Research Progress in Signaling Pathway and Related Drugs of Target GDF15

Growth differentiation factor 15 (GDF15), being a kind of endocrine hormone and a member of transforming growth factor β (TGF β) superfamily, acts as an autocrine regulatory molecule in macrophages, which was identified and found from the clone of activated macrophage cell line. According to GDF15's tissue source or function, it is given different names: MIC-1, PLAB, PTGF-β, NAG-1, PDF, etc.

GDF15 is mainly involved in organ growth, differentiation and development, as well as the cell repair. Under physiological condition, the GDF15 expression is low in other tissues except placenta, but under pathologic condition such as inflammation or traumatic stress, its expression is up-regulated, with many stimulating factors such as TGF β, interleukin 1β (IL-1β) and tumor necrosis factor-α (TNF-α). GDF15 expression in the liver cell can be induced by the IL-1β or tunicamycin stimulated endoplasmic reticulum stress, and its expression in the liver cell in patients with non-alcoholic fatty liver disease (NAFLD) is directly related to the content of IL-1β and the severity of steatosis. Thus, GDF15 can be used as an inflammatory marker or stress response protein. A large number of studies have shown that the rise of GDF15 is related to cardiovascular diseases, such as myocardial hypertrophy, heart failure, atherosclerosis, and endothelial dysfunction, as well as obesity, diabetes, cancer and cachexia, and it has been proved that GDF15 is a new biomarker in the diagnosis, progression and prognosis of the above diseases. As the biomarker of obesity, diabetes, tumor, NAFLD, and ischemic diseases, GDF15 has become the new target of new drug R&D.

The application of GDF15 target in the disease 

1. GDF15 and obesity and metabolic related diseases

GDF15 is able to control the food intake and energy metabolism, which promotes the study on target GDF15's potential function to the overnutrition (obesity) and malnutrition (anorexia / cachexia) under the pathological condition. GDNF family receptor alpha like (GFRAL), located in the area postrema neuron, is a receptor necessary for anorexia mediated by GDF15, which the ligand-receptor relationship has outlined a new pathway to control energy homeostasis. GDF15 has some same characteristics with other endocrine factors controlling food intake, but it still has its uniqueness, for example, the regulation of GDF15/GFRAL is beneficial to increase and maintain its extensive tissue expression level under many conditions; Unlike short-term postprandial anorexia signals, the postprandial GDF15 level will not increase.

With the dual function of regulating appetite suppression and increasing peripheral energy consumption, GDF15 plays an important role in preventing and treating obesity. The discovery of GDF15 opens up a new idea for anti-obesity treatment. Studies have shown that anorexia of patients with advanced cancer is related to the TGFβ pathway and mediated by the regulation of feeding center by MIC-1. Normal mouses given systemic MIC-1 and transgenic mouses overexpressing MIC-1 showed insufficient swallowing and weight loss. In addition, as a star molecule of anti-diabetes drugs, metformin's anti-obesity function has also been proved to be related to GDF15, which it can increase the GDF15 in serum, reduce the food intake and lose weight by limiting brain stem, and it has nothing to do with reducing blood glucose. GDF15 has been proved to be the biomarker in patients with abnormal blood glucose taking metformin, which concentration reflects the dose of metformin. And the increased serum GDF15 in patients with Type 2 diabetes taking metformin is also related to the weight loss. Therefore, it is possible to develop drugs to treat obesity and cancer-induced cachexia based on the brain GDF15-GFRAL-RET receptor signal transduction complex. In addition to the central function of inhibiting food intake, GDF15 also plays an anti-obesity role by peripheral functions such as promoting thermogenesis and reducing lipogenesis. During cold exposure and adrenaline stimulation, GDF15, released by brown and beige adipose tissues, can target macrophage, mediate the downregulation of local inflammation pathway, and play a thermogenic effect, indicating that GDF15 may be a brown adipocyte factor.

2. GDF15 and NAFLD

Studies have shown that the GDF15 expressed in the mouse liver could be increased by the excess lipid accumulation in the liver and the endoplasmic reticulum stress, and in the livers of animal model of non-alcoholic steatohepatitis (NASH) and human subjects with NASH, the GDF15 expression increases. NASH phenotype of mouse with Gdf15 gene knockout in liver is increased, such as steatosis deterioration, inflammation, fibrosis, liver injury and metabolic deterioration. However, Gdf15 transgenic mouse or the ectopic expression of GDF15 in the liver can enhance the β-oxidation of fatty acids in the liver of mouse fed with high fat diet and reduce the lipid accumulation in the liver, slowing down the development and metabolic deterioration of NAFLD and NASH.

GDF15 can be regarded as a new biomarker of fibrosis in the middle and advanced stage of NAFLD. In patients with NAFLD, the highest quartile of GDF15 level is significantly related to the risk of advanced fibrosis. In LX-2 cells treated with GDF15, the expression of α-smooth muscle actin and collagen I can be enhanced through Smad2 and Smad3 phosphorylation. On the other hand, the improvement of metabolic inflammation and weight loss reduces the GDF15 expression in liver, therefore, GDF15 in liver may play a negative feedback role in controlling the energy balance of NAFLD.

3. GDF15 and cancer

GDF15, the biomarker in the cancer diagnosis, disease progression and prognosis, with an increasing level in many solid tumor cancers, is the biomarker in the diagnosis of pancreatic cancer, intestinal cancer, ovarian cancer, prostatic cancer, primary liver cancer and lung cancer, and is related to the disease progression and prognosis of a variety of cancers, such as rectal cancer, gastric cancer, hepatocellular carcinoma, non-small cell lung cancer, urothelial carcinoma / renal cell carcinoma, ovarian cancer, breast cancer and so on, but not to the hematological tumors.

GDF15 is also a biomarker to predict therapeutic effect and drug resistance reaction of chemotherapy drugs. Studies have shown that GDF15 level in the serum of patients with epithelial ovarian cancer resistant to platinum first-line chemotherapy drugs (carboplatin or cisplatin) is obviously higher than that of chemotherapy sensitive patients, and patients with high expression of GDF15 have a short progression-free survival. In addition, the GDF15 level also plays an important role in the diagnosis of primary liver cancer and the evaluation of chemotherapy effect. As an immune checkpoint, GDF-15 is the new target of cancer immunotherapy. The evasion of tumor cell from immune surveillance is the mark of cancer. Based on the fact that GDF15 can be used as an inflammatory marker, it can be expected that GDF15 will affect the immunity of tumor. The exhaustion of GDF15 derived from glioma will enhance the sensitivity of mouse glioma cells to homologous natural killer cells and spleen cells, which decreases tumorigenicity and increases T cell infiltration, thereby improving the immune response and prolonging the survival. Therefore, endogenous GDF15 is helpful to the proliferation and immune escape of malignant glioma. Dendritic cells (DC) play a key role in the initial stage of antigen-specific immune response. Studies have shown that GDF15, an effective inhibitor of DC maturation and function, may inhibit the formation of surface protrusions during DC maturation, promote TGFβ1 secretion, and inhibit T cell stimulation and cytotoxic T lymphocyte activation to inhibit tumor-specific immune response and promote immune escape of tumor cells. As a clear biomarker for cancer diagnosis, prognosis and chemotherapy resistance, as well as an immune checkpoint, GDF15 is a new target of cancer immunotherapy, providing a new idea for the R&D of anti-tumor drugs.

4. GDF15 and cardiovascular disease

GDF15 is involved in the occurrence of many cardiovascular diseases, and increase of its level is related to myocardial hypertrophy, heart failure, atherosclerosis, endothelial dysfunction, etc. At the time of myocardial ischemia reperfusion injury, the stress of cardiomyocyte, macrophage, endothelial cell, vascular smooth muscle cell and adipocyte will induce the increase of GDF15. GDF15 increases in both the endothelial dysfunction (the first step in the cardiovascular disease development) period and cardiovascular disease. Studies have shown that GDF15 produced by aging endothelial cell's colony-forming cells may act on non-aging cells in a paracrine way and play a beneficial role in vascular dysfunction by limiting endothelial dysfunction related to vascular stress. Thus, according to the present study results, GDF15 is regarded as a new cardiac cytokine, but it still needs more experimental data to prove its function in cardiovascular diseases and its role as the target in R&D of drugs for cardiovascular diseases.

GDF15, a pleiotrophin, plays an important role in many complex diseases and has become a new biomarker and a new therapeutic target for disease diagnosis, progression or prognosis. At present, the drug indications with GDF15 as the therapeutic target in the R&D involve different therapeutic fields such as obesity, diabetes, tumor and anorexia, being in different stages such as preclinical or Phase I clinical trials. For GDF15's exact anorexia and immune checkpoint function, anti-obesity drugs have been developed using its activation, such as GDF15 analogue, GFRAL receptor agonist, etc.; and drugs for anorexia syndrome and anti-tumor have been developed using its antagonism, such as GDF15 monoclonal antibody, monoclonal antibody of GFRAL antagonist, etc.

References:

1. Zheng Lei, Feng Yingming, Song Yang, Li Hong, Nie Na, and Su Haichuan. Preparation, Identification and Medicinal Value of Monoclonal Antibody against Growth Differentiation Factor-15 of Human [J]. Progress in Modern Biomedicine, 2015, 15(24): 4601-4604.DOI: 10.13241/j.cnki.pmb.2015.24.001.

2. Xu Chuanyang, Wang Zhaowei, He Lei, Pang Zhijun, Zhu Yichao, Li Weina, and Li Zhengmin. Research Progress of New Target GDF15/GFRAL Signaling Pathways for the Treatment of Obesity and Metabolic Related Diseases [J]. China Medical Herald, 2019, 16(18): 25-29.

3. Qiang Hao, Sun Mingxia, Wang Hongjian, Zhu Tingting, and Ji Tengfei. The Mechanism of Action of New Target GDF15 and Current Research and Development of Related Drugs [J]. Acta Pharmaceutica Sinica, 2021, 56(10): 2728-2734.DOI: 10.16438/j.0513-4870.2021-0675. 

About author: 

Xiaonisha

Xiaonisha, a practitioner in food science and technology, graduated from the School of Food Science and Engineering in the South China University of Technology as a Master of Food Science, and now works at a large drug R&D company in China, engaging in R&D of nutritional food.