive breast tumors (as well as other HER2-expressing cancers). In addition, this work will develop general principles that can be applied towards the establishment of a platform technology for generating targeted gene silencing therapies against other cancers. The successful completion of this work is expected to provide clinicians as well as breast cancer patients, including patients with refractory disease, with improved treatment choices for fighting HER2-positive cancers of the breast.

描述（由申请人提供）：认识到四分之一的乳腺癌表现出表皮生长因子受体2型（HER2）水平升高是乳腺癌研究中最重要的最新发现之一。HER2与晚期疾病相关，属于快速生长、高度转移和对治疗有耐药性的癌症。因此，her2阳性乳腺癌患者的预后比her2阴性乳腺癌患者差。尽管最近在治疗方面取得了进展，但her2阳性乳腺癌晚期患者的结局是死亡。对此提出了几个原因。其中一个原因是由于该病的复杂性导致对治疗的不敏感或抵抗。第二个原因是与治疗本身的非特异性有关的毒性。因此，越来越需要开发更安全、更有效的治疗her2阳性乳腺肿瘤的方法。我们建议开发一种新的试剂，它是特异性的，并绕过许多导致her2阳性乳腺癌耐药的适应性反应。这些特性将通过设计一种多功能抑制剂来实现，该抑制剂由靶向部分（与HER2结合的RNA适体）和治疗部分（针对乳腺癌特异性促生存因子的细胞毒性siRNA）组成。在与细胞表面的HER2结合后，该试剂将其治疗货物运送到细胞中，导致癌细胞死亡。除了抑制促生存因子外，该试剂还具有通过促进HER2降解（联合治疗）来拮抗HER2本身活性的潜力。在为期五年的项目中，我们建议在使用乳腺癌啮齿动物模型的概念验证研究中验证这种方法。从这项工作中获得的知识将用于开发一种强调安全性和疗效的人类特异性治疗方式。我们的具体目标是：(1)应用尖端RNA技术抑制her2阳性乳腺癌细胞中的促生存因子，(2)确定该试剂在啮齿动物乳腺癌模型中的有效性和安全性，(3)开发人类特异性试剂并评估在人类乳腺癌细胞和人类乳腺癌小鼠模型中的有效性。在这些研究完成后，我们期望能够确定针对her2阳性乳腺肿瘤（以及其他表达her2的癌症）的试剂。此外，这项工作将制定一般原则，可应用于建立一个平台技术，用于产生针对其他癌症的靶向基因沉默疗法。这项工作的成功完成有望为临床医生和乳腺癌患者，包括难治性疾病患者，提供更好的治疗选择，以对抗her2阳性乳腺癌。

项目成果

AFBI assay - Aptamer Fluorescence Binding and Internalization assay for cultured adherent cells.

AFBI 测定 - 适用于培养的贴壁细胞的适体荧光结合和内化测定。

• DOI: 10.1016/j.ymeth.2016.03.005
• 发表时间: 2016
• 期刊: Methods (San Diego, Calif.)
• 作者: Thiel,WilliamH;Giangrande,PalomaH
• 通讯作者: Giangrande,PalomaH

EphA2 receptor is a key player in the metastatic onset of Ewing sarcoma.

• DOI: 10.1002/ijc.31405
• 发表时间: 2018-09-01
• 期刊: International journal of cancer
• 影响因子: 6.4
• 作者: Garcia-Monclús S;López-Alemany R;Almacellas-Rabaiget O;Herrero-Martín D;Huertas-Martinez J;Lagares-Tena L;Alba-Pavón P;Hontecillas-Prieto L;Mora J;de Álava E;Rello-Varona S;Giangrande PH;Tirado OM
• 通讯作者: Tirado OM

Aptamer-miRNA-212 Conjugate Sensitizes NSCLC Cells to TRAIL.

• DOI: 10.1038/mtna.2016.5
• 发表时间: 2016-03-08
• 期刊: Molecular therapy. Nucleic acids

Methods for Evaluating Cell-Specific, Cell-Internalizing RNA Aptamers.

• DOI: 10.3390/ph6030295
• 发表时间: 2013-03-14
• 期刊: Pharmaceuticals (Basel, Switzerland)
• 作者: Hernandez LI;Flenker KS;Hernandez FJ;Klingelhutz AJ;McNamara JO 2nd;Giangrande PH
• 通讯作者: Giangrande PH

Analyzing HT-SELEX data with the Galaxy Project tools--A web based bioinformatics platform for biomedical research.

• DOI: 10.1016/j.ymeth.2015.10.008
• 发表时间: 2016-03-15
• 期刊: Methods (San Diego, Calif.)
• 作者: Thiel WH;Giangrande PH
• 通讯作者: Giangrande PH