Oncolytic Viruses with Therapeutic Genes in the Treatment of Breast Cancer

具有治疗基因的溶瘤病毒治疗乳腺癌

• 批准号: 8384916
• 负责人: Danuta B Kozbor
• 金额: $ 19.31万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8384916
• 关键词: Affect; Aftercare; Apoptosis; Autologous; Behavior; Blood Vessels; Blood flow; Breast Cancer Treatment; Breast Carcinoma; CSF3 gene; CXCL12 gene; CXCR; CXCR4 Receptors; CXCR4 gene; Cell Communication; Cell Differentiation process; Cells; Clinical; Combined Modality Therapy; Cytolysis; Development; Education; Effectiveness; Epithelial; Event; Excision; Exhibits; Fibroblasts; Fluorescence; Goals; Growth; Human; IFN consensus sequence binding protein; ITGAM gene; Inbred BALB C Mice; Infection; Infiltration; Inflammatory; Interleukin-10; Interleukin-12; Knock-out; Knockout Mice; Knowledge; Ligands; Lung; Malignant Epithelial Cell; Malignant Neoplasms; Malignant Stromal Cell; Mammary Neoplasms; Measures; Modeling; Mus; Myelogenous; Myeloid Cells; Neoplasm Metastasis; Oncolytic; Oncolytic viruses; Pathogenesis; Perfusion; Peripheral; Phenotype; Population; Primary Neoplasm; Process; Production; Proteins; Receptor Signaling; Relative (related person); Role; SCID Mice; Signal Pathway; Specimen; Spleen; Stromal Cell-Derived Factor 1; Stromal Cells; Therapeutic; Transgenic Mice; Tumor-Derived; Vaccinia virus; Vascular Endothelial Growth Factors; Virus; Xenograft procedure; adaptive immunity; cancer cell; cell transformation; chemokine; comparative; cytokine; density; design; granulocyte; killings; macrophage; malignant breast neoplasm; neoplastic cell; neutrophil; preclinical study; progenitor; research study; therapeutic gene; tumor; tumor growth; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Oncolytic viruses are designed to eliminate tumors by direct infection and lysis of cancer cells. Recently, we and others have observed that in addition to a direct tumor killing by the virus there is also an indirect cytopathic effect due to vascular collapse associated with a loss of blood flow to the interior of the tumor and infiltration by peripheral Gr1+CD11b+ neutrophils. Furthermore, our preliminary results demonstrated that oncolytic vaccinia virus (OVV) expressing an antagonist of the CXCR4 receptor for CXCL12 chemokine (OVV- CXCR4-A-Fc) was more effective in inhibiting growth of triple-negative (TN) breast carcinomas 4T1 in syngeneic mice compared to the treatment with OVV expressing the enhanced green fluorescence protein (OVV-EGFP). The inhibition of primary and metastatic tumors by OVV-CXCR4-A-Fc was associated with i) an increased expression of interferon regulatory factor-8 (IRF8), a putative determinant of protumorigenic behavior of MDSCs, in tumor-infiltrating granulocytes, ii) reduced percentage of FAP+ cancer associated fibroblasts (CAFs), iii) decreased levels of CXCL12, and iv) collapse of the tumor vasculature. These changes within the tumor microenvironment were either not observed (such as elevated expression of IRF8) or were less pronounced after treatment with OVV-EGFP. The mechanism by which OVV-CXCR4-A-Fc affects interaction between CAFs and MDSCs and expression of IRF8 is unclear. We hypothesize that the enhanced expression of IRF8 in MDSCs and promotion of their differentiation toward type 1 phenotype with antitumorigenic activity is regulated by the CXCL12/CXCR4 ligand/receptor signaling pathway in CAFs. We propose to identify the key events of the CAF/MDSC interaction that regulates expression of IRF8 by analyzing changes in the production of tumor- derived factors (TDFs) in 4T1-bearing syngeneic mice and human breast carcinoma MDA-MB-23 xenografts in SCID mice. The Specific Aims are: 1). We will compare quantitative and qualitative changes in CAFs, myeloid cells, epithelial tumor cells, TDFs, and tumor vasculature induced by OVV-EGFP and OVV-CXCR4-A-Fc treatments. 2). Using IRF8 knockout and IRF8 transgenic mice and autologous AT-3 breast carcinoma cells, we will explore the role of IRF8 in modulation of myeloid differentiation after blocking the CXCL12/CXCR4 ligand/receptor signaling pathway by OVV-CXCR4-A-Fc. 3). Using the established 4T1 breast tumor model for spontaneous lung metastasis, we will compare the reciprocal dynamics in colonization of a metastatic niche in the lungs by IRF8+ MDSCs and mature neutrophils after OVV-CXCR4-A-Fc and OVV-EGFP treatments. We anticipate that understanding the activation of inflammatory cells can be used for enhancing the effectiveness of OV therapeutics for treatment of the highly aggressive tumors. PUBLIC HEALTH RELEVANCE: We propose to investigate changes in the dynamic interaction between malignant and stromal cells that facilitate tumor-free survival and provide a clear understanding of the role of the CXCR4/SDF-1 signaling pathway in breast cancer pathogenesis. The goal of this application is to target CXCR4 expression in triple- negative breast carcinomas by an oncolytic virotherapy expressing CXCR4 antagonist and elucidate the mechanism of primary and metastatic tumor growth inhibition in preclinical studies in mice. We anticipate that a combination therapy that attacks both malignant cells and the 'other half' of the tumor mass (that is, the stromal cells) could be more effective and might also elicit long-lasting adaptive immunity to the transformed cells.

描述（由申请人提供）：溶瘤病毒旨在通过直接感染和癌细胞裂解来消除肿瘤。最近，我们和其他人观察到，除了病毒直接杀死肿瘤外，还由于血管塌陷而导致的间接细胞病变作用，与流向肿瘤内部的血液流失相关，并被外周GR1+ CD11b+中性粒细胞浸润。此外，我们的初步结果表明，表达CXCR4受体的拮抗剂cxcl12趋化因子（OVV-CXCR4-A-A-FC）在抑制Triple-Nagation（TN）乳腺癌4T表达中的cxcr12趋化因子（OVV-CXCR4-A-FC）方面，表达CXCR4受体的拮抗剂（OVV-CXCR4-A-A-FC）相比，我们的初步疫苗的癌疫苗（OVV）更有效蛋白质（OVV-EGFP）。 OVV-CXCR4-A-FC对原发性和转移性肿瘤的抑制与I）与MDSC的产生性行为的推定的决定因素相关，这是MDSC的推定的，在肿瘤浸润型肉芽肿的摄入率（II）降低fap+ canfib cance canf canf caffibs）的推定的决定因素，II CXCL12和IV）肿瘤脉管系统的崩溃。未观察到肿瘤微环境中的这些变化（例如IRF8的表达升高），或者在用OVV-EGFP处理后不太明显。 OVV-CXCR4-A-FC影响CAFS与MDSC之间的相互作用以及IRF8表达的机制尚不清楚。我们假设MDSC中IRF8的表达增强，并促进其对具有抗肿瘤活性的1型表型的分化，受CAF中的CXCL12/CXCR4配体/受体信号通路调节。我们建议通过分析在SCID小鼠中识别肿瘤衍生因子（TDFS）的产生变化，以确定CAF/MDSC相互作用的关键事件，该事件通过分析4T1含有的syngeneic小鼠和人类乳腺癌MDA-MB-23 Xenograft在SCID小鼠中调节IRF8的表达。具体目的是：1）。我们将比较由OVV-EGFP和OVV-CXCR4-A-FC处理诱导的CAF，髓样细胞，上皮肿瘤细胞，TDF和肿瘤脉管系统的定量和定性变化。 2）。使用IRF8基因敲除和IRF8转基因小鼠以及自体AT-3乳腺癌细胞，我们将通过OVV-CXCR4-A-A-A-A-A-A-A-A-A阻断CXCL12/CXCR4配体/受体信号传导途径后，我们将探索IRF8在调节髓样分化中的作用。 3）。使用已建立的4T1乳腺肿瘤模型用于自发肺转移，我们将比较OVV-CXCR4-A-A-FC和OVV-EGFP处理后，IRF8+ MDSC和成熟的中性粒细胞在肺中通过IRF8+ MDSC和成熟的中性粒细胞在肺中定植的相互动力学。我们预计了解炎性细胞的激活可用于增强OV疗法治疗高度侵袭性肿瘤的有效性。 公共卫生相关性：我们建议研究恶性和基质细胞之间动态相互作用的变化，以促进无肿瘤生存，并清楚地了解CXCR4/SDF-1信号传导途径在乳腺癌发病机理中的作用。该应用的目的是通过表达CXCR4拮抗剂的溶瘤病毒疗法靶向三重阴性乳腺癌中的CXCR4表达，并阐明小鼠临床前研究中原发性和转移性肿瘤生长抑制的机制。我们预计，一种攻击恶性细胞和其他“另一半”的组合疗法 肿瘤质量（即基质细胞）可能更有效，也可能引起对转化细胞的持久适应性免疫。