Breast cancer is the main malignant tumor that endangers women’s health. About 1.2 million women worldwide develop breast cancer and 500,000 women die from breast cancer every year. Although China is a low incidence area for breast cancer, its incidence rate is increasing year by year, especially Shanghai, Beijing, Tianjin and coastal areas are the high incidence areas for breast cancer in China. However, it is encouraging to note that although the number of new cases of breast cancer is increasing year by year worldwide, the mortality rate has decreased. In addition to the improvement of early diagnosis rate, the use of various adjuvant therapies such as chemotherapy, radiotherapy, endocrine therapy and targeted therapy after surgery has played a great role. Among them, targeted therapy has the advantages of high specificity, selectivity, affinity and non-cytotoxicity, and plays an increasingly important role in the current comprehensive treatment of breast cancer. Molecular targeted therapy for breast cancer refers to the treatment of oncogenes and their related expression products related to the occurrence and development of breast cancer. Molecularly targeted drugs control the alteration of cellular gene expression by blocking the signal transduction of tumor cells or related cells, thus inhibiting or killing tumor cells.
I. Targeted drugs for HER-2 receptor
HER2, also known as human epidermal growth factor 2, is a HER2 receptor encoded by a proto-oncogene. HER2 plays an important role in regulating the growth and development of normal cells and differentiation. amplification of the HER2 proto-oncogene leads to overexpression of the HER2 receptor on the cell surface. This often predicts that HER2-positive breast cancer patients have significantly shorter disease-free and overall survival, tumors are prone to rapid recurrence or metastasis, and are ineffective to conventional therapy. The overexpressed HER-2/neu protein activates itself by polymerizing on the cell surface, independent of ligand activation. The activated HER-2/neu proteins eventually lead to malignant transformation of cells through different signaling pathways and induction of TNF-α resistance.
Trastuzumab: The target of trastuzumab is the nucleus HER-2/neu gene that regulates the glycoprotein on the cell surface. The available information shows that the mechanism of action of trastuzumab includes specific binding to HER-2, blocking ligand-mediated cell growth signaling, affecting epithelial cell growth, promoting the internalization and degradation of HER-2 protein receptor, reducing its cell surface density, thus inhibiting further tumor growth, gathering immune cells to attack and kill tumor cells through antibody-dependent cytotoxic effect (ADCC), and downregulating intravascular tumor cells. It also inhibits the growth of intra-tumor vascular tissue by down-regulating vascular endothelial growth factor.
2. Patuximab: Patuximab is a recombinant humanized monoclonal antibody that binds to the extracellular domain II region of HER-2 receptor and inhibits the formation of dimer, thus inhibiting the receptor-mediated signal transduction pathway.
II. Targeted drugs against EGFR/HER-1
The human epidermal growth factor receptor (EGFR) family consists of four members: HER-1, HER-2, HER-3, and HER-4 (EGFR-4), all of which have the active structure of endogenous tyrosine kinase, so EGFR can be used as a target to inhibit tumor proliferation. The treatment targeting EGFR, i.e. HER-1, mainly has two types of drugs, one is the small molecule tyrosine kinase inhibitor targeting the intracellular part of EGFR, represented by gefitinib, and the other is the monoclonal antibody targeting the extracellular part of EGFR, represented by cetuximab.
1, Lapatinib (Lapatinib): Lapatinib is an oral reversible small molecule epidermal growth factor tyrosine kinase inhibitor, can effectively inhibit ErbB1 and ErbB2 tyrosine kinase activity.
Gefitinib: Gefitinib is a small molecule tyrosine kinase inhibitor that penetrates the cell membrane and acts on the intracellular portion of EGFR.
Cetuximab: Cetuximab is an IgG monoclonal antibody that binds specifically to the epidermal growth factor receptor (EGFR) and blocks the endogenous ligand-mediated EGFR signaling pathway, thereby inhibiting tumor growth.
Protein kinase C (PKC)-a inhibitors
Protein kinase C(PKC)-a inhibitors are a class of phospholipid-dependent serine/threonine enzymes. PKC-a is a member of the PKC family and is widely found in a variety of tissues and transformed cell lines. PKC-a is associated with tumor aggressiveness and modulates cellular sensitivity to cytotoxic drugs.
IV. Cyclooxygenase 2 (Cox-2) inhibitors
High expression of cyclooxygenase 2 can be measured in breast cancer (especially in metastatic breast cancer). Celecoxib is a selective COX-2 inhibitor. It can be used for chemoprevention and adjuvant treatment of breast cancer.
V. Molecularly targeted drugs targeting tumor angiogenesis
VEGF (vascular endothelial growth factor) plays an important role in the occurrence, development and prognosis of breast cancer. In general, there are four pathways of angiogenesis inhibitors: directly inhibiting the function of endothelial cells, blocking the ability of endothelial cells to degrade the surrounding stroma, blocking the synthesis and release of angiogenic factors, and blocking the action of integrins on the surface of endothelial cells.
1.Bevacizumab (avastin): It is a recombinant human-derived anti-VEGF monoclonal antibody, which inhibits tumor growth by specifically inhibiting the ligand VEGF, thus preventing VEGF from binding to VEG2FR-1 and VEGFR-2 receptors.
2.Endostar: Endostar is an angiogenesis inhibitor, targeting at the endothelial cells of blood vessels, which can inhibit the migration of endothelial cells forming blood vessels, inhibit the generation of tumor neovascularization and block the nutrient supply of tumor cells, so as to inhibit tumor proliferation or metastasis.
3.Thalidomide (thalidom ide): thalidomide is a glutamate derivative, which can inhibit angiogenesis by down-regulating VEGF.
VI. Outlook
In recent years, with the development of science and technology, significant breakthroughs have been made in the treatment of tumors, from traditional chemotherapy and radiotherapy to today’s molecular targeted therapy, and then to the future targeted agents located in important cellular metabolic pathways, targeted therapy will benefit a wider range of people. However, the development and application of new targeted drugs still have to face many problems: finding the real tumor cell-specific targets; screening of the best target for benefit; resistance to targeted drugs; early efficacy evaluation of targeted drugs and the most practical cost of targeted drugs, etc.