BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10796340
• 负责人: Xiao-Jing Wang
• 金额: --
• 依托单位: VA NORTHERN CALIFORNIA HEALTH CARE SYS
• 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/10796340
• 关键词: BLRD; Research; Career; Scientist; Award

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(SCCs)的干预，从而改善退伍军人的健康结果。SCCS产生 来自复层上皮；退伍军人最相关的器官部位是皮肤和口腔，在那里 暴露于紫外线照射和烟草致癌物使总的和高危的体细胞显著高于 在平民人口中。鳞状细胞癌最糟糕的结局是远处转移导致的死亡。皮肤鳞状细胞癌死亡 超过黑色素瘤死亡和头颈部鳞状细胞癌死亡人数是皮肤鳞状细胞癌死亡人数的3-4倍。 我的退伍军人事务部研究计划的长期目标是确定预后和治疗干预的标志 对于SCC来说，因此改善了退伍军人的健康结果。自从2016年获得退伍军人事务部荣誉奖以来，我的 实验室一直在研究与鳞癌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 医疗保健结果。我的实验室率先开发了可诱导的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和转移的模型(GEMM)。 这些模型为与人类SCC进行跨物种比较和执行 实验疗法，包括免疫疗法，在我过去和正在进行的功勋奖研究。SCC是 往往懒惰了几十年。在之前的资助期间，我们重点研究了SCC如何打破懒惰 变成侵袭性和转移性癌症。我们发现一组癌症干细胞的特性 (CSCs)负责通过克隆形成和入侵来打破惰性。我们发现 在人类30%-50%的头颈部SCC中，肿瘤抑制基因Smad4的“杂合性丢失”是由 在单细胞水平上存在显著的肿瘤内和肿瘤内异质性，并且Smad4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。这些发现 为在单细胞水平上检测Smad4基因组状态提供关键的预后价值。此外，Smad4- 有缺陷的SCC细胞在DNA损伤修复中有“BRCA样”缺陷，易患癌症 针对DNA修复途径的疗法。这一发现为治疗标记物提供了一个重要的联系 和策略，并发起了一项由研究人员发起的临床试验，以治疗局部晚期头颈部鳞状细胞癌 放射治疗(RT)联合奥拉帕利，包括招募VA患者。在肿瘤间质中，我们 研究发现，Smad4基因组缺失会触发转化生长因子β1的过度生产，转化生长因子Smad1是一种免疫抑制因子，也是 癌症进展。此外，癌症相关成纤维细胞(CAF)比癌细胞分泌更多的转化生长因子β 为CSC的克隆扩增提供了远处转移部位的CSC生态位。我们还发现， 肿瘤相关巨噬细胞(TAMs)通过抗肿瘤相关巨噬细胞(TAMs)的抗肿瘤效应，促进CSC的扩张，从而打破惰性 细胞凋亡和血管生成。此外，Smad4突变的SCC细胞在克隆形成和 免疫逃避，但矛盾的是，产生更多与DNA损伤相关的新抗原，容易感染 抗肿瘤免疫，指向治疗干预策略。我们发现Smad4缺失的鳞状细胞 将TME改为富含转化生长因子β和PD-L1的髓系细胞，这两种细胞对免疫易感 转化生长因子β/PD-L1双靶向治疗。这些发现已经准备好转化为临床试验。 放疗联合双重转化生长因子β/PD-L1靶向治疗晚期头颈部鳞癌 为退伍军人带来实时的治疗干预。正在进行的研究领域 包括：1)评估有助于自我扩张和转移的SCC细胞的固有特性。 2)确定由基质细胞建立的鳞癌转移生态位。3)确定鳞状细胞癌免疫逃避机制 以及对干细胞的免疫治疗干预。