Determining the role of the SDF-1/CXCR4 pathway and its intersection with chronic stress to establish novel precision approaches to head and neck cancer management

确定 SDF-1/CXCR4 通路的作用及其与慢性应激的交叉点，以建立头颈癌管理的新型精准方法

• 批准号: 10642091
• 负责人: Joseph Zenga
• 金额: $ 21.88万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642091
• 关键词: AMD3100; Animal Model; Animals; Autologous; Biological Models; Bone Marrow; CD34 gene; CXCR4 gene; Cancer cell line; Cell Line; Chronic; Chronic stress; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Complex; Data; Deglutition; Development; Disease; Disease Outcome; Disease-Free Survival; Engineering; Engraftment; Excision; Exposure to; Foundations; Gene Expression Profile; Growth; HPV-negative head and neck cancer; Harvest; Head and Neck Cancer; Hematopoietic stem cells; High Prevalence; High-Risk Cancer; Human; Immune; Immune response; Immune system; Immunodeficient Mouse; Immunologic Deficiency Syndromes; Immunophenotyping; Immunosuppression; Injections; Intervention; Investigation; Ligands; Link; Malignant Neoplasms; Measures; Metastatic Neoplasm to the Lung; Methodology; Modeling; Mouth Neoplasms; Mus; Neoplasm Metastasis; Observational Study; Operative Surgical Procedures; Oropharyngeal; Outcome; Pathway interactions; Patient Recruitments; Patients; Plasma; Play; Population; Pre-Clinical Model; Precision therapeutics; Prognosis; Randomized; Recurrent Malignant Neoplasm; Research Design; Role; Sampling; Social isolation; Specimen; Speech; Stress; Stromal Cell-Derived Factor 1; Surgical Flaps; System; Testing; Therapeutic; Time; Transplantation; Tumor-Derived; Umbilical Cord Blood; Up-Regulation; Xenograft Model; Xenograft procedure; antagonist; arm; bone; cancer cell; cancer recurrence; cancer surgery; carcinogenesis; chemoradiation; clinical investigation; clinically relevant; cytokine; design; drug development; experience; experimental study; fibula; head and neck cancer patient; high risk; human stem cells; humanized mouse; improved; in vivo Model; mouse model; novel; patient derived xenograft model; patient subsets; personalized approach; pre-clinical; prospective; reconstruction; recruit; socioeconomic adversity; socioeconomics; stressor; transcriptome sequencing; tumor; tumor growth; tumor microenvironment; tumor progression

PROJECT ABSTRACT/SUMMARY Substantial pre-clinical evidence has demonstrated stress-induced tumor progression in animal models of head and neck cancer (HNC). Clinically, patients with locoregionally advanced Human Papillomavirus (HPV)-negative HNC are exposed to a broad range of chronic stressors. The link between cancer progression and chronic stress may be one contributing explanation for the persistently poor oncologic outcomes of the HPV-negative HNC population. To evaluate mechanism and develop therapeutics, animal models of chronic stress are needed. However, existing models use either immunodeficient mice or syngeneic murine tumors, neither of which recapitulate the human tumor microenvironment (TME). To overcome these limitations, we developed a novel mouse model of chronic stress engineered to have a human immune system and carry human HNC xenografts. In preliminary studies using this model, chronic stress led to increased tumor growth and metastases associated with higher levels of circulating stromal-derived factor 1 (SDF-1) and immune alterations in the TME. Taken together, we hypothesize that chronic stress leads to SDF-1/CXCR4 pathway upregulation which induces an immunotolerant TME and increased tumor growth and metastasis in HNC. To test this hypothesis and determine clinical relevance, we will investigate the mechanisms underlying stress-induced tumor growth in both cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) humanized models of HNC. We will further evaluate clinical relevance through a prospective observational study in patients undergoing HNC surgery. In Aim 1, humanized CDX mice will be randomized to chronic social isolation stress or control conditions. Three arms will be designed including (1) animals treated with a CXCR4 antagonist, (2) HNC xenografts with a CXCR4 deletion, and (3) a control arm with wild-type HNC xenografts. Tumor growth and lung metastases will be measured. Intra-tumoral immunophenotyping and RNA sequencing will be performed. In Aim 2, we will recruit patients with locoregionally advanced HPV-negative HNC planned for surgical resection, a population with a poor prognosis and significant baseline exposure to chronic stressors. Patients will undergo plasma cytokine assessment and tumor resection specimens will undergo immunophenotyping and RNA sequencing. In a subset of these patients, autologous humanized patient-derived xenograft (PDX) models will be generated, in which the human immune system and tumor are derived from the same patient. This is uniquely feasible for HNC surgery with fibula reconstruction, as a segment of fibula bone is routinely discarded from which hematopoietic stem cells can be harvested for autologous humanization. These autologous PDX models will be randomized to chronic stress and control conditions and treated with a CXCR4 antagonist as compared with control injection. This study will be the first to investigate the mechanism of stress-induced HNC growth in the context of the SDF- 1/CXCR4 axis and the human TME. Results from the humanized pre-clinical models and parallel prospective clinical analyses will lay the foundation for development of precision therapeutics and rational clinical trial design.

项目摘要/总结 大量的临床前证据表明，在头部动物模型中， 颈癌（HNC）临床上，局部晚期人乳头瘤病毒（HPV）阴性患者 HNC暴露于广泛的慢性应激源。癌症进展与慢性压力之间的联系 可能是HPV阴性HNC的肿瘤学结局持续较差的一个解释 人口为了评估机制和开发治疗方法，需要慢性应激的动物模型。 然而，现有的模型使用免疫缺陷小鼠或同基因小鼠肿瘤，两者都不适用。 人类肿瘤微环境（TME）。为了克服这些限制，我们开发了一种新的 慢性应激小鼠模型，其经工程改造以具有人类免疫系统并携带人类HNC异种移植物。 在使用该模型的初步研究中，慢性应激导致肿瘤生长增加和相关转移 具有较高水平的循环基质衍生因子1（SDF-1）和TME中的免疫改变。 综上所述，我们假设慢性应激导致SDF-1/CXCR 4通路上调， 免疫耐受性TME和HNC中增加的肿瘤生长和转移。为了验证这一假设， 为了确定临床相关性，我们将研究应激诱导肿瘤生长的机制， 细胞系来源的异种移植物（CDX）和患者来源的异种移植物（PDX）人源化HNC模型。我们将进一步 通过在接受HNC手术的患者中进行的前瞻性观察性研究评价临床相关性。 在目标1中，将人源化CDX小鼠随机分配至慢性社会隔离应激或对照条件。三 将设计包括（1）用CXCR 4拮抗剂治疗的动物，（2）用CXCR 4拮抗剂治疗的HNC异种移植物， 缺失，和（3）具有野生型HNC异种移植物的对照组。肿瘤生长和肺转移将是 测定了将进行肿瘤内免疫表型分析和RNA测序。在目标2中，我们将招募 计划手术切除的局部晚期HPV阴性HNC患者， 预后不良和长期压力源的显著基线暴露。患者将接受血浆细胞因子 评估和肿瘤切除标本将进行免疫表型分析和RNA测序。的子集中 在这些患者中，将产生自体人源化患者来源的异种移植物（PDX）模型，其中 人类免疫系统和肿瘤来源于同一个病人。这对于HNC手术是唯一可行的 对于腓骨重建，因为腓骨的一部分通常被丢弃， 可以收获用于自体人源化。这些自体PDX模型将随机分配至慢性 应激和对照条件下并用CXCR 4拮抗剂处理的小鼠的免疫组化结果与对照注射相比。 这项研究将是第一个调查的机制，应力诱导的HNC生长的背景下，SDF- 1/CXCR 4轴和人TME。人源化临床前模型和平行前瞻性研究的结果 临床分析将为开发精确治疗和合理的临床试验设计奠定基础。