Hematopoietic stem cell based gene therapy of breast cancer

基于造血干细胞的乳腺癌基因治疗

• 批准号: 9035380
• 负责人: ANDRE Michael LIEBER
• 金额: $ 16.8万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9035380
• 关键词: AMD3100; AP20187; Adenoviruses; Affect; Affinity; Beta-glucuronidase; Binding; Biopsy; Blood Circulation; Bone Marrow; Breast Cancer Cell; Breast Cancer Detection; Breast Cancer Early Detection; Breast Cancer Model; Breast Carcinoma; CD46 Antigen; CSF3 gene; Cancer Patient; Carmustine; Cell Culture Techniques; Cell Transplantation; Cells; Chemicals; Clinical Research; Cytosine deaminase; Cytotoxic T-Lymphocytes; Data; Diagnostic; Dimerization; Disadvantaged; Disease Resistance; Disease remission; Early Diagnosis; Engineered Gene; Engraftment; Enzymes; Equus caballus; Flucytosine; Fluorouracil; Gene Expression; Gene Expression Regulation; Gene Transfer; Genetic; Genetic Engineering; Glucuronides; Goals; Health; Hematopoietic stem cells; Heterogeneity; Human; Immune; Implant; Injection of therapeutic agent; Intervention; Intravenous; Lentivirus Vector; Luciferases; MGMT gene; Macrophage Activation; Malignant Neoplasms; Malignant neoplasm of ovary; Mammary Neoplasms; Membrane; MicroRNAs; Monitor; Mus; Myeloid Cells; Neoplasm Metastasis; Operative Surgical Procedures; Patients; Pattern; Pharmaceutical Preparations; Physiological Processes; Procedures; Prodrugs; Protocols documentation; Recruitment Activity; Recurrence; Regulatory T-Lymphocyte; Relaxin; Reporter; Reporter Genes; Reporting; Resistance; Severities; Signal Transduction; Site; Source; Spleen; Stem cells; Supporting Cell; System; Tacrolimus Binding Proteins; Testing; Thrombopoietin; Time; Transgenes; Transgenic Mice; angiogenesis; base; bone; cancer cell; cancer therapy; cell growth; cellular transduction; chemokine; chemotherapy; cytokine; gene therapy; genome editing; implantation; in vivo; in vivo imaging; killings; macrophage; malignant breast neoplasm; neoplastic cell; outcome forecast; pluripotency; progenitor; response; stem; targeted treatment; therapeutic gene; therapeutic transgene; transgene expression; tumor; tumor growth; tumor microenvironment; tumor progression; vector

 DESCRIPTION (provided by applicant): Although initial response rates of breast cancer to surgery and mAb/chemotherapy are high, most patients will recur with treatment resistant disease, and maintaining complete remission has proven elusive. All of the current classical and experimental treatment options for ovarian cancer patients are focused on destroying the malignant cells. These genetically unstable and heterogeneous cells are a moving target for therapies. The tumor stroma contains genetically stable tumor-infiltrating myeloid cells, of which the tumor-associated macrophages (TAMs) are the dominant species. The central new idea of this proposal is to use the patho-physiological process of recruitment of hematopoietic stem cells (HSC) to the tumor stroma to deliver therapeutic genes into tumors. We propose a simple procedure involving G-CSF/AMD3100 mobilization and intravenous HD-Ad5/35++ vector injection to genetically engineer HSCs in cancer patients. These HSCs will provide a long-term source of genetically modified TAM progenitors that will be actively recruited by the tumor. Once differentiated into TAMs, a gene expression system will be activated that allows for the elimination of TAMs and neighboring tumor cells. Potentially our approach can also allow for the early detection of recurrent breast cancer based on the recruitment of TAMs and activation of TAM-specific reporter gene expression. The goals of this proposal are to increase the percentage of transgene-expressing TAMs and to test whether in vivo gene-engineered HSCs can be used for breast cancer detection and therapy. The Specific Aims are: Specific Aim 1. Test approaches that allow for the in vivo expansion of gene-engineered HSCs. Specific Aim 2: Track TAM differentiation and recruitment to tumor and test whether this can be used for early detection of breast cancer. Specific Aim 3. Test whether the selective killing of TAMs and neighboring tumor cells stops tumor growth in mouse breast cancer models.

 描述(申请人提供)：尽管乳腺癌对手术和单抗/化疗的初步应答率很高，但大多数患者会因耐药疾病而复发，保持完全缓解已被证明是难以捉摸的。目前对卵巢癌患者的所有经典和实验治疗方案都集中在摧毁恶性细胞上。这些遗传上不稳定和异质的细胞是治疗的移动目标。肿瘤间质含有遗传稳定的肿瘤浸润性髓系细胞，其中肿瘤相关巨噬细胞(TAMs)是优势细胞。这一提议的中心新想法是利用造血干细胞(HSC)向肿瘤间质募集的病理生理过程将治疗基因输送到肿瘤中。我们提出了一种简单的方法，包括G-CSF/AMD3100动员和静脉注射HD-Ad5/35++载体来对癌症患者的HSC进行基因工程。这些造血干细胞将为肿瘤主动招募的转基因祖细胞提供长期来源。一旦分化成TAMs，就会激活一个基因表达系统，从而消除TAMs和邻近的肿瘤细胞。潜在地，我们的方法还可以基于TAMs的招募和特异性报告基因的激活来早期发现复发的乳腺癌。这项提议的目标是增加转基因表达TAMs的比例，并测试体内基因工程HSCs是否可以用于乳腺癌的检测和治疗。具体目标是：特定目标1.允许基因工程造血干细胞体内扩增的测试方法。具体目标2：追踪对肿瘤的分化和募集情况，并检验其是否可以用于乳腺癌的早期发现。特定目的3.检测选择性杀伤TAMs及邻近肿瘤细胞是否能阻止小鼠乳腺癌模型的肿瘤生长。