I. Preface
Gastric cancer is one of the common malignant tumors of the digestive system, and most patients are already in the advanced stage of the disease at the time of diagnosis. Worldwide, the number of deaths from gastric cancer accounts for the second highest number of tumor deaths each year. The annual mortality rate of gastric cancer in China is 25.21% per 100,000 population, which is the first among all kinds of malignant tumors. Chemotherapy is still the main treatment for advanced gastric cancer, but the efficacy of chemotherapy is not satisfactory, and local recurrence and distant metastasis are the main reasons affecting the 5-year survival rate after surgery. The current level of chemotherapy has reached a bottleneck, with an optimal response rate of less than 50% and a median overall survival rarely exceeding 12 months, so biologic therapy has become a necessary option if we want to make a breakthrough. Molecular targeted therapies are new therapeutic tools that have emerged in recent years in the treatment of hematologic and solid tumors. With the research on the molecular biological mechanisms involved in the occurrence, development and metastasis of gastric cancer, this therapeutic tool is gradually applied to the clinical practice of gastric cancer treatment. At present, this treatment strategy mainly includes EGFR inhibitors, VEGFR inhibitors, m-TOR inhibitors, etc. A variety of specific molecular biologic targeted therapies have made great progress in the comprehensive treatment of gastric cancer. Ma Ning, Department of Medical Oncology, Henan Provincial People’s Hospital
Table 1: Types of targeted drugs in the treatment of common gastric cancer
TKIs
Mabs
EGFR inhibitors
Gefitinib, erlotinib, lapatinib
Cetuximab, panitumumab
HER-2 inhibitors
lapatinib
Trastuzumab
VEGFR inhibitors
Sunitinib, sorafenib
Bevacizumab
m-TOR inhibitors
RAD001
Epidermal growth factor receptor-targeted therapy
Epidermal growth factor receptor (EGFR) is a multifunctional glycoprotein transmembrane receptor, a member of the tyrosine kinase growth factor receptor family, which binds to specific ligands such as epidermal growth factor (EGF), transforming growth factor alpha (TGFα), bidirectional regulatory protein (AR), and beta-cellulose (BTC), and activates the receptor through the auto-phosphorylation of the corresponding tyrosine kinase. This stimulates multiple intracellular signaling pathways such as MAPK, PI3K, c-Src, etc. to promote tumor cell division, migration and tumor neovascularization. EGFR is expressed to varying degrees in a large number of tumors, such as gastric cancer, colorectal cancer, head and neck squamous cancer, pancreatic cancer, lung cancer, breast cancer, kidney cancer, and glioblastoma. Therefore, the selection of specific sites as targets to inhibit tumor proliferation, infiltration and distant metastasis by interfering with EGFR signaling provides a new idea for molecular targeting therapy for gastric cancer.
1. Anti-EGFR monoclonal antibody
Cetuximab (Epiduo) is the first approved IgG1 monoclonal chimeric antibody specifically targeting the epidermal growth factor receptor (EGFR), which has high affinity and specificity for EGFR, preventing EGFR from binding to its natural ligand, interrupting the vicious circle of unlimited cell proliferation, thus blocking downstream signaling pathways, inhibiting tumor cell proliferation and inducing apoptosis. It also reduces the production of matrix metalloproteinase and vascular endothelial growth factor. It has been shown to have excellent anti-tumor activity in EGFR-positive malignant tumors, either as monotherapy or in combination with radiotherapy or chemotherapy, and significantly enhances the efficacy of radiotherapy or chemotherapy.
1. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI)
The representative drugs are gefitinib (gefitinib iressa), erlotinib (erlotinib, tarceva), lapatinib (lapatinib) and so on. Doi et al treated 75 patients with progressive gastric cancer with gefitinib 250 mg or 500 mg po daily, and reported stable disease (SD) in 12 patients and partial remission (PR) in 1 patient after 28 d. The mean time to tumor progression (mTTP) was 1.2 months. In another phase II clinical study of gefitinib 250 mg po daily for pancreatic and esophageal cancers, a median remission of 4.6 months was reported, with an overall clinical efficacy rate of 30%. The expression of proliferative nuclear antigen Ki-67 was found to be significantly inhibited. In the Southwest Oncology Group (SWOG) 0127 trial, the response rate of erlotinib for the treatment of gastric or esophagogastric junction adenocarcinoma was 9%, but the cases with good response rates were all types of esophagogastric junction adenocarcinoma.
2. Anti-HER-2 monoclonal antibody
The representative drugs are trastuzumab (herceptin), pertuzumab (Omnitarg), EGFR and HER-2, which are members of the erbB family, can form heterodimers, and phosphorylation by HER-2 kinase can initiate signal transduction to enhance malignant transformation of cells and promote tumor progression. Trastuzumab, the first humanized mAb derived from recombinant DNA approved by the FDA in 1998, affects growth signaling by binding specifically to HER2 receptors, and also down-regulates vascular endothelial growth factor and other vascular growth factor activities. “It was introduced into China in 2002 under the trade name Herceptin. Patuximab is a second-generation recombinant humanized monoclonal anti-HER-2 antibody that binds to the extracellular domain II of the HER-2 receptor and prevents dimerization with other HER-2 receptors. The results showed that HER-2/neu was overexpressed in 16 (12.2%) of gastric cancer specimens and 24 (24%) of cardia cancer specimens using colorimetric in situ hybridization (CISH). Trastuzumab treatment prolonged OS in HER-2-positive breast cancer patients, but HER-2 expression was also only 20-30% in breast cancer and 6-35% in gastric cancer, so the use of trastuzumab in gastric cancer became the main report of the congress at this year’s ASCO annual meeting.
FISH-/IHC3+
15
17.7
17.5
0.83 (0.20-3.38)
Finally for targeted therapy in gastric cancer, can trastuzumab be the standard targeted therapy for patients with HER-2-positive gastric adenocarcinoma? It was concluded that trastuzumab was the first biomarker shown to benefit OS in the treatment of patients with gastric adenocarcinoma and that trastuzumab combined with DDP + fluorouracil-based chemotherapy is safe and effective and should become a novel standard of care for patients with HER-2-positive gastric adenocarcinoma.The clinical significance of the ToGA trial is that despite a mean survival difference of only 2.8 months, continued treatment has great prognostic value for patients with gastric adenocarcinoma with a very poor prognosis The clinical value of
The success of trastuzumab led to the investigational use of Lapatinib. Trastuzumab only inhibits the extracellular region of HER-2, which is an IgG monoclonal antibody, while Lapatinib, produced by GlaxoSmithKline, is an intracellular kinase inhibitor, which is a dual target of EGFR (HER-1) and HER-2, inhibiting the intracellular kinase region of HER-2 and the kinase region of HER-1 (EGFR), so its efficacy should be better than that of trastuzumab, and it has shown good efficacy in the treatment of breast cancer. LOGIC, a phase III clinical trial for HER2-positive gastric cancer patients using CAPE+OXA±lapatinib, is underway in 2009, and the results are worth looking forward to.
I. Anti-VEGFR monoclonal antibodies
Tumor growth is clearly vascular-dependent, as tumors obtain nutrients from the host through neovascularization and deliver tumor cells to the host through vascularization, enhancing the ability of tumor foci to metastasize distantly. Therefore, anti-angiogenesis is also a hot topic of research in molecular targeting therapy for gastric cancer. One of the major advantages of these drugs is that they do not generate tumor resistance and are very beneficial in combination chemotherapy. Several angiogenesis inhibitors are currently in clinical trials. Vascular endothelial growth factor (VEGF) is the most potent pro-angiogenic cytokine known to date. Several studies have shown that VEGF expression is significantly increased in progressive gastric cancer tissues, which is closely related to the infiltration and prognosis of tumor metastasis.