The principle of vascular endothelial growth factor (VEGF) monoclonal antibodidy (mAb) is to block tumor angiogenesis. It is currently commonly used to treat colorectal cancer, renal cell carcinoma, non-small cell lung cancer, and macular degeneration in the elderly. For driver-positive NSCLC small molecule TKIs, it is a first-line treatment plan, and for driver-negative non-squamous NSCLC, the first-line treatment plan is bevacizumab combined with chemotherapy; colorectal cancer is mainly applicable to KRAS or BRAF mutation-positive metastasis colorectal cancer. In the field of macular degeneration, because the frequency of injection of the fusion protein is lower and the price is more advantageous, it is sold better than monoclonal antibodies. The macromolecule drugs currently on the market include bevacizumab and ranibizumab.

Vascular Endothelial Growth Factor (VEGF) is a key regulator of physiological angiogenesis during embryonic development, bone growth and reproductive function. At the same time, VEGF is also related to tumor-related pathological blood vessels and intraocular neovascularization.

The VEGF signaling system is more complex, including five ligands VEGF-A, VEGF-B, VEGF-C, VEGF-D, and PIGF, and three tyrosine kinase receptors VEGFR1, VEGFR2, and VEGFR3. There are differences in body affinity and selectivity. VEGF-A can bind to VEGFR-1 and VEGFR-2, PIGF and VEGF-B bind to VEGFR-1, and VEGF-C and VEGF-D specifically bind to VEGFR-3.

Among all the ligands, VEGF specifically refers to VEGF-A, which plays an irreplaceable role in the process of angiogenesis and maintenance. VEGF-C and VEGF-D are ligands that mediate lymphangiogenesis. Among them, VEGF-C can mediate angiogenesis through VEGFR-2, and lymphangiogenesis through VEGFR-3. Among all the receptors, VEGFR-2 plays the most important role, mediating almost all cellular responses known to VEGF, and the role of VEGFR-1 is not fully understood.

The combination of VEGF and VEGFR-2 activates a series of signal transduction molecules, such as phospholipase Cγ (PLCγ) and phosphatidylinositol 3-kinase (PI3K), and then triggers a series of cascade reactions in the cell. The final role includes cell division, migration, vascular permeability changes and promote cell survival. Experiments have shown that VEGF can increase vascular permeability, cause tumors to spread through the circulation, and cause more nutrients to be transported to the tumor site. At the same time, VEGF can also recruit endothelial precursor cells in the circulatory system and serve as a component of new tumor blood vessels. Despite the existence of a variety of tumor angiogenic factors, VEGF has been selected as the main target for tumor treatment, which is the cause of cancer cell gene mutations and the tumor microenvironment. The tumor microenvironment, especially hypoxia, inflammatory factors, and inflammation-related cell aggregation , make the expression of VEGF up. In many solid tumors, tumor cells often have mutations in genes that overexpress VEGFRs.

Monoclonal drugs have been approved for colorectal cancer, lung cancer, etc. Small molecule TKIs have been approved for renal cell carcinoma, etc.

Anti-VEGF drugs are drugs that block vascular endothelial growth. They are often used to treat colorectal cancer, renal cell carcinoma, NSCLC, etc. and macular degeneration in the elderly. The drugs mainly include monoclonal antibodies and small molecule TKIs.

The only monoclonal antibody used in the treatment of renal cell carcinoma is bevacizumab, which is combined with interferon to enhance the therapeutic effect. Possibly due to the filtering effect of the kidney, the penetration of macromolecular drugs into renal cell carcinoma is poor. By comparing the treatment of bevacizumab and sunitinib, despite the combination of chemotherapeutics, the treatment effect of bevacizumab is not as good as that of sunitinib in terms of gain in ORR and PFS. To some extent, it reflects that in the field of renal cell carcinoma treatment, monoclonal antibodies are not as good as small molecule TKI drugs.

Multi-target anti-angiogenesis and combined immunotherapy become new directions for anti-VEGF

Tumor angiogenesis is achieved by pro-angiogenic factor signaling (such as VEGF), so anti-tumor therapies that inhibit VEGF are effective for some solid tumors. Anti-VEGF therapy is not effective in all tumors. The failure principles mainly include: different sensitivity caused by tumor heterogeneity; multiple signaling pathways of tumor angiogenesis; resistance caused by infiltrating stromal cells; resistance caused by anti-VEGF enhanced tumor metastasis; VEGF suppresses immune response.

1. Different sensitivity due to tumor heterogeneity

2. Multiple signal pathways exist to mediate tumor angiogenesis

When the VEGF signaling pathway is blocked, other signal transduction pathways can also stimulate blood vessel growth. Such as epidermal growth factor, placental growth factor and so on. Studies have shown that targeted therapy of VEGF and the treatment of these factors can play a synergistic effect and can significantly improve the efficacy. This can partly explain the excellent treatment effect of some multi-target TKIs (such as sunitinib, sorafenib, etc.), which can inhibit the transmission of a variety of pro-angiogenic signals including VEGF, FGF, and PDGF.

3. Infiltration of stromal cells leads to resistance to VEGF

A tumor is a community composed of cancerous malignant proliferating cells and different stromal cell types. These stromal cells include fibroblasts and different types of immune cells, which can promote tumor growth and develop drug resistance. The exact mechanism is not yet clear, but it is known that stromal cells can promote tumor blood vessel growth or tumor cell survival by secreting growth factors such as BV8.

4. Enhanced tumor metastasis caused by anti-VEGF

A preclinical study published in the journal Angiogenesis in 2014 showed that targeted therapy with VEGF can promote tumor invasion and metastasis. Currently only found in the treatment of breast cancer and melanoma by sunitinib, although the growth of the primary tumor is inhibited, the treated tumor is more aggressive and the incidence of tumors in the liver and lung is increased. One possible reason is that TKIs can cause tumors to produce related circulating factors (including G-CSF, SDF-1α and osteopontin), and changes in these factors may cause tumor metastasis.

5. VEGF has been proven to suppress immune response, anti-VEGF drugs combined with immunotherapy become a new direction

VEGF monoclonal antibodies in combination with immune checkpoint inhibitors have become one of the new treatment options (such as CTLA-4, PD-1 or PD-L1 monoclonal antibodies). More and more literature shows that in addition to the related effects of promoting angiogenesis, VEGF also has a role in suppressing the immune response in vivo. VEGF can inhibit the maturation of dendritic cells (DC) and disrupt the normal differentiation of hematopoietic precursor cells; VEGF can also induce the expression of PD-L1, an immunosuppressive molecule on DCs; it can also regulate nerves on T cells (TReg) by immunoregulation Feltin 1 (NRP1) signals activate antigen-specific immunoregulatory T cells (with a down-regulating effect on T cells). Therefore, in addition to the definite antiangiogenic effect of VEGF monoclonal antibody drugs, it can also indirectly activate the immune response to promote the tumor invasion effect of T cells, as well as initiate and activate the response of T cells to immune antigens, and help enhance the role of immune checkpoint inhibitor .

To be continued in Part Two…