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.

我的研究计划的首要目标是确定预后和治疗的标志物 对鳞状细胞癌（SCC）进行干预，从而改善退伍军人的健康状况。 来自复层上皮；退伍军人最相关的器官部位是皮肤和口腔，其中高度 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，鳞状细胞癌最严重的后果是远处转移引起的死亡。 超过黑色素瘤死亡人数，头颈部鳞状细胞癌死亡人数比皮肤鳞状细胞癌死亡人数高3-4倍。 我的 VA 研究项目的长期目标是确定预后和治疗干预的标志物 自从 2016 年获得 VA 优异奖资助以来，我的 实验室一直在研究与鳞状细胞癌进展和治疗干预相关的机制。 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 我的实验室首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形成鳞状细胞癌和转移的模型（GEMM）。 这些模型为与人类 SCC 进行跨物种比较和执行提供了独特的资源 在我过去和正在进行的鳞状细胞癌研究中，包括免疫疗法在内的实验疗法都是优秀奖。 在之前的资助期间，我们重点研究了SCC如何打破惰性。 我们发现癌症干细胞亚群的特性。 （CSC）通过克隆形成和侵袭来打破惰性。 SMAD4（一种肿瘤抑制因子）在人类 30-50% 的头颈 SCC 中出现“杂合缺失”，其原因是 在单细胞水平上显着的肿瘤间和肿瘤内异质性，并且 SMAD4 突变细胞具有 生长/生存优势使它们能够接管整个肿瘤细胞群。 为在单细胞水平检查 SMAD4 基因组状态提供关键的预后价值。 缺陷性鳞状细胞癌细胞在 DNA 损伤修复方面存在“类 Brca”缺陷，容易罹患癌症 这一发现为治疗标记物提供了重要的联系。 和策略，并发起了一项由研究者发起的治疗局部晚期头颈部 SCC 的临床试验 与奥拉帕尼联合放疗（RT），其中包括招募肿瘤基质中的 VA 患者。 发现 SMAD4 基因组丢失会触发 TGFβ1 的过度产生，TGFβ1 是一种免疫抑制剂和促进剂 此外，癌症相关成纤维细胞 (CAF) 比癌细胞分泌更多的 TGFβ。 并在远处转移位点为 CSC 克隆扩增提供 CSC 生态位。 肿瘤相关巨噬细胞 (TAM) 有助于通过抗肿瘤干细胞 (CSC) 扩张来打破惰性 此外，SMAD4突变体SCC细胞在克隆形成和血管生成方面具有优势。 免疫逃避，但矛盾的是产生更多与 DNA 损伤相关的新抗原，易受 抗肿瘤免疫，指出了治疗干预策略。 将 TME 更改为富含 TGFβ 和 PD-L1 的骨髓细胞，这些细胞对免疫高度敏感 通过双重靶向 TGFβ/PD-L1 来根除这些发现已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 患者应计，从而为我们正在进行的研究领域提供实时治疗干预。 包括：1) 评估 SCC 细胞有助于自我扩张和转移的内在特性。 2) 识别基质细胞建立的鳞状细胞癌转移微环境 3) 识别鳞状细胞癌免疫逃避的机制。 以及鳞状细胞癌的免疫治疗干预。