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.

我的研究项目的总体目标是确定预后和治疗的标志物 鳞状细胞癌（SCC）的干预措施，从而改善退伍军人的健康结果。SCC出现 退伍军人中最相关的器官部位是皮肤和口腔， 暴露于紫外线照射和烟草致癌物使总的和高风险的SCC显着高于 在平民中。SCC最严重的结局是因远处转移而导致死亡。皮肤SCC死亡 超过黑色素瘤死亡，头颈部SCC死亡是皮肤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的标志物 从而改善退伍军人的健康状况。自2016年获得VA优异奖资助以来，我的 实验室一直在研究与SCC进展和治疗干预相关的机制。这些 研究不断转化为临床诊断和治疗干预，直接影响退伍军人的健康。 医疗结果。我的实验室开创了诱导型和上皮特异性基因工程小鼠 在自然微环境和免疫系统中发展SCC和转移的GEMM模型。 这些模型为与人类SCC进行跨物种比较提供了独特的资源， 实验疗法，包括免疫疗法，在我过去和正在进行的优异奖研究。SCC是 常常是几十年的懒惰。在上一个资助期，我们专注于研究SCC如何打破懒惰 变成侵袭性和转移性癌症。我们发现一部分癌症干细胞的特性 CSC负责通过克隆形成和侵袭打破惰性。我们发现 在30-50%的人类头颈部SCC中，SMAD 4（一种肿瘤抑制因子）的“杂合丢失”是以下原因的结果： 在单细胞水平上显著的肿瘤间和肿瘤内异质性，并且SMAD 4突变细胞具有 生长/存活优势使它们能够接管整个肿瘤细胞群体。这些发现 为在单细胞水平上检查SMAD 4基因组状态提供了关键的预后价值。此外，SMAD 4- 缺陷型SCC细胞在DNA损伤修复中具有“Brca样”缺陷，易患癌症 靶向DNA修复途径的疗法。这一发现为治疗标记物提供了重要的联系 和策略，并发起了一项治疗局部晚期头颈部SCC的临床试验 放疗（RT）联合奥拉帕尼，包括招募VA患者。在肿瘤间质中，我们 发现SMAD 4基因组缺失触发TGFβ1的过度产生，TGFβ1是一种免疫抑制剂和促进剂， 癌症进展此外，癌相关成纤维细胞（CAFs）分泌比癌细胞更多的TGFβ 并在远处转移部位提供CSC小生境用于CSC克隆扩增。我们还发现 肿瘤相关巨噬细胞（TAMs）通过抗肿瘤细胞因子的作用， 凋亡和血管生成。此外，SMAD 4突变体SCC细胞在克隆形成和增殖方面具有优势。 免疫逃避，但矛盾地产生更多DNA损伤相关新抗原， 抗肿瘤免疫，指向治疗干预策略。我们发现Smad 4缺失的SCC 将TME改变为骨髓细胞中富含TGFβ和PD-L1，这些细胞对免疫敏感性很高。 通过双重TGFβ/PD-L1靶向根除。这些发现已经准备好转化为临床试验， 放疗联合TGFβ/PD-L1双重靶向治疗晚期头颈部SCC患者，包括 VA患者增加，从而为我们的退伍军人带来真实的治疗干预。正在进行的研究领域 包括：1）评估SCC细胞有助于自主扩增和转移内在特性。 2)识别由基质细胞建立的SCC转移小生境。3)识别SCC免疫逃避机制 和免疫疗法干预SCC。