According to statistics from the World Health Organization in 2018, cancer is the main cause of human death. It shortens life expectancy and threatens human life and health. At present, the incidence and fatality rate of malignant tumors worldwide are increasing year by year. Anti-tumor treatment methods mainly include surgical treatment, chemotherapy, radiotherapy, immunotherapy, Chinese medicine treatment, etc. It is particularly important to find safe and effective therapeutic targets.
Molecular targeted therapy is also called “biological missile”. It designs corresponding therapeutic drugs for the identified carcinogenic sites at the cellular level. After the drugs enter the human body, they can selectively and specifically bind to the carcinogenic sites and exert their effects, leading to specific cancer cells. Sexual death without damaging normal tissue cells. The therapeutic effect is closely related to the characteristics of the drug itself and whether there is a molecular target and abnormal state of the targeted drug in the tumor. The choice of molecular targeted therapy relies on molecular pathological diagnosis. However, because pathological examination of tumor heterogeneity cannot obtain all tumor information, the efficacy of molecular targeted therapy is not necessarily consistent with the expected efficacy. The current targeted therapy sites for tumors mainly start from the tyrosine kinase receptor family, anti-angiogenesis and related intracellular and extracellular signaling pathways.
- Trastuzumab for cancer treatment
Her2 is a transmembrane tyrosine kinase receptor protein in the epidermal growth factor receptor (EGFR) family. Its positive expression is closely related to the occurrence, development and prognosis of tumor cells. The molecular structure of Her2 includes intracellular domain, transmembrane domain and extracellular ligand binding domain, of which only the intracellular domain has tyrosine kinase activity. At present, no activated Her2 ligand has been found. Once Her2 is overexpressed, Her2 can form dimers, activate intracellular domains and phosphorylate at tyrosine kinase sites, activate downstream PI3K/Akt, MAPK pathways, and regulate tumor cell proliferation, differentiation, migration and apoptosis. Her2 oncogene is an oncogene that encodes Her2 protein on the q21 band of chromosome 17. The amplification of Her2 oncogene causes Her2 receptor overexpression, promotes the transformation of tumor cell phenotype, and promotes cell proliferation and tumorigenesis.
Trastuzumab (Trastuzumab, trade name Herceptin, herceptin) is a humanized monoclonal antibody that has become an important tumor-targeting drug. It mainly interacts with the Her2 oncogene expression product P185 on the tumor cell membrane. Protein binding produces anti-tumor activity. With the deepening of clinical research, Trastuzumab is used in the treatment of a variety of tumors, including breast cancer, ovarian cancer, gastric cancer, lung cancer, and kidney cancer. It has the characteristics of broad anti-tumor spectrum, definite curative effect and low side effects. However, its anti-tumor mechanism is still unclear.
At present, Trastuzumab has been widely used in the clinical treatment of Her2 positive tumors, but the anti-tumor mechanism found in research mainly includes the following points: 1) Inhibition of Her2 dimerization: Trastuzumab and Her2 The extracellular segment of Her2 specifically binds, blocking its formation of homodimers, inhibiting Her2 from binding to other ErbB receptors to form heterodimers, or blocking ligand-independent Her2/Her3 heterodimerization 2) Inhibit PI3K/AkT pathway: Trastuzumab can free the non-receptor tyrosine kinase Src from ErbB2 by acting on tumor cells, reduce the activity of Src kinase, and inhibit the phosphorylation of PTEN and transfer to the ion membrane It up-regulates its expression, inhibits the activation of PI3K, blocks the PI3K/AkT pathway, induces cell cycle G1 phase arrest and cell cycle-dependent kinase (CDK) inhibitor p27 kip1 accumulation and activation, and reduces tumor cell proliferation; 3) Inhibit the cleavage of the extracellular segment of ErbB2 and down-regulate its expression: Trastuzumab activates the receptor domain P95 connected to the cell membrane, induces endocytosis of ErbB2 and degrades it in the lysosome, and down-regulates the expression of ErbB2 4) Inhibition of angiogenesis: Trastuzumab can inhibit the production of vascular endothelial growth factor (vascular endothelial growth factor, VEGF), up-regulate the expression of thrombin sensitive protein 1, down-regulate blood vessel density, and inhibit tumor growth; 5) induce Immune response: The Fc region of Trastuzumab combines with natural killer cells (NKCs) to induce an immune response and reduce the production of VEGF; 6) induce antibody-dependent cytotoxicity and inhibit DNA damage repair.
Potential mechanisms for breast cancer treatment include: inhibiting the heterodimerization of Her2 and activating the cleavage of the extracellular segment of Her2, inducing the expression of p27 kip1; inhibiting PI3K signal, down-regulating Her2 and enhancing apoptosis regulation. Trastuzumab inhibits AP1510-induced Erk1/2 phosphorylation, blocks the combination of Shc and Her2 homodimers, regulates the proliferation of tumor cells, and has high therapeutic activity against breast cancer, while its adverse reactions are mild, mainly manifested as hypokalemia, thrombocytopenia and fatigue, and it has good tolerance to the treatment of advanced metastatic breast cancer. For decades, it has been found in clinical application that Trastuzumab can significantly improve the survival of breast cancer patients, but its treatment of patients still has certain limitations, such as neonatal and acquired tolerance, and blood-brain barrier. Among the patients who were initially treated with Trastuzumab, most of them developed significant drug resistance after 1 year of treatment. New adjuvant treatments such as Trastuzumab + paclitaxel and Trastuzumab + Pertuzumab were used clinically and achieved good therapeutic effects. Therefore, when breast cancer patients develop drug tolerance, the combination of drugs will provide breast cancer patients with new treatment hope.
To be continued in Part Two…