Targeting innate immune pathways in breast cancers with chromosomal instability

针对染色体不稳定乳腺癌的先天免疫途径

基本信息

批准号：
10704103
负责人：
Samuel F Bakhoum
金额：
$ 46.23万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
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：
2020-08-13 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10704103
关键词：
Address Adenosine Adjuvant Chemotherapy Autophagocytosis Behavior Biological Markers Biological Specimen Banks Breast Cancer Cell Breast Cancer Model Breast Cancer Treatment Breast cancer metastasis Cell Death Cell Senescence Induction Cell physiology Cells Cellular Immunity Chromosomal Instability Chromosome Segregation Chromosomes Chronic Clinical Colon Carcinoma Cyclic AMP Cytoplasm Cytosol Cytotoxic Chemotherapy DNA Data Development Disease Distant Encapsulated Epithelial Cells Exposure to Extracellular Space Flow Cytometry Generations Genomic DNA Genomic Instability Genomics Goals Human Hydrolysis Immune Immune Evasion Immune signaling Immunohistochemistry Immunologic Surveillance Immunophenotyping Immunosuppressive Agents Immunotherapeutic agent Immunotherapy Inflammation Inflammatory Interferon Activation Interferon Type I Interferons Malignant Neoplasms Mammary Neoplasms Measures Mediating Metabolic Metastatic breast cancer Metastatic/Recurrent Microdialysis Mitosis Modeling Mus Mutation Neoadjuvant Therapy Neoplasm Metastasis Nuclear Organ Paclitaxel Pathologic Pathology Pathway interactions Patient-derived xenograft models of breast cancer Patients Preclinical Testing Prediction of Response to Therapy Recurrence Research Resistance Role Rupture Sampling Second Messenger Systems Signal Transduction Source Specimen Stimulator of Interferon Genes System T-Lymphocyte Techniques Testing Therapeutic Tumor Subtype Validation Viral Work Xenograft procedure aggressive breast cancer cancer cell cancer subtypes cancer therapy chemotherapy chromosome missegregation ds-DNA ecto-nucleotidase extracellular first-in-human genetic manipulation inhibitor innate immune pathways malignant breast neoplasm melanoma micronucleus mouse model neoplastic cell new therapeutic target novel novel marker novel therapeutic intervention patient derived xenograft model pharmacologic pre-clinical predicting response predictive marker prevent prospective response response biomarker senescence single-cell RNA sequencing therapy resistant tool treatment response triple-negative invasive breast carcinoma tumor tumor-immune system interactions viral DNA

项目摘要

PROJECT SUMMARY/ABSTRACT While considerable progress has been made in treating primary breast cancers, metastatic breast cancers re- main a challenge. Metastatic breast cancer cells typically have chromosomal instability (CIN) that involves chromosome-level alterations leading to genomic copy number abnormalities. A major challenge in targeting breast cancers driven by CIN is the lack of known targetable alterations. We recently found that CIN pro- motes chronic inflammatory signaling in cancer cells. As chromosomes missegregate, they often become en- capsulated in micronuclei. Subsequent micronuclear rupture exposes genomic double-stranded DNA to the cytosol. Cytosolic DNA activates anti-viral innate immune pathways, chief among which is cGAS-STING signal- ing. Under normal circumstances, cGAS-STING activation promotes type I interferon and facilitates cell- mediated immunity. Engagement of STING in normal epithelial cells induces senescence and cell death. We have shown that cancer cells, however, are intrinsically resistant to cGAS-STING activation by virtue of their chronic exposure to cytosolic DNA. Instead, they upregulate alternative pathways downstream of STING, such as NF-κB signaling. The extent to which cancer cells depend on chronic inflammatory signaling is poorly un- derstood. More importantly, how they subvert innate immune signaling to avoid immune surveillance remains unknown. Our ongoing work reveals that cGAS-STING signaling is sequestered in cancer cells away from the host. Furthermore, human breast tumors upregulate ENPP1, a negative regulator of cGAS-STING signaling. ENPP1 enables immune evasion by degrading cGAMP, the second messenger produced by cGAS, only in the extracellular space. As such ENPP1 prevents host STING activation in response to tumor-to-host cGAMP transfer. Strikingly, pharmacologic inhibition of STING suppresses metastasis in syngeneic models of melano- ma, breast, and colon cancers. We postulate this is because its inhibition in tumor cells outweighs its protective role in the host. Building on this work, we will expand our pre-clinical testing of STING inhibition in breast can- cer probing its efficacy in delaying metastasis and therapeutic resistance (Aim 1). We will then examine whether cGAMP contributes toward the formation of an immune suppressive microenvironment through meta- bolic breakdown in the extracellular space (Aim 2). Finally, we will develop cGAS-STING-based biomarkers in prospectively collected tumor specimens. We will test whether the status of cGAS-STING signaling and ENPP1 levels can predict response to neoadjuvant chemotherapy and atezolizumab, an immunotherapeutic recently approved for the treatment of metastatic breast cancer (Aim 3). Our work addresses a clinically unmet need by targeting a subset of breast cancers with CIN and for which there are limited therapeutic options. If successful it will provide pre-clinical rationale for first-in-human testing of STING inhibitors for the treatment of cancer metastasis as well as the development of novel CIN-related biomarkers to predict therapeutic response.

项目概要/摘要虽然在治疗原发性乳腺癌方面取得了相当大的进展，但转移性乳腺癌仍然存在主要的挑战是转移性乳腺癌细胞通常具有染色体不稳定性（CIN）。染色体水平的改变导致基因组拷贝数异常是靶向的主要挑战。 CIN 驱动的乳腺癌是缺乏已知的可靶向改变，我们最近发现 CIN 亲-。当染色体错误分离时，它们常常会导致癌细胞中的慢性炎症信号传导。随后的微核破裂使基因组双链 DNA 暴露于微核中。胞浆 DNA 激活抗病毒先天免疫途径，其中主要是 cGAS-STING 信号 - 正常情况下，cGAS-STING 激活可促进 I 型干扰素并促进细胞- STING 参与正常上皮细胞会诱导衰老和细胞死亡。然而，已经表明癌细胞凭借其自身特性对 cGAS-STING 激活具有本质抵抗力。相反，它们会上调 STING 的替代下游途径，例如 NF-κB 信号传导癌细胞对慢性炎症信号传导的依赖程度尚不清楚。更重要的是，他们如何破坏先天免疫信号以避免免疫监视仍然存在。我们正在进行的工作表明，cGAS-STING 信号被隔离在癌细胞中，远离癌细胞。此外，人类乳腺肿瘤上调 ENPP1，这是 cGAS-STING 信号传导的负调节因子。 ENPP1 通过降解 cGAMP（cGAS 产生的第二信使）来实现免疫逃避，仅在因此，ENPP1 可以阻止宿主 STING 响应肿瘤至宿主 cGAMP 的激活。引人注目的是，STING 的药理学抑制可抑制黑素同基因模型中的转移。我们推测这是因为它对肿瘤细胞的抑制作用超过了它的保护作用。在这项工作的基础上，我们将扩大对乳腺癌 STING 抑制的临床前测试。 cer 探讨其在延迟转移和治疗耐药方面的功效（目标 1）。 cGAMP 是否有助于通过元-抑制免疫微环境的形成最后，我们将开发基于 cGAS-STING 的生物标志物。我们将前瞻性地收集肿瘤标本来测试cGAS-STING信号传导的状态。 ENPP1 水平可以预测对新辅助化疗和 atezolizumab（一种免疫治疗药物）的反应最近被批准用于治疗转移性乳腺癌（目标 3）。我们的工作解决了临床上未满足的问题。需要针对患有 CIN 的乳腺癌子集，并且治疗选择有限。成功将为 STING 抑制剂治疗的首次人体测试提供临床前依据癌症转移以及开发新的 CIN 相关生物标志物来预测治疗反应。