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Development of Oncolytic Reovirus for Triple-Negative Breast Cancer

用于三阴性乳腺癌的溶瘤呼肠孤病毒的开发

基本信息

批准号：
10084268
负责人：
Anice C Lowen
金额：
$ 38.18万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-10 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10084268
关键词：
Apoptosis Biology Breast Cancer Cell CASP3 gene Cancer Etiology Caspase Cell Death Cell Death Induction Cells Cessation of life Childhood Clinical Trials Cytotoxic Chemotherapy DNA Damage Data Development Disease Double Stranded RNA Virus Doxorubicin Drug Delivery Systems ERBB2 gene Epirubicin Estrogen Receptors Etoposide Growth Factor Receptors Human Immune signaling Infection Innate Immune Response Integration Host Factors Knowledge Malignant Neoplasms Mammalian Orthoreovirus Mediating Oncolytic Organoids Outcome Pathway interactions Patients Phase Plasmids Progesterone Receptors Property Radiation therapy Regimen Reovirus Reovirus 3 Reovirus Infections Reovirus Type 1 Role Serotyping Signal Pathway Survival Rate Testing Therapeutic Topoisomerase Inhibitors Topotecan Viral Virus Virus Diseases Woman base cancer cell cancer cell subtype cancer subtypes cancer type cell killing cell transformation combinatorial cytotoxicity drug efficacy experimental study high throughput screening improved malignant breast neoplasm neutralizing antibody personalized therapeutic response reverse genetics small molecule inhibitor transcriptome sequencing triple-negative invasive breast carcinoma tumor virus host interaction

项目摘要

The objective of this proposal is to identify viral and host factors that promote reovirus infection and cell killing of TNBC cells and identify small molecule inhibitors that can augment viral-mediated killing of cancer cells. In the U.S., breast cancer is the leading cause of cancer and a leading cause of cancer-related deaths in women. Mammalian orthoreovirus (reovirus) is a segmented, nonenveloped dsRNA virus that predominantly infects transformed cells and is in Phase I-III clinical trials to assess its efficacy as a viral oncolytic against several cancers. Preliminary data indicate that serotype 1 reoviruses induce more efficient TNBC cell death than serotype 3 reoviruses and that cell death occurs via a caspase 3-independent pathway. RNA sequencing showed that IL-24 is highly upregulated during reovirus infection of TNBC cells and high-throughput screening identified topoisomerase inhibitors (doxorubicin, epirubicin, etoposide, and topotecan) that when paired with reovirus promote efficacious TNBC cell death. The central hypothesis is that reovirus infection with serotype 1 reoviruses in the presence of topoisomerase inhibitors induces complementary signaling pathways that result in TNBC cell death. Two integrated specific aims are proposed. Specific Aim 1 will elucidate mechanisms of reovirus-induced cell death of triple-negative breast cancer cells. Specific Aim 2 will determine how topoisomerase inhibitors impact reovirus infection. These experiments will enhance an understanding of the mechanism viruses use to kill cancer cells, define how combinatorial virus and small molecule inhibitor regimens impact viral infection, and inform the development of personalized therapeutic options for patients afflicted with TNBC.

这项建议的目的是确定促进呼肠孤病毒感染和对TNBC细胞杀伤的病毒和宿主因素，并确定可以增强病毒介导的对癌细胞杀伤的小分子抑制剂。在美国，乳腺癌是导致癌症的主要原因，也是女性癌症相关死亡的主要原因。哺乳动物正病毒是一种节段性、无包膜的dsRNA病毒，主要感染转化的细胞，目前正处于I-III期临床试验，以评估其作为病毒溶瘤药物治疗多种癌症的疗效。初步数据表明，1型呼肠孤病毒比3型呼肠孤病毒更有效地诱导TNBC细胞死亡，并且细胞死亡是通过caspase 3不依赖的途径发生的。RNA测序表明，在呼肠孤病毒感染TNBC细胞的过程中，IL-24高度上调，高通量筛选确定的拓扑异构酶抑制剂(阿霉素、表阿霉素、依托泊苷和拓扑替康)与呼肠孤病毒配对时可促进有效的TNBC细胞死亡。中心假说是呼肠孤病毒感染1型呼肠孤病毒，在存在拓扑异构酶抑制剂的情况下，诱导互补的信号通路，导致TNBC细胞死亡。提出了两个综合的具体目标。具体目标1将阐明呼肠孤病毒诱导三阴性乳腺癌细胞死亡的机制。具体目标2将确定拓扑异构酶抑制剂如何影响呼肠孤病毒感染。这些实验将加强对病毒用来杀死癌细胞的机制的理解，确定病毒和小分子抑制物联合疗法如何影响病毒感染，并为患有TNBC的患者开发个性化治疗方案提供信息。