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: 10247752
• 负责人: MAGALY MARTINEZ-FERRER
• 金额: $ 17.49万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 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/10247752
• 关键词: Accounting; Address; African American; Automobile Driving; Cancer Center; Caucasians; Cell Line; Cells; Chemoresistance; Chronic; Clinic; Clinical; Collaborations; Coxibs; Cytotoxic T-Lymphocytes; Data; Development; Disease; Down-Regulation; Epithelial; 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; Pattern; Penile Neoplasms; Pilot Projects; Play; Population; Prognostic Factor; Puerto Rican; Puerto Rico; Reporting; Resources; Rest; Risk Factors; Role; Sampling; Signal Transduction; Squamous cell carcinoma; Technology; Testing; Therapeutic; Translational Research; Tumor Suppressor Genes; Tumor-infiltrating immune cells; Tyrosine Kinase Inhibitor; Universities; University of Texas M D Anderson Cancer Center; Up-Regulation; 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; patient derived xenograft model; penis; programmed cell death ligand 1; programs; refractory cancer; targeted treatment; therapeutic target; therapeutically effective; 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 -了解和靶向趋同免疫抑制剂