Endostatin and cancer therapy: a potential new alternative to anti-VEGF monoclonal antibodies. (2023)

Author(s): Gabriel Méndez-Valdés [1]; Francisca Gomez-Hevia [1]; José Lillo-Moya [1]; Tommy González-Fernández [1]; Joaquim Abelli [1]; Antonia Cereceda-Cornejo [1]; Maria Chiara Bragato [2]; Luciano Saso [3]; Ramón Rodrigo (corresponding author) [1,*]

1. Introduction

Cancer is one of the leading causes of death worldwide, responsible for almost 10 million deaths in 2020, according to the World Health Organization (WHO), and approximately 18 million new cases are diagnosed each year [1]. . This is one of the biggest public health problems in most countries in the world, since it affects both health and the economy.

Surgery can offer a complete cure if the cancer is diagnosed at an early stage, but unfortunately most cancers are detected when they are already locally advanced or have distant metastases, and in these cases surgery alone does not provide treatment. appropriate. In this scenario, the first line of treatment is chemotherapy. Chemotherapy can also be combined with radiation therapy [2], which is more effective in improving the survival of cancer patients. Unfortunately, this therapy is accompanied by a variety of side effects that often lead to discontinuation [2].

One of the fundamental characteristics of the pathophysiology of cancer is angiogenesis, a physiological process that consists of the formation of new blood vessels from existing ones. Therefore, several strategies targeting this process have already been proposed and are currently used in clinical practice.

The most studied and currently applied therapy consists of monoclonal antibodies directed against vascular endothelial growth factor (VEGF). These anti-VEGF monoclonal antibodies have been used as an adjunct to standard therapies in many different types of cancer, resulting in better patient outcomes. One of the main disadvantages of this family of drugs is its toxicity. This issue in the safety profile of anti-VEGF therapy may result in discontinuation of therapy. To overcome this problem, several options have been considered as possible alternatives, among which endostatin, an endogenous anticancer peptide, stands out. This review delves into the use of endostatin as a substitute for anti-VEGF monoclonal antibodies.

2. Angiogenesis

Angiogenesis is a biological process that consists of the growth of new capillaries from pre-existing vessels, which carry oxygen and nutrients to the tissues [3]. Capillaries are required in all tissues for the diffuse exchange of nutrients and metabolites. Changes in metabolic activity result in proportional changes in angiogenesis and therefore proportional changes in capillarity. Oxygen plays a central role in this regulation.

There are two types of angiogenesis, budding angiogenesis and intussusceptive angiogenesis.

Intussusceptive angiogenesis involves the formation of blood vessels through a disruptive process in which interstitial tissue elements invade existing vessels and form transvascular columns of expanding tissue [4].

Budding angiogenesis is characterized by budding composed of endothelial cells that normally grow in response to an angiogenic stimulus such as VEGF-A. Thus, germ line angiogenesis can add blood vessels to parts of tissues that previously lacked blood vessels.

This last type of angiogenesis is one of the characteristics of cancer. In this scenario, pathologic angiogenesis is driven by overexpression of proangiogenic factors, resulting in an imbalance with antiangiogenic factors and recruitment of new vasculature [5]. This process is primarily triggered by tissue hypoxia, leading to the expression of multiple growth factors via hypoxia-inducible factors (HIFs) by cancer cells and stromal cells that are recruited into the tumor [6]. . This pathological process leads to the formation of tortuous, weak and highly permeable blood vessels and heterogeneous vascular zones in tumors [7,8].

One of the most important angiogenic inducers is vascular endothelial growth factor (VEGF). VEGF is a homodimeric glycoprotein with a molecular weight of approximately 45 kDa [9]. The family of growth factors and receptor tyrosine kinases includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor (P1GF), of which VEGF-A is the major mediator of angiogenesis. tumor [10]. It induces angiogenesis through a direct action on endothelial cells by binding to two homologous receptor tyrosine kinases, VEGF receptor 1 (VEGF-R1) and VEGF receptor 2 (VEGF-R2), which are predominantly expressed on endothelial cells. endothelial cells [9]. , can also be found in non-endothelial cells [11]. Although VEGF-R2 is mainly involved in tumor pathological processes, such as tumor angiogenesis, VEGF-R1 activation also plays an important role, including several mechanisms. The main ones are chemotaxis of inflammatory cells, secretion of inflammatory cytokines, recruitment of marrow progenitor cells to the site of injury, secretion of growth factors, interaction with PlGF, and activation of proteolytic enzymes [11].

Vascular endothelial growth factor gene expression is upregulated by several factors, such as PDGF, fibroblast growth factor (FGF), epidermal growth factor (EGF), tumor necrosis factor (TNF), etc. [9]. VEGF is also upregulated by HIF [12]. Vascular endothelial growth factor signaling by VEGFR1/R2 regulates the activities of multiple kinases, resulting in cell proliferation, migration, survival, and vascular permeability during angiogenesis [12]. It plays an important role in pathological angiogenesis and induces the development and progression of certain pathological conditions, including tumor growth and metastasis [11]. Solid tumors need an adequate blood supply to grow, without which they cannot grow to more than 106 cells due to lack of oxygen and nutrients. Tumors in their avascular phase can remain latent and maintain a state between cell proliferation and apoptosis. VEGF plays a key role in converting the tumor to an angiogenic type, allowing access to oxygen and nutrients and growth [8]. VEGF is expressed in most cancers and its increased expression is generally associated with a worse prognosis [10].

3. Anti-VEGF monoclonal antibodies

The angiogenic pathway consists of different steps, so each step can be directed to the development of a new antihumoral therapy. Antiangiogenic agents that target the VEGF signaling pathway include monoclonal antibodies against VEGF, tyrosine kinase inhibitors, the VEGF decoy receptor, and specific inhibitors against VEGFR-2 [13]. Among the different classes of drugs, the most common are monoclonal antibodies. A well-known anti-angiogenic monoclonal antibody is bevacizumab [13].

Bevacizumab is a humanized monoclonal antibody that binds to circulating VEGF-A isoforms, thereby inhibiting their binding to cell surface receptors. This results in inhibition of VEGF signaling pathway activation, leading to decreased tumor perfusion and blood vessel growth [14]. Thanks to its mechanism of action, bevacizumab leads to less angiogenesis and less growth of various tumors, both primary and metastatic. This monoclonal antibody is administered intravenously and can be used to treat colon, lung, glioblastoma, and kidney cancer [15].

There are several studies that show the benefit of the use of bevacizumab as adjuvant therapy to chemotherapy, mainly in colorectal and lung cancer. In a study by Goldberg et al. [16] For first-line treatment of metastatic colorectal cancer, the addition of bevacizumab to bolus chemotherapy with irinotecan, leucovorin, and fluorouracil (IFL) resulted in clinically significant and statistically significant benefit for all study endpoints, including overall survival, progression-free survival and response rate and was associated with an acceptable side-effect profile. Furthermore, Ferrara et al. [17] conducted a study in which patients with previously untreated non-squamous cell non-small cell lung cancer received bevacizumab in combination with standard chemotherapy (paclitaxel and carboplatin). Preliminary results from this large phase III randomized clinical trial showed that patients treated with bevacizumab as adjuvant therapy lived longer than patients who received the same chemotherapy without bevacizumab.

Anti-VEGF agents show high variability in their clinical response. Recent studies reported that patients with metastatic colorectal cancer who also carried the VEGF-A rs699947 A/A allele, a single nucleotide polymorphism, had significantly higher PFS and OS after bevacizumab administration. In addition, carriers of the ICAM rs1799969 G/G and BRAF rs113488022 mutant (78.3%, 26%, and 8.6% of the study population, respectively) showed a significantly increased OS [18].

Another study in metastatic colorectal cancer reported an association between the CXCR1 rs2234671 G>C allele and a lower relative risk of metastatic cancer. A correlation was also made between different alleles and results based on breed. In particular, the CXCR2 rs2230054 T>C and EGF rs444903 A>G alleles (71%, 38%, and 44% of patients were homozygous, respectively) were associated with better clinical outcome and tumor response in Caucasian but not Asian patients and hispanics. 19] .

In patients with advanced breast cancer, a significant improvement in median OS was associated with the AA/AA alleles of VEGF-2578/-1154, present in 7.6% of patients, with the most common alleles showing a worse prognosis [20]. Furthermore, Etienne-Grimaldi et al. [21] reported that a higher TTP was associated with VEGF-936C>T with 936T carried by 23.3% of the patients tested and that the VEGF-A -634 G>C polymorphism was associated with a toxicity score - Higher 634C associated with allelic carriers is likely to develop hypertension and thromboembolic events. Exposure to this monoclonal antibody was correlated with OS in patients with metastatic colorectal cancer, with higher doses showing better results [22], which may be related to the complex pharmacokinetic behavior of this drug.

Collateral damage

Anti-VEGF drugs, in particular bevacizumab, have been introduced in oncology to inhibit tumor-induced angiogenesis nourishing neoplastic tissue. These agents are administered by the systemic and intravitreal routes.

When drugs are administered locally intravitreal into the eyeball, they are injected in much smaller amounts [23]. Even if the amount of drug administered is less, side effects still occur. This is because the presence of side effects is not due to the route of administration or the amount of drug administered, but to the suppression of signaling pathways that regulate microvasculature maintenance and inhibit anti-VEGF therapy [ 24] . Consequently, systemic exposure has been observed with intravitreal administration, even at low doses [25]. The incidence of these side effects varies according to the drug used, ranging from high frequency, such as hypertension and proteinuria, to less frequent, such as healing disorders, gastrointestinal perforation, hemorrhage and thrombosis, posterior reversible leukoencephalopathy, cardiac and endocrine failure. dysfunction [24].

Regarding anti-VEGF intravitreal therapy, used specifically in retinal diseases, the systemic effects are the same as those mentioned above, with the addition of ocular complications, the frequency of which also depends on the drug used. Examples of ocular complications are endophthalmitis, intraocular inflammation, rhegmatogenous retinal detachment, increased intraocular pressure [26].

As mentioned above, angiogenesis is carried out by signaling a family of five members, VEGF-A, VEGF-B, VEGF-C, VEGF-D and P1GF, necessary to carry out processes such as wound healing. , vascular and embryonic permeability. vasculogenesis. All these processes can be used by the tumor to ensure its growth in situ and its ability to metastasize.

Thus, blockade of the VEGF signaling pathway by various drugs, including monoclonals (mAbs), ligand inhibitors, and TKI inhibitors, has been shown to be beneficial in various types of cancer [27] .

However, as a result of the inhibition of the VEGF signaling pathways, the physiological functions of the cells can no longer be adequately maintained, so side effects can be observed after the administration of such therapies. Several studies have shown that common adverse events such as high blood pressure are associated with reduced nitric oxide (NO) production in arterioles and other vessels. Furthermore, proteinuria can be explained by blocking VEGFR-2 signaling in glomerular capillaries, thereby reducing the number of fenestrations [24].

In angiogenesis in an adult organism, VEGFR-1 does not play a relevant role in physiological functions, but plays an important role in angiogenesis related to tumor growth and nutrition.

On the other hand, VEGFR-2 performs pro-angiogenic functions in healthy and damaged adult tissues and is also involved in tumorigenesis.

Currently approved therapies for many solid tumors inhibit VEGF-A signaling (bevacizumab, aflibercept), VEGFR-2 (ramucirumab), or VEGF receptor activation.

In fact, the problem with the appearance of adverse events lies in the fact that the interruption of VEGF-A/VEGFR-2 signaling also inhibits the normal physiological processes carried out by the activation of this receptor [28]. Clinical studies have shown that anti-VEGF monoclonal antibodies have associated toxicity in addition to the toxicity that chemotherapy already has.

In a phase 3 RCT, 903 patients with renal cell carcinoma were divided into two groups: 451 patients received standard care plus sorafenib, a VEGFR inhibitor, and 452 received standard care with placebo. Although PFS showed a statistically significant benefit of the first group over placebo, there was a significant difference in the incidence of serious adverse events between the sorafenib and placebo groups (34% and 24%, respectively; p<0.01). In the sorafenib group, 76 patients had some degree of hypertension, compared with only eight in the placebo group. Sorafenib has also been associated with other adverse events such as gastrointestinal and dermatologic [29].

In another phase 3 RCT, Wakelee et al. administered chemotherapy (Arm A) and chemotherapy plus bevacizumab (Arm B) to patients with resected non-small cell lung cancer. In this study, 8.4% of patients in group A and 27.6% of patients in group B had to discontinue treatment due to adverse events. Furthermore, hypertension was more common in patients treated with bevacizumab [30].

Given the above, although anti-VEGF monoclonal antibodies seem to improve survival, they still have significant toxicity that can manifest to different degrees in different patients.

These results make it crucial to discover new drugs with a better safety profile and the same or better therapeutic results. Therefore, in this review we evaluated the use of endostatin, a peptide also associated with angiogenesis, as a treatment for cancer.

4. Endostatina

Endostatin is one of the best studied peptides with inhibitory effects on angiogenesis [3]. This peptide is a 20 kDa C-terminal cleavage fragment of the a1 chain of type XVIII collagen, an extracellular matrix protein known for its antiatherosclerotic activity and as a potent inhibitor of angiogenesis [3]. Endostatin was artificially synthesized in recombinant human form with the addition of nine additional amino acids that confer greater stability, solubility, and antiangiogenic activity [31]. The mechanism of action of endostatin is not fully understood. There is evidence that this molecule exerts its angiostatic effects through multiple mechanisms involving elements of the extracellular matrix, as well as proteins and signaling cascades associated with endothelial cell migration and proliferation.

Firstly, it was recognized that endostatin is capable of inhibiting matrix metalloproteinases (MMPs), specifically MMP-2, MMP-9 and MMP-13, which, due to their proteolytic effects, facilitate endothelial cell migration and invasion. during the process of angiogenesis. .

Furthermore, endostatin inhibits the FAK/Ras/p38-MAPK/ERK signaling cascade with the suppression of HIF-1a/VEGF-A through the binding of the α5β1 integrin and thus leads to an inhibition of endothelial cell migration. Endostatin can also induce autophagy in endothelial cells [32] through a signaling pathway mediated by activation of the Src family of kinases [33].

In addition, endostatin is responsible for the downregulation of the β-catenin-dependent Wnt signaling pathway. This last mechanism is related to a repression of the transcription of important genes involved in the cell cycle, which is strongly linked to endothelial cell apoptosis.

Alternatively, endostatin binds directly to VEGF-R2, blocking the action of VEGF and thus suppressing the formation of vascular endothelial tubes [34]. These mechanisms are summarized in Figure 1. Consistent with the angiostatic profile of endostatin, in vitro models using human umbilical cord endothelial cells have shown that this agent has the ability to inhibit endothelial cell migration as well as the formation of capillaries and the union between them [35]. As a result of these findings and considering angiogenesis as one of the characteristics of cancer, this agent was tested in several experiments to investigate its ability to reduce tumor growth and prevent metastasis.

Preclinical results in a murine xenograft lung cancer model demonstrated that endostatin is able to normalize the structure and function of the tumor vasculature, characterized by a decrease in microvessel density and improved vessel wall structure [ 36]. In the same study, it was shown that this effect translates into increased delivery of cytotoxic drugs to the tumor area, so endostatin would have a synergistic effect when administered together with cytotoxic drugs [36]. In addition, it has been shown that endostatin alone can decrease the number and size of metastatic lung nodules, which correlates with prolonged overall survival in mice treated with this drug [37]. It has also been tested in models of ovarian cancer, characterized by its aggressiveness and high metastatic capacity. Cancer patients who received the treatment showed a significant reduction in tumor growth associated with a decrease in the ability of tumor cells to migrate. Furthermore, this was correlated with lower expression of angiogenesis-promoting proteins and lower epithelial-mesenchymal junction [38].

One of the main problems with the use of endostatin is that the dose administered to make this compound biologically active is too high. Therefore, it must be manufactured in large quantities, which also makes it a potential financial burden. Another issue that contributes to this problem is that its purification process can denature its structure and reduce its yield. In fact, the endostatin production system can disable proper folding in the production of soluble protein, affecting its bioactivity. Finally, this peptide has a short half-life [39], resulting in the need to infuse it continuously for long periods of time.

Most human studies of endostatin have been performed in patients with metastatic or locally advanced cancer, in whom endostatin has been added to the first line of treatment, usually chemotherapy or chemoradiotherapy.

The following sections review the results of the most relevant human studies using endostatin to treat various types of cancer, emphasizing its safety profile.

4.1. lung cancer

Most endostatin studies have involved patients with non-small cell lung cancer (NSCLC), which accounts for 85% of all lung cancers. A large proportion of this type of cancer is diagnosed in advanced stages (III or IV), where the first line of treatment is platinum-based chemotherapy together with new generation cytotoxics such as etoposide and gemcitabine and/or radiotherapy [40] .

Several clinical studies have been conducted in recent years showing that the addition of endostatin to standard care for advanced NSCLC improves overall survival (OS) and progression-free survival (PFS) in patients with locally advanced disease [41, 42,43,44 , 45,46,47,48,49,50,51] or metastasis [43,49,50,51,52,53,54]. Studies on small cell lung cancer have also been tested, showing promising results in terms of survival and tolerability of therapy [55,56,57].

Interestingly, the addition of endostatin to these different studies did not significantly increase the incidence of adverse events compared to their respective control groups. Side effects seen with endostatin combination therapy regimens in addition to chemotherapy or chemoradiotherapy include hematologic toxicity (neutropenia, thrombocytopenia, and anemia), nausea, vomiting, and fatigue [57]. Fortunately, none of these side effects led to discontinuation of treatment.

In addition, other authors have compared the efficacy and safety of the use of long-term regimens of endostatin during concomitant chemotherapy [43,51]. The results indicate that prolonged treatment with endostatin is not only associated with a significant improvement in the patient's prognosis, but also does not lead to a significant increase in the most common side effects associated with therapy. The only exceptions are heart disease and hypertension, which occur more frequently in patients who have received a long course of endostatin, although neither have led to treatment discontinuation [43,51].

4.2. Stomach cancer

Gastric cancer is responsible for more than 1 million cases diagnosed worldwide each year. Those diagnosed with stage IA or IB have a 5-year survival rate of 60-80%. Unfortunately, most of them are already in the metastatic stage at the time of diagnosis, drastically worsening the prognosis, with a 5-year survival rate of only 18% for those diagnosed at stage III [58]. . In this setting, the first line of treatment is chemotherapy with the regimens FOLFOX (folic acid with 5-fluorouracil and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) with or without trastuzumab when HER2 is overexpressed [58]. Recently, clinical guidelines recommend that ramucirumab, a VEGF-R2 monoclonal antibody, can be added to the treatment regimen in the context of disease progression [59]. There are few human studies that have used endostatin to treat stomach cancer. These studies mainly include patients with locally advanced disease or with distant metastases.

In a study by Yao J et al. [31], who recruited 33 patients with advanced gastric cancer with peritoneal carcinoma, demonstrated that treatment with endostatin plus chemotherapy was superior to chemotherapy alone, with a significantly higher median OS in the endostatin group compared with the endostatin group. control (15.8 vs. 9.8 months).

The main adverse reactions that led to dose reduction and discontinuation were neutropenia and severe thrombocytopenia. However, they were present in both groups with no significant difference. Adverse events associated with endostatin included only hypertension and bleeding, but did not lead to treatment discontinuation.

In another clinical study conducted by Yang H et al. [60] demonstrated that endostatin plus SOX (S-1 with oxaliplatin) is effective in the treatment of liver metastases in patients with gastric cancer. The most common side effects, such as gastrointestinal reactions, haematological toxicity, and heart disease, were equally present in both groups, but interestingly, the severity of these side effects was less in the endostatin group.

One of the largest clinical studies examined the safety and efficacy of molecular targeted therapy in patients with advanced gastric cancer [61]. A total of 200 patients were divided equally into four groups, with one control group receiving chemotherapy and others receiving bevacizumab (VEGF-R monoclonal antibody), apatinib (tyrosine kinase inhibitor) and endostatin. The results showed that molecular therapies were significantly more efficient than chemotherapy in reducing and controlling tumor lesions and that there were no significant differences between the three experimental groups.

The main adverse events that occurred in all groups were neutropenia, nausea, vomiting, and rash, but their incidence was significantly higher in the control group. The results of this study suggest that targeted molecular therapies are the treatment of choice for patients with advanced gastric cancer due to their greater efficacy in controlling tumor lesions and the lower frequency of treatment-emergent side effects.

4.3. esophagus cancer

Esophageal cancer accounts for approximately 5% of cancer deaths worldwide, with an estimated 570,000 cases diagnosed in 2018, with esophageal squamous cell carcinoma (ESCC) being the most common subtype. common [62]. It is a cancer with a poor prognosis, more than 70% is diagnosed in an advanced stage, with a 5-year survival of 25.1% for local-regional extension and only 4.8% for distant metastases [62]. In patients with locally advanced disease, the first line of treatment is surgery followed by neoadjuvant chemoradiotherapy before surgery; however, in patients with metastatic disease at diagnosis, chemotherapy or chemoradiotherapy is the preferred treatment alternative [63].

Early clinical trials of Endostatin in esophageal cancer showed that the Endostatin plus DP (docetaxel and cisplatin) regimen did not have a higher rate of the most common side effects than the PD regimen alone.

Of note, three of the ten patients in the endostatin group had ECG changes (T wave). However, these changes normalized towards the end of the treatment cycles [64].

No Hu Z et al. [65] in 50 patients who received treatment with endostatin plus irinotecan/cisplatin demonstrated the efficacy and safety of this treatment for advanced SCEC. The median PFS was 4.01 months and the median OS was 12.32 months.

The most frequently reported adverse reactions were leukopenia (18.0%) and neutropenia (16.0%); in five patients (10.0%) they were grade 3 or greater in severity, leading to discontinuation of treatment.

Likewise, another phase II clinical trial conducted by Wang Z et al. [66] demonstrated the safety and efficacy of endostatin plus paclitaxel/nedaplatin. The study was conducted in 53 patients with locally advanced or metastatic squamous cell carcinoma of the esophagus. The most frequently observed Grade 3 or higher adverse reactions were neutropenia (17.0%) and anemia (3.8%), and there were no treatment-related deaths during the duration of the study.

Another noteworthy study is that of Zhong Z et al. [67], where endostatin therapy plus chemoradiotherapy was shown to be superior to chemoradiotherapy for the treatment of SCEC that is locally advanced but not distantly metastatic. The 1-year and 3-year overall survival rates were significantly higher in the endostatin group than in the chemoradiotherapy group (72% vs. 50% and 32% vs. 22%, respectively), and the median PFS was 11.3 months for the endostatin group and 8.1 months for the control. In addition, there was no treatment-related toxicity that could be directly attributed to endostatin. In fact, the most commonly observed side effects were probably related to chemoradiotherapy.

4.4. colon cancer

Colorectal cancer is the third most common cancer worldwide, with 1,931,590 new cases in 2020 [68].

The most common treatments for metastatic colorectal cancer are infusion regimens of FOLFIRI (5-fluorouracil with leucovorin and irinotecan) or FOLFOX (5-fluorouracil with leucovorin and oxaliplatin), combined with anti-VEGF or EGFR antibodies in recent years [ 69] .

Bevacizumab is an example of an anti-VEGF antibody approved for first-line use in colorectal cancer.

Although its efficacy as monotherapy has been demonstrated, a meta-analysis reported that there is insufficient evidence to support its use as adjunctive therapy with other regimens such as FOLFIRI or FOLFOX.

In addition, its association increased the frequency of adverse events such as hypertension, proteinuria, bleeding, and thromboembolism, in addition to increasing treatment interruptions [70].

Several studies have tested the use of endostatin in combination with several popular chemotherapy regimens for colorectal cancer, such as: B. FOLFOX4 [71], modified FOLFOX6 [72], FOLFIRI [73] or several of these included [74].

read to conducted a randomized controlled trial to evaluate the efficacy and safety of the use of Endostatin plus FOLFIRI chemotherapy in patients with advanced colorectal cancer and reported a significantly higher ORR (42.9 vs 29.4%) and PFS (14, 5 vs. 11 months) than the control group [73].

Furthermore, Xu et al. investigated the use of Endostatin in combination with FOLFOX4 in patients with non-metastatic colorectal cancer in a retrospective controlled study, and showed a significantly higher ORR (38.9 vs 22.3%), PFS (6.4 vs 3, 8 months) and OS (12.1 vs 3.8 months). 11.4 months) as a control group [71].

In addition, a pilot study evaluated the efficacy and safety of the use of Endostatin in combination with different chemotherapy regimens (CAPIRI, GP, XELOX, DCF, FOLFIRI, or FOLFOX4) in patients with metastatic colorectal and gastric cancer and reported a survival of 10.3 months (95% CI, 3.9-16.7 months), median time to progression 2.6 months (95% CI, 2.0-3.2 months), disease control rate of 47.6% and an ORR of 19.0%, and in patients treated first with line therapy, the response rate was 57.1%.

Another interesting aspect is that endostatin was also administered to a small cohort of patients (n = 5), in addition to previously unsuccessful third-line therapies. The results of the study showed stability of the disease with a maximum TTP of more than 11.0 months. Therefore, the authors suggest that the combination of endostatin and chemotherapy may also reverse chemoresistance. This is one aspect of endostatin therapy that should certainly be investigated [74].

Regarding the safety of Endostatin in patients with colorectal cancer, a Phase I clinical trial evaluated the safety, tolerability, and pharmacokinetics of the use of Endostatin in combination with the modified chemotherapy regimen FOLFOX6 as first-line treatment in patients with advanced colorectal cancer. using a dose escalation methodology.

Among the outcomes, the most common drug-related adverse events reported were leukopenia, neutropenia, anemia, anorexia, ST-segment/T-wave changes, and nausea, but only those with grade 3-4 severity were neutropenia, leukopenia, and thrombocytopenia. . .

There were also two patients in the endostatin group who discontinued therapy after an episode of ventricular arrhythmia [72].

However, these results are similar to those reported in controlled clinical trials, where haematological and gastrointestinal side effects were the most common, with no significant difference between the endostatin plus chemotherapy group and the control group [71,73].

Despite this, cardiac adverse events vary between studies, with Zhou et al. reported that three patients had transient sinus bradycardia with spontaneous remission [74]; Xu et al. that 17.7% had hypertension and 11.1% cardiac ischemia, both grades 1-2 vs. 5.6% and 0.0% in the control group, respectively [71]; and Li et al. reported that three patients had grade 1 electrocardiographic abnormalities that were reversed with the administration of fructose diphosphate sodium, and two patients had reversible and controllable grade 1-2 hypertension [73].

4.5. Nasopharyngeal cancer

Nasopharyngeal carcinoma (NPC) is a relatively rare type of cancer compared to the others. It had an estimated global incidence of 129,000 cases in 2018 [75]. NPC generally responds favorably to radiation therapy, with intensity-modulated radiation therapy (IMRT) being the first line of treatment in stage I disease. Patients with metastatic or locally advanced (stage II-IV) disease benefit from chemotherapy in addition to the IMRT [75]. Existing studies of endostatin in this form of cancer are focused on comparing whether the addition of this agent to conventional therapy represents an improvement in long-term results with an acceptable safety profile, since the existing first-line treatment until date has been very effective in improving survival in the short and medium term.

A study by Guan Y et al. [76] with 22 patients with stage III-IV NPC evaluated the safety profile of the endostatin plus IMRT regimen together with chemotherapy.

The results showed that this regimen was not associated with a higher rate of side effects than has been reported in the past for standard treatment of IMRT plus chemotherapy. In addition, endostatin treatment was associated with a lower incidence of nasopharyngeal mucosal necrosis/infection compared with reports in the literature for the treatment of stage III-IV NPC (31.8% vs 40.6%). .

A phase II multicenter clinical trial conducted by Li Y et al. [77] recruited 114 patients with stage III-IV NPC to determine the efficacy and safety of endostatin treatment. The experimental group received endostatin plus IMRT with chemotherapy, while the control group received only IMRT plus chemotherapy.

After a median follow-up of 67 months, the results showed that the experimental group showed a slight but significant improvement in ORR 3 months after treatment, but this did not lead to significant differences in the healing effect of nasopharyngeal lesions with the long-term treatment. . Post-treatment term. At 5-year follow-up, there were no significant differences in OS, PFS, distant metastasis-free survival (DFMS), and locoregional disease-free survival between the two groups.

In this study, there was no toxicity associated with endostatin treatment, and the frequency of side effects was also not significantly different.

In contrast, a retrospective study showed that endostatin treatment together with chemoradiation was associated with a significant improvement in PFS and distant metastasis-free survival rates at 3-year follow-up compared with chemoradiation alone (81, 4% vs. 63.6%). % and 88.3%). % vs. 77.3%), although no improvement in OS was observed [78].

Another retrospective study by Chen W et al. [79] compared the efficacy and long-term side effects between IMRT plus endostatin and IMRT plus chemotherapy. The results showed that the IMRT plus endostatin group showed no significant difference in long-term efficacy at 5-year follow-up in terms of OS, PFS, and DMFS scores. However, the IMRT plus endostatin group was characterized by a significantly more favorable long-term adverse event profile, with a significant decrease in both the incidence and severity of xerostomia, difficulty opening the mouth, and fibrosis of the mouth. the soft tissues.

4.6. breast cancer

Breast cancer is currently the most common type of cancer worldwide [80]. Although there are different histologic types, triple-negative breast cancer (estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 are all negative) is characterized by aggressive biologic behavior, poor response to treatment, and poor prognosis [81]. , 82]. However, in recent years the efficacy of treatments and the survival of patients with advanced breast cancer of different molecular subtypes have improved, mainly due to the deepening of the use of personalized strategies based on anti-VEGF monoclonal antibodies, inhibitors of tyrosine kinase inhibitors and checkpoint immunological agents, CDK4/6 inhibitors [83].

The incorporation of anti-VEGF monoclonal antibodies into breast cancer therapy has shown promising results in ORR and PFS, but not in OS [84].

The use of endostatin in combination with chemotherapy has been shown to be effective and safe in patients with triple negative breast cancer [85].

Several clinical studies have reported encouraging results evaluating the efficacy and safety of endostatin use in combination with conventional therapy in patients with different subtypes or clinical stages of breast cancer, achieving high overall response rates and unincreased overall survival rates. the incidence of side effect events [84,86,87,88].

A prospective study evaluated the use of endostatin in combination with taxane-based chemotherapy in patients with HER-2 negative metastatic breast cancer and reported an overall response rate of 68.4%, with a greater response in those patients who received the therapy. as first line treatment. (79.3%) compared to those who received it as second and third line or more (54.5% and 16.7%, respectively). Additionally, patients who had not been previously treated with taxanes had a higher overall response rate. With respect to PFS, the median was 10.8 months [86].

In addition, another prospective study evaluated the use of endostatin in combination with platinum-based chemotherapy in patients with triple-negative breast cancer and reported an ORR of 47.6%, a PFS of 8.8 months (95% CI: 7, 2–10.4 months) and a median overall survival of 13.3 months (95% CI: 11.6–15.0 months) [87].

Another noteworthy study is that of Chen et al. They conducted a phase 3 clinical trial to evaluate the use of endostatin with docetaxel and epirubicin as first-line treatment in patients with stage IIA-IIIC breast cancer [88]. In this study, the authors used clinical and pathologic response as the primary endpoint and defined an objective response as those patients in whom all target lesions disappeared or the sum of the largest diameter of target lesions decreased by at least 30%. and a pathological response response as those patients who did not have viable residual invasive tumor. An objective response of 91.0% and a pathologic response of 10.7% were reported as outcomes in patients who received endostatin plus chemotherapy versus 77.9% and 7.7%, respectively, in patients who received chemotherapy alone [88] .

In addition, there are studies examining the efficacy of endostatin as monotherapy. A phase II clinical trial evaluated the use of endostatin alone in patients with stage III TNM breast cancer. Patients were randomized to receive neoadjuvant therapy consisting of endostatin in combination with docetaxel, epirubicin, and cyclophosphamide or chemotherapy alone.

Most importantly, the authors reported significant differences in ORR, with 81.82% in patients receiving endostatin plus chemotherapy versus 58.14% in patients receiving chemotherapy alone, noting that patients with infiltrating ductal carcinoma they had higher sensitivity compared to endostatin treatment. In addition, the median OS was significantly longer in the endostatin group at 74.2 months versus 59.1 months, which was also reflected in the 3-year and 5-year OS rates. Finally, the median reported recurrence-free survival was 67.3 months versus 55.0 months in the control group [84].

Regarding the evidence from prospective studies on adverse events associated with the association of endostatin with chemotherapy, Huang et al. reported neutropenia (80.7%), leukopenia (77.2%), hepatic dysfunction (10.5%), and peripheral neurotoxicity (8.8%) as the most common grade 3-4 adverse reactions, while Tan et al. to the. reported neutropenia (14.3%), anemia (14.3%), leukopenia (9.5%), thrombocytopenia (9.5%), febrile neutropenia (4.8%), and hypertension (4.8%) degrees 3-4 side effects [86,87].

In addition, randomized clinical trials did not report significant differences in the incidence of adverse events between the groups that received endostatin plus chemotherapy and those that received chemotherapy alone [84,88]. A summary of these articles can be found in Table 1.

5. Discussion

Cancer remains one of the leading causes of death worldwide and a major public health challenge. In particular, what complicates their treatment is the fact that most cancers are diagnosed in advanced stages of the disease. In this scenario, chemotherapy plays an important role as the first line of treatment.

In recent years, targeted therapies have been increasingly used in oncology, where molecular markers and tumor pathophysiological events have become more important than tumor location.

As detailed in this review, one of the most important processes for tumor development is angiogenesis. Angiogenesis in cancer provides the blood supply for tumor growth and the ability to metastasize. In fact, its inhibition has become a priority as an object of studies aimed at preventing tumor progression.

There are already several therapies that complement the traditional chemotherapy scheme.

In particular, anti-VEGF therapies aimed at blocking signaling pathways that promote angiogenesis are widespread. Anti-VEGF therapies improve parameters such as OS, PFS and ORR, but also cause a number of side effects ranging from common events such as hypertension and proteinuria to rarer events such as wound healing disorders, gastrointestinal perforation, bleeding and thrombosis, reversible . posterior leukoencephalopathy, heart failure and endocrine dysfunction.

Given this scenario, the use of combination therapies creates a dilemma regarding the balance between therapeutic benefit and the patient's quality of life.

Currently, there are new drugs that appear to be as effective as or better than classic chemotherapy/anti-VEGF drugs, but few studies have been done to understand whether these drugs can permanently replace anti-VEGF therapies.

In one of Chen et al. [94] Platinum-based dual chemotherapy in combination with endostatin had similar OS and PFS but less severe side effects than the same regimen added to bevacizumab in patients with advanced NSCLC. The limitations of this study may explain the lack of statistical significance, leaving the true efficacy of this drug uncertain.

In one of Shi et al. [95] on the influence of angiogenesis inhibitors on the survival of patients with SCLC only found an improvement in PFS with bevacizumab. As evidence and studies in this area are sparse, only nine articles could be analysed, including non-randomised clinical trials, where there was only one study testing endostatin.

Most of the studies using endostatin to treat different types of cancer focus on patients with advanced stages of the disease, mainly stage III-IV, to assess whether this agent can improve survival and also has an acceptable safety profile that does not leads to the abandonment of lead. to treatment

Consistent with several RCTs conducted in lung, stomach, oesophageal, colorectal, and breast cancer, endostatin treatment together with conventional therapy provides a significant improvement in patient prognosis compared with initial treatment with chemoradiotherapy or chemoradiotherapy alone [ 41,44,48,49 ,54,67,71,73,88,89,91]. Furthermore, studies by Hu W et al. and Zhao J et al. showed that the use of prolonged regimens of endostatin, i. H. 4 or more cycles is not associated with a higher rate of side effects and is correlated with a better prognosis [43,51]. The exception to this pattern is the case of nasopharyngeal carcinoma, where endostatin treatment only correlates with an improvement in ORR at 3 months, but does not result in an improvement in long-term survival parameters, as demonstrated. in a phase II clinical study conducted by was conducted by Li Y et al. [77].

However, a retrospective analysis indicates that although endostatin treatment in nasopharyngeal carcinoma is not associated with a significant improvement in OS at 3 years, it does represent an improvement in PFS and DMFS [78]. The authors suggest that this discrepancy may be due to the fact that first-line treatment, consisting of chemoradiotherapy, is highly effective even in patients with advanced-stage nasopharyngeal carcinoma [77,78].

Regarding the safety profile of endostatin, most studies indicate that it is not associated with an increase in the rate or severity of the most common side effects associated with conventional therapy, which are usually haematological toxicity and gastrointestinal reactions [31]. ,57,60 ,61 ,65,76,84,88]. The most frequently reported grade 3-4 adverse reactions were leukopenia, neutropenia, thrombocytopenia, nausea, and vomiting, but were related to treatment with radiation and/or cytotoxic drugs and not to endostatin [61,67].

In the study by Yang H et al. [60] targeting metastatic gastric cancer, the addition of endostatin to conventional therapy was found to be associated with less severity of chemotherapy-related side effects. In addition, endostatin treatment in patients with nasopharyngeal carcinoma was associated with a lower incidence of nasopharyngeal mucosal necrosis/infection [76], but also with a significant reduction in the frequency and severity of long-term sequelae associated with radiotherapy. such as xerostomia, difficulty opening the mouth, and soft tissue fibrosis [79].

The most important side effects directly attributed to endostatin therapy are cardiovascular changes. Several reports indicate that the most common are arterial hypertension, electrocardiographic abnormalities (ST/T wave changes), cardiac ischemia, and transient sinus bradycardia, which are more common in hypertensive patients or with a history of coronary artery disease [3]. However, none of them resulted in discontinuation of therapy, were easily manageable, or resulted in spontaneous remission after completion of the treatment cycles [55,64,73]. One of Guan et al. [96] showed that dihydromyricetin can protect against this side effect. Chen et al. [72] on colorectal cancer was the only study in which two patients in the endostatin group had to discontinue treatment after having an episode of ventricular arrhythmias.

In summary, the current problems with endostatin studies appear to be the lack of studies and, among those that currently exist, their small number of patients, their reduced statistical power, and the lack of these studies in other settings outside of China, which may affect your Results as mentioned above; VEGF polymorphisms affect the efficacy of bevacizumab, which cannot be excluded for this drug. Another explanation for the lack of clinical trials with endostatin could be the uncertainty of its mechanism of action, leaving uncertain its interactions with other drugs.

Furthermore, as previously reported in this review, Mohajeri et al. [39] specifically reported the challenges of recombinant endostatin in clinical use and highlighted the problems in achieving endostatin stability and finding the appropriate vehicle for drug delivery. Strategies such as PEGylation of this molecule have been tested with the aim of increasing its half-life and stability. In vitro studies showed similar efficacy to recombinant endostatin but with a longer half-life [97] and no serious side effects in mice [98]. Furthermore, an endostatin liposome encapsulation approach has shown beneficial results in prolonging its half-life [99]. The cost of producing this molecule could be reduced as advances in technology and industry make it cheaper to produce.

Despite the above problems, endostatin has shown potential as an alternative therapy to anti-VEGF monoclonal antibodies due to its efficacy in advanced stages of cancer, mainly associated with NSCLC, showing similar efficacy and a good safety profile. In fact, targeting angiogenesis with monoclonal antibodies has been a breakthrough in cancer therapy; however, significant associated toxicity remains a problem, forcing some patients to discontinue therapy.

Therefore, we believe that endostatin may be a valuable resource in the field of oncology, both as adjuvant therapy and as monotherapy. Therefore, we believe that the main guidelines for Endostatin to be considered for use are to demonstrate its efficacy in a different setting outside of China and to continue to search for a viable option to extend half-life. In fact, this molecule could be an option for patients whose clinical characteristics do not favor the use of anti-VEGF antibodies or whose cancer is resistant to them.

author contributions

Conceptualization, G.M.-V. e F G H.; Writing - Preparation of the original draft, G.M.-V., F.G.-H., J.L.-M., T.G.-F., J.A., A.C.-C., M.C.B.; Writing - Review and Editing, G.M.-V., J.L.-M., M.C.B., T.G.-F. and R.R.; Display, G.M.-V. and J.L.-M.; Supervision, G.M.-V., L.S. and R.R.; Financing Acquisition, L.S. and R. R. All authors have read and agree to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

consent form

Not applicable.

Data Availability Statement

Not applicable.

conflicts of interest

The authors declare no conflict of interest.

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figures and tables

Figure 1: Diagram summarizing the main effects of endostatin on endothelial cells. Bcl-2, B cell leukemia/lymphoma protein 2; FAK, focal adhesion kinase; HIF-1a, hypoxia-induced factor 1-alpha; LRP-5/6, leucine responsive regulatory protein; MAPK, mitogen-activated protein kinase; MEK1/2, mitogen-activated protein kinase kinase; VEGFA, vascular endothelial growth factor A; VEGFR2, Vascular endothelial growth factor receptor 2. [Download PDF to view image]

Table 1: A summary of relevant articles testing endostatin.

MC, breast cancer; CB, carboplatin; CF, calcium folinate; PC, cisplatin; CPT, carboplatin; CPC, capecitabine; CR, complete remission; CT, chemotherapy; CRC, colorectal cancer; CTX, cyclophosphamide; DCR, disease control rate; DTX, docetaxel; E, endostatin; PE, etoposide; RPE, epirubicin; FA, folinic acid; FU, fluorouracil; GEM, gemcitabine; IMRT, Intensity Modulated Radiation Therapy; ICD, nedaplatin; IR, irinotecan; m, months; ORR, objective response rate; OS: overall survival; OX, oxaliplatin; PEM, pemetrexed; PFS, progression-free survival; QoL, quality of life; NPC, nasopharyngeal carcinoma; NSCLC, non-small cell lung cancer; NVB, vinorelbine; RCT, randomized controlled trial; RFS: relapse-free survival; RT, radiotherapy; SCLC, small cell lung cancer; TAX, paclitaxel; TNBC, triple negative breast cancer; TTP, time to progression.

author links):

[1] Clinical and Molecular Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago 8380000, Chile

[2] Department of Biomedical Sciences, Humanitas University, 20090 Mailand, Italy

[3] “Vittorio Erspamer” Institute of Physiology and Pharmacology, Faculty of Pharmacy and Medicine, University of Sapienza, P.le Aldo Moro 5, 00185 Rome, Italy

Note(s) of the author(s):

[*] Correspondence: rrodrigo@med.uchile.cl; Phone: +56-229786126

DOI: 10.3390/biomedicinas11030718