Prognosis and treatment of squamous cell carcinomas

A squamous cell carcinoma and cell technology, applied in the direction of cytokines/lymphokines/interferons, antibody medical components, chemical instruments and methods, etc., can solve the problems of poor understanding of molecular mechanisms

Inactive Publication Date: 2018-08-28
UNIV OF COLORADO THE REGENTS OF +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, little is known about the molecular mechanisms underlying HPV-driven HNSCC disease progression, especially in the context of host immunity

Method used

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  • Prognosis and treatment of squamous cell carcinomas
  • Prognosis and treatment of squamous cell carcinomas
  • Prognosis and treatment of squamous cell carcinomas

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0090] Example 1: Analyze the global gene expression profile of 84 fresh frozen human cervical and head / neck tissue samples to compare HPV + And HPV-cancer.

[0091] The previous results revealed a significant HPV-specific gene expression signature that allows distinguishing HPV+ HNSCC and cervical cancer (CxCa) from HPV-HNSCC. These findings clearly indicate that HPV plays a key role in the development of HPV-related cancers. The inventors further analyzed the global gene expression profiles of 128 cervical tissue samples in different disease stages, including normal, early and late malignant preepithelial lesions, and squamous carcinoma. The results reveal a cascade of molecular changes that culminates in changes in the expression of multiple genes when it eventually transforms into invasive epithelial cancer. In order to understand the immune regulation of HPV in the local microenvironment during the progression of HPV-related cancers, the inventors used gene expression dat...

Embodiment 2

[0096] Example 2: CXCL14 promoter hypermethylation in HPV+ cells

[0097] Previous studies have shown that promoter hypermethylation can inhibit the expression of CXCL14. In order to determine whether reduced CXCL14 expression is associated with promoter hypermethylation, the inventors performed methylation-specific PCR (MSP) using NIKS and W12 cell lines. The methylation of the CXCL14 promoter was inversely correlated with the expression of CXCL14, and the hypermethylation of the CXCL14 promoter was significantly increased in HPV+keratinocytes and HNSCC cells (Figure 4). CXCL14 promoter hypermethylation disappeared in NIKS-16ΔE7 cells. These results indicate that CXCL14 promoter hypermethylation is induced by high-risk HPV and accumulates throughout cancer progression. Previous studies have shown that HPV oncoprotein E7 activates the methyltransferase activity of DNMT1. In addition, epigenetic silencing of many genes has been shown in HPV+ cells and CxCa. The inventor's dat...

Embodiment 3

[0098] Example 3: Re-expression of CXCL14 in HNSCC cells clears tumors through adaptive immunity:

[0099] CXCL14 is an evolutionarily conserved chemokine, showing 98% homology between human CXCL14 and mouse Cxcl14. To determine whether CXCL14 affects tumor growth in vivo, the inventors studied mouse oropharyngeal epithelial cells (MOE / E6E7) that form tumors in immunocompetent, syngeneic C57BL / 6 (B6) mice. Consistent with human cell lines and patient tissues, it was found that MOE / E6E7 cells expressed significantly less Cxcl14 than syngeneic HPV-MOE cells and showed a highly methylated Cxcl14 promoter ( Figure 7 ). In order to test the tumor suppressor function of CXCL14, the inventors established the MOE / E6E7 cell line, which then expressed its physiological level of Cxcl14. Strikingly, most B6 mice injected with MOE / E6E7 cells expressing Cxcl14 cleared their tumors, while all mice injected with control MOE / E6E7 cells died of tumor burden within 21 days ( Figure 8A ). Howev...

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Abstract

DNA methylation profiles predictive of head and neck squamous cell carcinoma (HNSCC) patient prognosis, as well as therapeutic protein and adoptive cell compositions useful in the treatment of HNSCC.

Description

[0001] Government interest [0002] This invention was completed under the grant number AI091968 funded by the National Institutes of Health (NIH) with government support. The US government has certain rights in this invention. Invention field [0003] The present invention relates to DNA methylation as a predictor of patient prognosis (especially in the field of cancer biology) and a therapeutic protein and adoptive cell composition for the treatment of head and neck squamous cell carcinoma (HNSCC). Background of the invention [0004] Human papillomavirus (HPV) is causally linked to a variety of human cancers including cervical cancer and head and neck cancer (HNC) and causes approximately 500,000 deaths worldwide each year (1,2). HPV-related cancer progression is a multi-step process in which the cumulative effect of some molecular changes ultimately leads to cancer decades after the initial infection. Although most sexually active women are infected with HPV, only about 10-20%...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K35/17A61K39/39C12Q1/70G01N33/574
CPCA61K35/17C12Q1/6886C12Q2600/118C12Q2600/154C12Q2600/158A61K38/195G01N33/57484G01N2333/025G01N2333/521G01N2800/52A61P35/00C07K14/521A61K39/001136A61K39/39A61K2300/00C12Q1/70G01N33/6863
Inventor D.派翁J.李
Owner UNIV OF COLORADO THE REGENTS OF
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