BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10481521
• 负责人: Xiao-Jing Wang
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10481521
• 关键词: Address; Affect; Area; Award; Biological Models; CD44 gene; CD8B1 gene; Cancer Patient; Cause of Death; Cell Lineage; Cells; Cessation of life; Clinical Trials; Clonal Expansion; Collaborations; DNA Damage; DNA Repair; DNA Repair Pathway; Defect; Development; Disseminated Malignant Neoplasm; Distant Metastasis; Epithelial; Exposure to; Fibroblasts; Funding; General Population; Genes; Genetic Engineering; Genomics; Goals; Growth; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Health; Healthcare; Human; Immune; Immune Evasion; Immune system; Immunologic Surveillance; Immunosuppression; Immunosuppressive Agents; Immunotherapy; Indolent; Intervention; Investigational Therapies; Laboratories; Link; Lung; MADH4 gene; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Metastatic Squamous Cell Carcinoma; Modeling; Myeloid Cells; Neoplasm Metastasis; Oral cavity; Organ; Outcome; Pathologic; Patients; Play; Population; Prognostic Marker; Property; Proteins; Radiation therapy; Reporting; Research; Research Personnel; Resources; Role; Scientist; Site; Skin; Squamous cell carcinoma; Stratified Epithelium; Stromal Cells; T-Cell Receptor; T-Lymphocyte; Therapeutic Intervention; Time; Tobacco-Associated Carcinogen; Transforming Growth Factor beta; Translating; Tumor Immunity; Tumor Suppressor Proteins; Tumor-associated macrophages; Up-Regulation; Veterans; WNT Signaling Pathway; angiogenesis; cancer cell; cancer site; cancer stem cell; cancer type; care outcomes; career; clinical diagnosis; clinical prognosis; cytotoxic; design; effective therapy; experimental study; high risk; human genome sequencing; improved; innovation; liquid biopsy; melanoma; migration; military veteran; mouse model; multipotent cell; mutant; neoantigens; neoplastic cell; pharmacodynamic biomarker; prognosis biomarker; prognostic value; programmed cell death ligand 1; programs; promoter; recruit; skin squamous cell carcinoma; stem cell expansion; stem cell niche; targeted cancer therapy; therapeutic biomarker; therapeutic evaluation; therapeutic target; therapeutically effective; tumor; tumor eradication; tumor heterogeneity; tumor microenvironment; tumor progression; ultraviolet irradiation; whole genome

The overarching objective of my research program is to identify markers for prognosis and therapeutic interventions for squamous cell carcinomas (SCCs), hence improving health outcomes for veterans. SCCs arise from stratified epithelia; the most relevant organ sites in veterans are the skin and oral cavity where high exposure to UV irradiation and tobacco carcinogens make the total and high-risk SCCs significantly higher than in the civilian population. The worst outcome of SCC is death caused by distant metastasis. Skin SCC deaths exceed melanoma deaths and SCC deaths in the head and neck are 3-4 times higher than skin SCC deaths. The long-term goal of my VA research program is to identify markers for prognosis and therapeutic interventions for SCCs, hence improving health outcomes for veterans. Since being funded in 2016 by a VA Merit Award, my laboratory has been studying mechanisms related to SCC progression and therapeutic interventions. These studies continuously translate into clinical diagnosis and therapeutic interventions directly impacting veterans’ healthcare outcomes. My laboratory pioneered inducible and epithelial-specific genetic engineered mouse models (GEMMs) that develop SCCs and metastasis in the natural microenvironment and immune system. These models provide unique resources for cross-species comparisons with human SCCs and performing experimental therapeutics, including immunotherapy, in my past and ongoing Merit Award research. SCCs are often indolent for decades. In the previous funding period, we focused on studying how SCCs break indolence to become aggressive and metastatic cancers. We found that the properties of a subset of cancer stem cells (CSCs) are responsible for breaking indolence through both clonogenicity and invasion. We found that “heterozygous loss” of SMAD4, a tumor suppressor, in 30-50% of head and neck SCCs in humans, is a result of significant inter- and intra-tumor heterogeneity at the single cell level, and that SMAD4 mutant cells have a growth/survival advantage allowing them to take over the entire population of tumor cells. These findings provide critical prognostic value for examining SMAD4 genomic status at the single cell level. Further, SMAD4- deficient SCC cells have “Brca-like” defects in DNA damage repair that are susceptible to cancer therapies that target DNA repair pathways. This finding provides an important link for a therapeutic marker and strategy, and instigated an investigator-initiated clinical trial to treat locally advanced head and neck SCC with radiotherapy (RT) in combination with Olaparib, which included recruiting VA patients. In tumor stroma, we found that SMAD4 genomic loss triggers overproduction of TGFβ1, an immune suppressor and promoter for cancer progression. In addition, cancer associated fibroblasts (CAFs) secret more TGFβ than cancer cells and provide a CSC niche at the distant metastasis site for CSC clonal expansion. We also found that tumor-associated macrophages (TAMs) contribute to breaking indolence by CSC expansion through anti- apoptosis and angiogenesis. Further, SMAD4 mutant SCC cells have advantages in clonogenicity and immune evasion but paradoxically produce more DNA damage-associated neoantigens susceptible to anti-tumor immunity, pointing to therapeutic intervention strategies. We identified that SCCs with Smad4 loss changed the TME to be TGFβ and PD-L1-rich in myeloid cells, which are highly susceptible to immune eradication by dual TGFβ/PD-L1 targeting. These findings are ready to be translated to a clinical trial of radiotherapy in combination with dual TGFβ/PD-L1 targeting in advanced head and neck SCC patients including VA patient accrual, thus bringing therapeutic intervention in real time to our veterans. Ongoing research areas include: 1) Assess intrinsic properties of SCC cells that contribute to self-autonomous expansion and metastasis. 2) Identify SCC metastatic niche established by stromal cells. 3) Identify mechanisms of SCC immune evasion and immunotherapy interventions for SCCs.

我的研究计划的总体目的是确定促进性和治疗的标记 鳞状细胞癌（SCC）的干预措施，从而改善了退伍军人的健康状况。 SCC出现 来自分层上皮；退伍军人中最相关的器官位置是高度高的皮肤和口腔 暴露于紫外线辐射和烟草致癌物，使总和高风险SCC显着高于 在平民中。 SCC最糟糕的结果是由远处转移引起的死亡。皮肤SCC死亡 头部和颈部的黑色素瘤死亡和SCC死亡超过皮肤SCC死亡的3-4倍。 我的VA研究计划的长期目标是确定预后和治疗干预措施的标记 对于SCC，可以改善退伍军人的健康状况。自从2016年获得VA功绩奖资助以来，我 实验室一直在研究与SCC进展和治疗干预有关的机制。这些 研究不断转化为直接影响退伍军人的临床诊断和治疗干预措施 医疗保健结果。我的实验室开创性诱导和上皮特异性基因工程小鼠 在天然微环境和免疫系统中发展SCC和转移的模型（GEMM）。 这些模型为跨物种与人类SCC进行比较提供了独特的资源并执行 在我的过去和正在进行的优点奖研究中，包括免疫疗法在内的实验疗法。 SCC是 几十年来常常懒散。在上一个资金期间，我们专注于研究SCC如何破坏懒惰 成为侵略性和转移性癌症。我们发现癌症干细胞子集的特性 （CSC）负责通过粘性和侵袭来破坏懒惰。我们发现 肿瘤抑制剂Smad4的“杂合损失”，在人类中的30-50％的头颈部SCC中是由30-50％ 在单细胞水平上明显的肿瘤内和肿瘤内异质性，Smad4突变细胞具有 生长/生存优势使他们能够接管整个肿瘤细胞的人群。这些发现 为检查单细胞水平检查SMAD4基因组状态提供关键的预后价值。此外，Smad4- 不足的SCC细胞在DNA损伤修复中具有“ BRCA样”缺陷，容易受到癌症的影响 靶向DNA修复途径的疗法。这一发现为治疗标记提供了重要的链接 和策略，并激发了一项研究人员发起的临床试验，以治疗本地高级颈部SCC 与Olaparib结合使用放射疗法（RT），其中包括招募VA患者。在肿瘤基质中，我们 发现SMAD4基因组损失会触发TGFβ1的过量生产，TGFβ1是一种免疫抑制剂和启动子 癌症进展。此外，与癌细胞相比，癌症相关的成纤维细胞（CAFS）秘密TGFβ的秘密 并在遥远的转移部位提供CSC的CSC利基市场，以进行CSC克隆膨胀。我们还发现 肿瘤相关的巨噬细胞（TAMS）有助于通过CSC扩张通过抗 - 破坏 凋亡和血管生成。此外，SMAD4突变体SCC细胞在结合性和 免疫进化，但自相矛盾地产生了更多与DNA损伤相关的新抗原敏感 抗肿瘤免疫，指出治疗性干预策略。我们确定了SMAD4损失的SCC 将TME更改为髓样细胞中的TGFβ和PD-L1富含PD-L1，它们非常容易受到免疫的影响 双重TGFβ/PD-L1靶向消除。这些发现准备转化为一项临床试验 放射疗法与晚期SCC患者的双重TGFβ/PD-L1结合使用 VA患者的准确性，从而为我们的退伍军人带来了治疗性干预。正在进行的研究领域 包括：1）评估有助于自主扩张和转移的SCC细胞的内在特性。 2）确定由基质细胞建立的SCC转移性生态位。 3）确定SCC免疫进化的机制 SCC和免疫疗法干预措施。