更新于：2024-11-01

GFRA4

更新于：2024-11-01

基本信息

别名

GDNF family receptor alpha 4、GDNF family receptor alpha-4、GDNF receptor alpha-4

+ [4]

简介

Receptor for persephin. Mediates the GDNF-induced autophosphorylation and activation of the RET receptor. May be important in C-cell development and, in the postnatal development of the adrenal medulla.

关联

靶点

GFRA4

作用机制

GFRA4 inhibitors

在研机构

University of Pennsylvania

原研机构

University of Pennsylvania

在研适应症

甲状腺髓样癌

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

GFRalpha4 CAR-T(Tmunity Therapeutics)

靶点

GFRA4

作用机制

GFRA4调节剂

在研机构

Tmunity Therapeutics, Inc.初创企业

原研机构

Tmunity Therapeutics, Inc.初创企业

在研适应症

甲状腺髓样癌

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与 GFRA4 相关的临床试验

NCT04877613 / Recruiting临床1期IIT

Phase I Trial of GFRα4 CAR T Cells in Adult Patients With Recurrent or Metastatic Medullary Thyroid Cancer

This is an open-label phase 1 study to assess the safety and feasibility of autologous T cells expressing a single-chain scFv targeting GFRα4 with tandem TCR/CD3ζ and 4-1BB (TCRζ/4-1BB) co-stimulatory domains (referred to as "CART-GFRa4 cells") in patients with incurable medullary thyroid cancer (MTC).

开始日期2021-08-19

申办/合作机构

University of Pennsylvania

100 项与 GFRA4 相关的临床结果

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100 项与 GFRA4 相关的转化医学

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0 项与 GFRA4 相关的专利（医药）

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项与 GFRA4 相关的文献（医药）

2023-01-01·Frontiers in oncology

ImmuneScore of eight-gene signature predicts prognosis and survival in patients with endometrial cancer.

Article

作者: Ma, Xiaoxin ; Wang, B O ; Gu, Jiahui ; Wang, Zihao

BackgroundEndometrial cancer (EC) is a common gynecological cancer worldwide and the sixth most common female malignant tumor. A large number of studies conducted through database mining have identified many biomarkers that may be related to survival and prognosis. However, the predictive ability of single-gene biomarkers is not sufficiently accurate. In recent years, tumors have been shown to interact closely with their microenvironment, and tumor-infiltrating immune cells in the tumor microenvironment were associated with therapeutic effects. Furthermore, sequencing technology has evolved and allowed the identification of genetic signatures that may improve prediction results. The purpose of this research was to discover the Cancer Genome Atlas (TCGA) data to evaluate new genetic features that can predict the prognosis of EC.MethodsmRNA expression profiling was analyzed in patients with EC identified in the TCGA database (n = 530). Differentially expressed genes at different stages of EC were screened using the immune cell enrichment score (ImmuneScore). Univariate and multivariate Cox regression analyses was applied to evaluate genes significantly related to overall survival and establish the prognostic risk parameter formula. Kaplan-Meier survival curves and the logarithmic rank method were applied to verify the importance of risk parameters for the prognostic forecast. The accuracy of survival prediction was confirmed using the nomogram and Receiver Operating Characteristic (ROC) curve analysis. The mRNA expression of eight genes were measured by qRT-PCR. According to COX and HR values, NBAT1, a representative gene among 8 genes, was selected for CCK-8 assay, colony formation assay and transwell invasion assay to verify the effect on survival.ResultsEight related genes (NBAT1, GFRA4, PTPRT, DLX4, RANBP3L, UNQ6494, KLRB1, and PRAC1) were discovered to be significantly associated with the overall survival rate. According to these eight-gene signatures, 530 patients with EC were assigned to high- and low-risk subgroups. The prognostic capability of the eight-gene signature was not influenced by other elements.ConclusionsEight related gene markers were identified using ImmuneScore, which could predict prognosis and survival in patients with EC. These findings provide a basis for understanding the application of biological information in tumors and identifying the poor prognosis of EC.

2021-05-01·Molecular and Cellular Biochemistry3区 · 生物学

MiR-195-5p inhibits proliferation and invasion of nerve cells in Hirschsprung disease by targeting GFRA4

3区 · 生物学

Article

作者: Wu, Xiangyu ; Wang, Gang ; Wang, Hefeng ; Guo, Feng ; Liu, Yang ; Zhang, Lijuan

Studies have reported that miR-195-5p plays a role in the Hirschsprung disease (HSCR). Our previous work found GDNF family receptor alpha 4 (GFRA4) is also associated with HSCR. In this study, we focused on whether miR-195-5p induces the absence of enteric neurons and enteric neural crest in HSCR by regulating GFRA4. The expression levels of GFRA4 and miR-195-5p in colon tissues were evaluated by real-time PCR (RT-PCR) assay. We overexpressed GFRA4 or miR-195-5p in SH-SY5Y cells, the cell proliferation, cell cycle, apoptosis and invasion were subsequently investigated by CCK-8 assay, EdU staining, Flow cytometry analysis and Transwell assay, respectively. We also established the xenograft model to detect the effect of miR-195-5p on tumor growth and GFRA4 and p-RET expressions. GFRA4 expression was significantly downregulated in the HSCR colon tissues when compared with that in the control tissues. Overexpression of GFRA4 significantly promoted proliferation, invasion and cell cycle arrest, and inhibited apoptosis of SH-SY5Y cells. We also proved that GFRA4 is a direct target of miR-195-5p, and miR-195-5p inhibited proliferation, invasion, cell cycle arrest and differentiation, and accelerated apoptosis in SH-SY5Y cells which can be reversed by GFRA4 overexpression. Furthermore, we demonstrated that miR-195-5p suppressed tumor growth, and observably decreased GFRA4 and p-RET expressions. Our findings suggest that miR-195-5p plays an important role in the pathogenesis of HSCR. MiR-195-5p inhibited proliferation, invasion and cell cycle arrest, and accelerated apoptosis of nerve cells by targeting GFRA4.

2021-03-01·Molecular Therapy - Oncolytics2区 · 医学

Adoptive T cell immunotherapy for medullary thyroid carcinoma targeting GDNF family receptor alpha 4

2区 · 医学

ArticleOA

作者: Parvathaneni, Kalpana ; Peng, Haiyong ; Nasrallah, MacLean ; Mansfield, Keith ; Arhontoulis, Dimitrios ; Milone, Michael C ; Rader, Christoph ; Goydel, Rebecca S ; Zhang, Zheng ; McGettigan-Croce, Bevin ; Feldman, Michael D ; Siegel, Don L ; Boesteanu, Alina C ; Li, Lucy ; Zhou, Kenneth ; Nunez-Cruz, Selene ; Radaelli, Enrico ; Kacir, Stephen ; Bhoj, Vijay G ; Johnson, Laura ; Gulendran, Gayathri

Metastatic medullary thyroid cancer (MTC) is a rare but often aggressive thyroid malignancy with a 5-year survival rate of less than 40% and few effective therapeutic options. Adoptive T cell immunotherapy using chimeric antigen receptor (CAR)-modified T cells (CAR Ts) is showing encouraging results in the treatment of cancer, but development is challenged by the availability of suitable target antigens. We identified glial-derived neurotrophic factor (GDNF) family receptor alpha 4 (GFRα4) as a putative antigen target for CAR-based therapy of MTC. We show that GFRα4 is highly expressed in MTC, in parafollicular cells within the thyroid from which MTC originates, and in normal thymus. We isolated two single-chain variable fragments (scFvs) targeting GFRα4 isoforms a and b by antibody phage display. CARs bearing the CD3ζ and the CD137 costimulatory domains were constructed using these GFRα4-specific scFvs. GFRα4-specific CAR Ts trigger antigen-dependent cytotoxicity and cytokine production in vitro, and they are able to eliminate tumors derived from the MTC TT cell line in an immunodeficient mouse xenograft model of MTC. These data demonstrate the feasibility of targeting GFRα4 by CAR T and support this antigen as a promising target for adoptive T cell immunotherapy and other antibody-based therapies for MTC.