SLC1A1-mediated cellular and mitochondrial influx of R-2-hydroxyglutarate in vascular endothelial cells promotes tumor angiogenesis in IDH1-mutant solid tumors

Q1 · BIOLOGY

Article

Author: Yuan, Liang ; Chen, Yuehong ; Chen, Ziqi ; Jiang, Lei ; Gai, Xiameng ; Zhai, Linhui ; Tan, Minjia ; Zhang, Qiansen ; Guo, Siqi ; Zhang, Shaoying ; Zhang, Yixiang ; Cao, Siyuwei ; Lan, Xiaojing ; Xu, Jun ; Lin, Shu-Hai ; Li, Leping ; Chen, Yi ; Wang, Ting ; Zheng, Ying ; Zhang, Qingli ; Li, Yize ; Wang, Mingcheng ; Tang, Shuai ; Bi, Aiwei ; Fu, Yixian ; Liu, Yingluo ; Wang, Xiaomin ; Huang, Min ; Duan, Yichen ; Liu, Jia ; Mo, Kun ; Luo, Cheng ; Shen, Yanyan ; Chen, Shijie ; Tong, Linjiang ; An, Nan

Mutant isocitrate dehydrogenase 1 (mIDH1) drives tumorigenesis via producing oncometabolite R-2-hydroxyglutarate (R-2-HG) across various tumor types. However, mIDH1 inhibitors appear only effective in hematological tumors. The therapeutic benefit in solid tumors remains elusive, likely due to the complex tumor microenvironment. In this study, we discover that R-2-HG produced by IDH1-mutant tumor cells is preferentially imported into vascular endothelial cells and remodels mitochondrial respiration to promote tumor angiogenesis, conferring a therapeutic vulnerability in IDH1-mutant solid tumors. Mechanistically, SLC1A1, a Na⁺-dependent glutamate transporter that is preferentially expressed in endothelial cells, facilitates the influx of R-2-HG from the tumor microenvironment into the endothelial cells as well as the intracellular trafficking of R-2-HG from cytoplasm to mitochondria. R-2-HG hijacks SLC1A1 to promote mitochondrial Na⁺/Ca²⁺ exchange, which activates the mitochondrial respiratory chain and fuels vascular endothelial cell migration in tumor angiogenesis. SLC1A1 deficiency in mice abolishes mIDH1-promoted tumor angiogenesis as well as the therapeutic benefit of mIDH1 inhibitor in solid tumors. Moreover, we report that HH2301, a newly discovered mIDH1 inhibitor, shows promising efficacy in treating IDH1-mutant cholangiocarcinoma in preclinical models. Together, we identify a new role of SLC1A1 as a gatekeeper of R-2-HG-mediated crosstalk between IDH1-mutant tumor cells and vascular endothelial cells, and demonstrate the therapeutic potential of mIDH1 inhibitors in treating IDH1-mutant solid tumors via disrupting R-2-HG-promoted tumor angiogenesis.

100 Deals associated with HH-2301

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Biliary Tract Neoplasms	IND Application	US	Haihe Biopharma Co., Ltd.	-
Biliary Tract Neoplasms	IND Application	US	Shanghai Institute of Materia Medica Chinese Academy of Sci	-
Chondrosarcoma	IND Application	US	Shanghai Institute of Materia Medica Chinese Academy of Sci	-
Chondrosarcoma	IND Application	US	Haihe Biopharma Co., Ltd.	-
Glioma	IND Application	US	Shanghai Institute of Materia Medica Chinese Academy of Sci	-
Glioma	IND Application	US	Haihe Biopharma Co., Ltd.	-
Solid tumor	Discovery	CN	Haihe Biopharma Co., Ltd.	01 Feb 2021

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

HH-2301

Overview

Basic Info

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation