Whether it's a long-term viral infection (hepatitis B virus, hepatitis C virus), alcohol abuse, fatty diet, or an autoimmune disease, it can lead to ongoing liver damage that triggers a repair response – fibrosis. However, if this "repair" behavior is too uncontrolled, it will accelerate the chain reaction, accelerating chronic liver disease from fibrosis to cirrhosis, and eventually leading to liver cancer.
In short, fibrosis is a watershed moment in determining whether chronic liver disease will progress to the end-stage and a key pivot in determining whether it can "come back from the dead". Therefore, cutting off and reversing the fibrosis process in time is equivalent to opening a "road to cure" for patients. Otherwise, it means that the disease will be in its final stage forever. Therefore, there is an urgent need for a highly effective antifibrotic drug to reverse the fate of patients.
Cutting off the "vascular supply" of fibrotic lesions
Hopes and challenges of antiangiogenic drugs
Long-term inflammation and hypoxia are the main causes of pathogenic angiogenesis and revascularization, and are also important drivers of aggravation of liver fibrosis [1].
Liver cancer, for example, is known as a "solid tumor with dense blood vessels". A large number of new blood vessels grow wildly in cancer tissues, providing a pathway for the occurrence, development and metastasis of tumor cells for nutrition and diffusion. Accumulating evidence suggests that these dysplastic blood vessels also contribute to the progression of liver fibrosis [2].
It can be seen that there is an inseparable link between the deterioration of chronic liver disease and angiogenesis. In order to curb the development of the disease, cutting off the "blood vessel supply" has become the only way. Therefore, the use of anti-angiogenic therapy has become a "powerful weapon" to effectively curb liver fibrosis. Molecularly targeted therapy research has promoted anti-angiogenic therapy as a promising strategy in anti-tumor therapy. The most widely used anti-angiogenic drugs include monoclonal antibodies and tyrosine kinase inhibitors (TKIs) that target the vascular endothelial growth factor (VEGF) pathway.
Bevacizumab is a humanized monoclonal antibody that has been shown to exhibit a potent anti-fibrotic effect in human Tenorn fibrosis [3]. In animal experiments [4], it has also been confirmed that bevacizumab can significantly alleviate the development of liver fibrosis in rats. Bevacizumab down-regulates the expression of the fibrogenes α-SMA and TGF-β1 in vivo, and can also block the effect of VEGF on hepatic stellate cells (HSCs) to alleviate liver fibrosis.
Another anti-angiogenic drug, apatinib (APA), is a small molecule inhibitor of vascular endothelial growth factor receptor (VEGFR)2 tyrosine kinase. It binds to ATP with high selectivity and gradually reduces the binding of VEGF to VEGFR2. At the same time, the phosphorylation process of VEGFR2 itself was also inhibited, which in turn blocked the activation of several important signaling pathways such as ERK1/2-MAPK and PI3K-Akt-mTOR in the downstream, and ultimately achieved the effect of improving liver fibrosis [5].
However, there is still a long way to go in the research and development of innovative drugs for liver fibrosis. Antifibrotic drugs with a single target are often limited in efficacy and prone to adverse reactions, and it is difficult to fully exert anti-fibrotic effects against only one of these targets [6].
"Double combat effectiveness" is full of potential
- Donafenib dual-target against fibrosis
Donafenib (DON) is a novel oral multi-kinase inhibitor that can not only block tumor angiogenesis by inhibiting the activity of various tyrosine kinase receptors such as VEGFR and platelet-derived growth factor receptor (PDGFR), but also directly inhibit tumor cell proliferation by blocking the serine-threonine kinase (RAS/RAF/MEK/ERK) signaling pathway, thereby exerting dual inhibition and multi-target blockade of anti-tumor effects.
近期，广州医科大学附属第一医院熊斌教授发表在PH&C期刊上一项名为“Dual neovascular targets of vascular endothelial growth factor receptors and platelet‐derived growth factor receptor ameliorate thioacetamide induced liver fibrosis in rats”的最新研究显示[7],多纳非尼除强劲抗肿瘤作用外，还有可能成为一种潜力十足的抗纤维化新药。
In vitro, the investigators looked at the effects of the single-target VEGFR inhibitor apatinib and the dual-target VEGFR/PDGFR inhibitor donafenib on the activation, proliferation, and apoptosis of rat and human hepatic stellate cells. In vivo, a classical thioacetamide (TAA)-induced liver fibrosis model was established to further explore the anti-fibrotic effects of apatinib and donafenib.
The purpose of this study is to comprehensively elucidate the mechanism of action of dual neovascularization-targeting VEGFR and PDGFR in alleviating liver fibrosis, and to verify whether dual-target donafenib has superior therapeutic potential compared with single-target apatinib, laying the foundation for future clinical translation.
More powerful hepatic stellate cell inhibition: where the cornerstone lies
Abnormal activation and proliferation of hepatic stellate cells is the main culprit leading to liver fibrosis. In in vitro studies, donafenib has demonstrated a stronger ability to inhibit hepatic stellate cell activity than the single-target drug apatinib.
Specifically, for the semi-inhibitory concentration (IC50) required to block the proliferative activation of stellate cells, donafenib is only 0.625 uM/L, while apatinib is as high as 5.0 uM/L. When these two levels are reached, donafenib can induce apoptosis in a higher proportion of stellate cells, and the proportion of apoptosis will increase as the concentration continues to rise.
It can be seen that donafenib is not only more sensitive to the inhibitory effect of key effector cells of liver fibrosis, but also has a more outstanding ability to promote apoptosis, which kills the cause of fibrosis from the root. This undoubtedly lays a solid foundation for donafenib to surpass apatinib in anti-fibrotic efficacy.
Animal Model Validation: Visible Therapeutic Benefits
In the mouse model of liver fibrosis, donafenib also showed a more significant fibrosis alleviation effect than the apatinib group.
The TAA-induced model of liver fibrosis was used in animal studies, and compared with 2mg/kg/day apatinib, 1mg/kg/day donafenib showed a better liver fibrosis remission efficacy through a variety of analytical indicators such as optical, semi-quantitative and quantitative.
This not only further confirms that donafenib does have an anti-fibrotic advantage over single-target drugs at the in vivo level, but also lays a strong preliminary data foundation for its future clinical translation.
A two-pronged approach to solving the problem: molecular mechanism elucidation
Donafenib can simultaneously inhibit VEGF and PDGF, two key signaling pathways involved in angiogenesis and fibrosis, while apatinib can only act on the VEGF pathway alone.
Therefore, the researchers speculate that this two-pronged dual inhibition effect may be the key to the stronger efficacy of donafenib in in vitro and in vivo trials. By blocking two core pathways, donafenib has the potential to become a more promising treatment.
There is a long way to go in the treatment of liver cancer, and donafenib shines brightly and lives up to expectations
Patients with liver cancer often have liver fibrosis, a pathological change that can have an important impact on treatment. In patients with milder liver fibrosis, surgical removal of the tumour may be an effective treatment option. However, when liver fibrosis is severe, the structure and function of the liver are compromised and surgical resection is limited. In addition, liver fibrosis can lead to decreased liver function and reduce the ability to metabolize and excrete chemotherapy drugs, which may weaken the effectiveness of chemotherapy. Liver fibrosis also increases the risk of complications during treatment, and when the tumor is surgically removed, liver fibrosis can cause the blood vessels in the liver to twist, making surgery more difficult and increasing the risk of bleeding after surgery. In addition, treatments such as transarterial chemoembolization (TACE) may also cause further damage to the liver.
Treating liver cancer is like fighting a giant beast, and protecting liver function is like building a strong fortress to provide reliable backing for the battle. Only when liver function is effectively protected, the sword of treatment can better cut off the root cause of the tumor and prolong the survival time of patients. Therefore, in order to buy more time and hope for patients, it is necessary not only to pay attention to the treatment of the tumor itself, but also to take active measures to protect the patient's liver function.
It is worth noting that donafenib, as a new dual-target anti-angiogenic drug, is becoming a dazzling new star in the treatment of liver cancer. The dual mechanism of action gives donafenib an unbeatable advantage. On the one hand, it can directly combat cancer by anti-tumor angiogenesis and inhibition of tumor proliferation, and on the other hand, it can effectively improve liver fibrosis, improve the liver's reserve capacity, and ensure internal strength. This not only increases the possibility of patients receiving surgical treatment, but also creates more favorable conditions for the subsequent application of various treatment options.
In addition, compared with single-target drugs such as apatinib and bevacizumab, donafenib has shown significant efficacy advantages in anti-fibrotic studies in vitro and in vivo. The unique mechanism of action of this dual target allows it to act at the same time from multiple angles, making it the "trump card" of liver cancer treatment. In short, this "double-edged sword" with both anti-tumor and hepatoprotective functions gives us reason to believe that donafenib will shine in clinical practice in the future and become the "savior" of chronic liver disease. It will not only benefit patients who have developed to advanced liver cancer, but also help expand its indication to the early stage of liver disease. By effectively curbing the occurrence and progression of liver fibrosis and cutting off the root cause of liver cancer, it will truly open a new way for patients with chronic liver diseases to embrace health and regain their vitality.
With in-depth research into its mechanism of action and the continued development of new drugs, reversing liver fibrosis will ultimately not be a distant dream. In the future, patients will no longer passively bear the ravages of the disease, but take the initiative to kill the root cause of the disease and regain the hope and courage of health!
Bibliography:
[1] Li H. Angiogenesis in the progression from liver fibrosis to cirrhosis and hepatocelluar carcinoma. Expert Rev Gastroenterol Hepatol. 2021; 15(3):217-233.
[2] Coulon, Stephanie et al. “Angiogenesis in chronic liver disease and its complications.” Liver international : official journal of the International Association for the Study of the Liver vol. 31,2 (2011): 146-62.
[3] O'Neill EC, Qin Q, Van Bergen NJ, et al. Antifibrotic activity of bevacizumab on human Tenon's fibroblasts in vitro. Invest Ophthalmol Vis Sci. 2010; 51(12):6524-6532.
[4] Huang Y, Feng H, Kan T, et al. Bevacizumab attenuates hepatic fibrosis in rats by inhibiting activation of hepatic stellate cells. PLoS One. 2013; 8(8):e73492.
[5] Hu Y, Jing J, Shi Y, et al. Apatinib inhibits pancreatic cancer growth, migration and invasion through the PI3K/AKT and ERK1/2/MAPK pathways. Transl Cancer Res. 2021; 10(7):3306-3316.
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Source: International Hepatobiliary Information