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：
10319586
负责人：
Anice C Lowen
金额：
$ 38.1万
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 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10319586
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.

该提案的目的是确定促进呼肠孤病毒感染和 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癌细胞杀伤的小分子抑制剂。在美国，乳腺癌是癌症的主要原因，也是女性癌症相关死亡的主要原因。哺乳动物正呼肠孤病毒（呼肠孤病毒）是一种分节段、无包膜 dsRNA 病毒，主要感染转化细胞，目前正在进行 I-III 期临床试验，以评估其作为病毒溶瘤剂对抗多种癌症的功效。初步数据表明，血清型 1 呼肠孤病毒比血清型 3 呼肠孤病毒诱导更有效的 TNBC 细胞死亡，并且细胞死亡通过不依赖 caspase 3 的途径发生。 RNA测序显示，在呼肠孤病毒感染TNBC细胞期间，IL-24高度上调，高通量筛选鉴定出拓扑异构酶抑制剂（阿霉素、表柔比星、依托泊苷和托泊替康），当与呼肠孤病毒配对时，可有效促进TNBC细胞死亡。核心假设是，在拓扑异构酶抑制剂存在的情况下，血清型 1 呼肠孤病毒感染呼肠孤病毒会诱导互补信号通路，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。这些实验将加深对病毒杀死癌细胞机制的理解，定义病毒和小分子抑制剂的组合方案如何影响病毒感染，并为 TNBC 患者制定个性化治疗方案提供信息。