Full Project 1: Understanding and Targeting of Convergent Immunosuppressive Pathways and Molecular Signaling in HPV-positive and HPV-negative Penile Cancer

完整项目 1：了解和靶向 HPV 阳性和 HPV 阴性阴茎癌中的趋同免疫抑制途径和分子信号转导

• 批准号: 10020948
• 负责人: Curtis Pettaway
• 金额: $ 19.2万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-16 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020948
• 关键词: Accounting; Address; African American; Automobile Driving; Cancer Center; Caucasians; Cell Line; Cells; Chronic; Clinic; Clinical; Collaborations; Coxibs; Cytotoxic T-Lymphocytes; Data; Development; Disease; Down-Regulation; Epithelial; Epithelium; Estrogens; Etiology; Exhibits; Experimental Models; FRAP1 gene; Gene Chips; Genes; Genetically Engineered Mouse; Grant; HPV-High Risk; Hispanics; Histologic; Human; Human Papillomavirus; Human papilloma virus infection; Immune; Immune Evasion; Immunocompetent; Immunologics; Immunotherapeutic agent; Immunotherapy; Incidence; Infection; Infiltration; Inflammation; Interdisciplinary Study; Intervention; Knowledge; Lead; MADH4 gene; Malignant Neoplasms; Malignant neoplasm of penis; Modeling; Molecular; Mus; Myeloid-derived suppressor cells; Notch Signaling Pathway; Outcome; PD-1/PD-L1; PTGS2 gene; Pathway interactions; Patients; Pattern; Penile Neoplasms; Pilot Projects; Play; Population; Prognostic Factor; Puerto Rican; Puerto Rico; Reporting; Resistance; Resources; Rest; Risk Factors; Role; Sampling; Signal Transduction; Squamous cell carcinoma; Technology; Testing; Therapeutic; Translational Research; Treatment Efficacy; Tumor Suppressor Genes; Tumor-infiltrating immune cells; Tyrosine Kinase Inhibitor; Universities; University of Texas M D Anderson Cancer Center; Up-Regulation; Xenograft Model; Xenograft procedure; anticancer research; base; cancer subtypes; career; celecoxib; cyclooxygenase 2; design; differential expression; experimental study; human tissue; immune checkpoint blockade; insight; men; molecular targeted therapies; mortality; notch protein; novel; penis; programmed cell death ligand 1; programs; targeted treatment; therapeutic target; transcriptome; transcriptome sequencing; transcriptomics; treatment optimization; tumor; tumor microenvironment; tumor progression

FULL PROJECT 1 - UNDERSTANDING AND TARGETING OF CONVERGENT IMMUNOSUPPRESSIVE PATHWAYS AND MOLECULAR SIGNALING IN HPV-POSITIVE AND HPV-NEGATIVE PENILE CANCER PROJECT SUMMARY/ABSTRACT Penile cancer (PeCa) is a highly morbid disease that exhibits a higher mortality among Puerto Ricans than among the rest of the US population. The theme of the U54 grant, Infection-Driven Malignancies Program for Advancing Careers and Translational Sciences (IMPACT), fits well with our project because infection with human papillomavirus (HPV) has been identified as a risk factor for penile cancer. The etiology of penile cancer is incompletely understood. Therefore, there is an urgent need to address knowledge gaps. We recently developed the first genetically engineered mouse (GEM) models of penile squamous cell carcinoma (PSCC), the predominant histologic type of PeCa, through co-deletion of tumor suppressor genes (Smad4, Apc) in mouse penile epithelium. We have also generated the first set of patient-derived xenograft (PDX) models for PeCa (N=6). In our pilot project, using this GEM model of PSCC, we found: (1) substantial infiltration of immune cells in the penile tumors, especially myeloid-derived suppressor cells (MDSCs) that can inhibit cytotoxic T cells and cause immune evasion, and (2) strong cyclooxygenase-2 (COX2) expression in penile tumors and PI3K/mTOR signaling in MDSCs. Further using expression arrays we identified novel insights into expression patterns associated with human HPV+ and HPV- PeCa.The objective of this proposal is to develop therapeutic strategies for PeCa and validate molecular pathways associated with HPV+ and HPV- PeCa subtypes. Our hypotheses are that (1) PeCa formation is promoted by chronic inflammation as a result of HPV infection or downregulation of essential tumor suppressor genes SMAD4 and APC, (2) The key signaling hubs driving PeCa progression, including COX2 and PD-L1 upregulation, are effective targets for immunotherapeutic intervention,and (3) Estrogen and Notch signaling are upregulated in HPV+ PeCa and play important roles in PeCa progression. The specific aims of this proposal are to: (Aim 1) Eradicate mouse penile cancer by combining targeted therapy and immunotherapy, (Aim 2) Identify the immunologic profiles associated with HPV infection in human penile cancer to optimize therapy, and (Aim 3) Validate and target both Estrogen and Notch signaling in HPV+ penile cancer. The proposed studies will have a significant impact on both the understanding of the molecular pathways that drive HPV+ and HPV- PeCa subtypes and the identification of effective therapeutic strategies to treat these highly morbid tumors. Through this unique collaboration our multidisciplinary research teams from The University of Texas MD Anderson Cancer Center and the University of Puerto Rico are poised make novel contributions to understanding and curing this rare fatal cancer.

完整项目1 -了解和靶向融合免疫抑制剂 HPV阳性和阴性阴茎癌的分子信号通路 项目总结/摘要 阴茎癌（PeCa）是一种高度病态的疾病，波多黎各人的死亡率高于 在美国其他人口中。U 54赠款的主题，预防驱动的恶性肿瘤计划， 推进职业和转化科学（IMPACT），非常适合我们的项目，因为感染 人乳头瘤病毒（HPV）已被确定为阴茎癌的危险因素。阴茎的病因 对癌症的认识还不完全。因此，迫切需要解决知识差距问题。我们 最近开发了第一个阴茎鳞状细胞癌的基因工程小鼠（GEM）模型 （PSCC），PeCa的主要组织学类型，通过肿瘤抑制基因（Smad 4， Apc）在小鼠阴茎上皮中的表达。我们还产生了第一组患者来源的异种移植物（PDX） PeCa模型（N=6）。在我们的试点项目中，使用PSCC的GEM模型，我们发现：（1）实质性 阴茎肿瘤中免疫细胞的浸润，特别是髓源性抑制细胞（MDSC）， 抑制细胞毒性T细胞并引起免疫逃避，和（2）在 MDSC中的阴茎肿瘤和PI 3 K/mTOR信号传导。进一步使用表达阵列， 深入了解与人类HPV+和HPV- PeCa相关的表达模式。该提案的目的是 开发PeCa的治疗策略，并验证与HPV+和HPV-相关的分子途径 PeCa亚型。我们的假设是：（1）PeCa的形成是由慢性炎症促进的， HPV感染或下调重要抑癌基因SMAD 4和APC，（2）关键信号 驱动PeCa进展的枢纽，包括COX 2和PD-L1上调，是治疗的有效靶点。 免疫干预，和（3）雌激素和Notch信号在HPV+ PeCa中上调，并发挥作用。 在PeCa进展中发挥重要作用。这项建议的具体目标是：（目标1）根除老鼠阴茎 联合靶向治疗和免疫治疗，（目的2）确定免疫学特征 与人类阴茎癌中HPV感染相关，以优化治疗，并（目的3）消除和靶向 HPV+阴茎癌中的雌激素和Notch信号传导。拟议的研究将产生重大影响 对驱动HPV+和HPV- PeCa亚型的分子途径的理解， 确定治疗这些高度病态肿瘤的有效治疗策略。通过这种独特 合作我们来自德克萨斯大学MD安德森癌症中心的多学科研究团队 和波多黎各大学准备为理解和治愈这种罕见的 致命的癌症