Release date: 2007-09-12
Professor Bai Chunxue: Current Status and Prospects of Molecular Targeted Therapy for Lung Cancer--------------------------------------- ----------------------------------------- Department of Respiratory, Zhongshan Hospital, Fudan University (200032) )
Lung cancer is currently the most common solid tumor in the world and the most common cause of cancer death. Although a variety of third-generation chemotherapy drugs have been put into clinical use, their 5-year survival rate is still low after comprehensive treatment such as surgery, radiotherapy and chemotherapy. At 15%, there is an urgent need to find new treatments and therapeutic targets. Molecular targeted therapy utilizes molecular biological differences between tumor cells and normal cells, and blocks specific pathways, specific pathways, and angiogenesis by blocking signaling pathways, blocking receptors, and inhibiting angiogenesis. Sexually inhibit tumor cell proliferation, invasion and metastasis, and promote its apoptosis. Due to the specificity of the target, molecular targeted therapy has higher selectivity and less toxic side effects than traditional chemotherapy. At present, molecular targeted therapeutic drugs for lung cancer mainly include cell growth factor receptor inhibitors, angiogenesis inhibitors and signal transduction inhibitors.
1. Treatment with epidermal growth factor receptor (EGFR) as a target
Due to the abnormal regulation of EGFR and its downstream signaling pathways in tumor cells, a considerable number of tumor cells have overexpression of EGFR and are closely related to the malignant behavior of tumor cells. About 40% to 85% of NSCLC patients with lung cancer tissue samples detected EGFR expression or high expression, high expression of EGFR patients with faster progression, chemoradiotherapy is not sensitive and poor prognosis. Molecular targeted drugs developed for EGFR and entering clinical research are mainly divided into two categories: (1) EGFR tyrosine kinase inhibitors (EGFR-TKIs), which inhibit tyrosine kinase activity in EGFR intracellular region; (2) synthetic synthesis The monoclonal antibody (MAb), which binds to the extracellular domain of EGFR, blocks the activation of EGFR by ligand-dependent ligands. These drugs block EGFR-mediated intracellular signaling pathways through different pathways, thereby inhibiting tumor cell proliferation, invasion, metastasis, and angiogenesis, and promoting tumor cell apoptosis and increasing sensitivity to chemoradiotherapy.
(a) EGFR tyrosine kinase inhibitor
EGFR-TKIs are small molecule drugs that act on the intracellular epidermal growth factor receptor tyrosine kinase domain and inhibit tyrosine kinase phosphorylation and downstream signaling. Currently used in clinical gefitinib (gefitinib) , ZD-1839, trade name: Iressa) and erlotinib (trade name: Tarceva).
1. Gefitinib: Gefitinib is the first oral EGFR-TKI, marketed in Japan in June 2002, and officially launched in China on February 26, 2005. It is currently used in advanced NSCLC for platinum and paclitaxel chemotherapy failure. patient. It belongs to the aniline quinazoline small molecule compound, which inhibits EGFR intracellular tyrosine kinase (TK) phosphorylation, blocks tyrosine kinase activity, and blocks EGFR by competing with ATP for ATP binding site of EGFR in cells. Downstream signaling provides anti-tumor effects.
In two randomized, double-blind, multicenter, phase II clinical trials (IDEALI and IDEALII), a total of 426 patients with advanced NSCLC who failed chemotherapy with platinum and/or docetaxel were evaluated, with an effective rate of 8.8% to 19%. %, the symptom relief rate is 35% to 43%. A total of 2130 advanced NSCLCs were analyzed in two large, randomized, multicenter, phase III clinical trials (INTACT1 and INTACT2) of gefitinib combined with first-line chemotherapy (gemcitabine + cisplatin or paclitaxel + carboplatin) In patients, the results showed that gefitinib combined with chemotherapy did not increase efficacy. A phase III clinical trial evaluating whether gefitinib prolongs the survival of lung cancer patients (ISEL) showed no significant difference in prolonged patient survival compared with placebo, but gefitinib for the Eastern population or never People who smoke can significantly prolong their survival. The mutation of EGFR gene is related to the efficacy of gefitinib. The mutation rate of EGFR gene in Chinese NSCLC is 38% in Japan, 32% in Japan, and only 2% to 10% in the United States. This difference helps explain the effect to some extent. The difference; however, recent studies have shown that there are a large number of drug-resistant cases even in EGFR gene mutations.
Shah et al believe that the following factors can increase the sensitivity of gefitinib, never smoker, pathology for bronchoalveolar carcinoma, female, born in East Asia. Other studies have shown that the use of immunofluorescence in situ hybridization (FISH) to determine the increase in EGFR gene copy number is closely related to the patient's response to gefitinib treatment, tumor progression time and survival, suggesting that FISH assay for EGFR gene copy number is A good molecular marker for predicting the efficacy of gefitinib in patients with NSCLC.
2. Erlotinib: Erlotinib is another small molecule TKI against EGFR that is similar to the structure and mechanism of action of gefitinib and was approved by the US FDA for NSCLC treatment in November 2004. In a Phase III clinical trial of NSCLC second- and third-line treatment, 731 patients with NSCLC were randomized to a erlotinib (150 mg/day) or placebo in a 2:1 ratio, and the overall survival of the erlotinib group was found to be At 6.7 months, it was significantly longer than the control group at 4.7 months, and the quality of life in the erlotinib group was significantly higher than that in the control group. Among them, 293 patients with EGFR expression showed that it significantly prolonged the survival of EGFR-positive patients, but had no significant effect on EGFR-negative patients. This is the first clinical randomized trial to demonstrate that EGFR-TKI can prolong the survival of patients with NSCLC after chemotherapy, and that non-smoking, female, and adenocarcinoma patients are more sensitive to erlotinib treatment.
Similar to gefitinib, the most common adverse reaction to erlotinib treatment is rash and diarrhea. The most serious adverse reaction is interstitial lung disease (ILD), which occurs at a rate of about 0.8%. If ILD occurs, erlotinib should be discontinued and appropriate treatment should be taken. Patients with rash after erlotinib treatment have a higher rate of tumor remission and longer survival, but this is still controversial in the clinical study of gefitinib.
(B) anti-EGFR monoclonal antibody (MAb)
Cetuximab (trade name: Erbitus) is a human/mouse chimeric EGFR monoclonal antibody that acts on the extracellular ligand binding region of tumor cell EGFR and prevents EGFR from binding to its ligand. Preclinical results show that cetuximab can improve the effect of radiotherapy and chemotherapy by inhibiting tumor cell proliferation, angiogenesis and promoting apoptosis. Phase I clinical studies have shown that cetuximab 200-400mg/m2 alone or in combination with chemotherapy is safe. Hanna et al. reported a case of retreatment of NSCLC with cetuximab monotherapy. 58 cases were evaluable, with an effective rate of 4.5%, a disease control rate of 35%, a median survival of 9.6 months, and a half-year and one-year survival. The rates were 64% and 39%, respectively, and the most common toxic reaction was rash (77%). Rosell et al evaluated the efficacy of cetuximab in combination with chemotherapy (novine + cisplatin) in the treatment of narcotic NSCLC, 86 patients enrolled, 92% IV, plus cetuximab plus no use The overall response rate was 31.7% vs. 20%, the disease progression time was 4.7 months vs. 4.2 months, and the median survival time was 8.3 months vs. 7.0 months, but there was no statistical difference. Therefore, the value of cetuximab in combination with chemotherapy and radiotherapy in the treatment of NSCLC remains to be confirmed by large-scale clinical studies.
ABX-EGF is a high-affinity, fully humanized anti-EGFR monoclonal IgG2 antibody. Crawford et al. performed an open, dose escalation clinical trial of ABX-EGF combined with paclitaxel plus carboplatin regimen for stage IIIB/IV, EGFR-positive (++ or +++) NSCLC. Of the 19 patients enrolled, 1 confirmed CR and 4 had PR. The most common adverse event was rash (89%). The study concluded that the combination treatment regimen is tolerable and is currently undergoing further clinical studies.
(3) RNA interference against EGFR
In addition to EGFR-TKIs and anti-EGFR monoclonal antibodies, recent studies using RNA interference technology to inhibit EGFR gene expression have also made promising progress. Our Institute successfully silenced the growth of tumor cells by RNAi silencing the expression of EGFR in NSCLC cell lines, and further demonstrated the anti-tumor activity of RNAi targeting EGFR by in vivo experiments.
Using RNA interference technology to study new strategies for targeted therapy of lung cancer. Designing a small interfering RNA-specific sequence targeting the EGFR gene, sense strand: 5'-AAGGAGCUGCCCAUGAGAAAU-3'; antisense strand: 5'-AUUUCUCAUGGGCAGCUCC-3'; and using chemically synthesized small interfering RNA to preliminarily inhibit its expression of EGFR gene And the effect of lung adenocarcinoma growth.
Based on this sequence, a small hairpin RNA (shRNA) plasmid expression vector targeting the EGFR gene was constructed. The pShEGFR vector was transferred into human lung adenocarcinoma cell (HLAC) A549 and SPC-A1 using lipofectamine2000. At 2 days after transfection, the inhibition rates of EGFR mRNA in A549 and SPC-A1 by pShEGFR were 72.9% and 81.0%, respectively. After immunoblotting, the inhibition rate of EGFR protein was highest at 6 days after transfection, in A549 and SPC-A1 reached 74.1% and 84.6%, respectively. Plasmid-mediated shRNA expression vectors produce RNAi effects in human lung adenocarcinoma cells, downregulating expression of EGFR mRNA and protein levels. The inhibition rates of pShEGFR on A549 and SPC-A1 cells were 62.8% and 68.9%, respectively. By flow cytometry, pShEGFR significantly increased the G0/G1 phase ratio of A549 and SPC-A1 cells, and the S phase ratio decreased significantly, and promoted the apoptosis of A549 and SPC-A1 cells. After detection by Millcell chamber, pShEGFR significantly inhibited A549 and SPC-A1 cell migration; by MTT assay, pShEGFR increased the sensitivity of A549 and SPC-A1 cells to cisplatin, doxorubicin, and taxol by 6.7 and 6.0, 5.5, and 4.7, 6.6, and 6.4, respectively. The shRNA plasmid expression vector targeting EGFR gene can inhibit the growth and migration of lung adenocarcinoma cells, promote apoptosis, and increase the sensitivity of cells to different chemotherapeutic drugs by down-regulating EGFR protein levels.
The small interfering RNA hairpin DNA expression template targeting EGFR described above was ligated to a shuttle vector. The shuttle vector and the backbone vector were co-transfected into 293 packaging cells to prepare a recombinant adenovirus (Adv-shEGFR). Adv-shEGFR infects lung adenocarcinoma cells A549 and SPC-A1 in vitro. The expression of EGFR gene mRNA was detected by quantitative PCR. After 3 days of infection with Adv-shEGFR, the inhibition rates of EGFR mRNA in A549 and SPC-A1 cells were 81.2% and 79.8%, respectively. Western blot analysis showed that the inhibition rates of EGFR protein in A549 cells were 52.3% and 80.2%, respectively, and the inhibition rates of EGFR protein in SPC-A1 cells were 45.5% and 85.8%, respectively, after Adv-shEGFR infection for 3d and 6d. In vitro vaccination of HLAC infected with virus in vitro, A549 infected with Adv-shEGFR, SPC-A1 cells were significantly inhibited in vivo.
The A549, SPC-A1 nude mice xenograft model was established, and the inhibition rate of EGFR protein expression in tumor tissues was 51.5% and 44.8% by intratumoral injection of Adv-shEGFR. Tumor volume was measured to plot growth curves, tumor weights were recorded, and tumor inhibition rates were calculated to be 62.8% and 52.4%, respectively. The shRNA recombinant adenovirus targeting EGFR can effectively introduce nucleic acid into the animal and produce RNAi effect, and inhibit the growth of HLAC by down-regulating the expression of EGFR in HLAC.
Second, the treatment of tumor angiogenesis as a target
Tumor angiogenesis is an extremely important step in tumor growth, metastasis and dissemination, and anti-angiogenesis has become a hot spot for tumor drug development and tumor-targeted therapy. It mainly includes: drugs targeting VEGF/VEGFR, drugs targeting vascular endothelial cells, and matrix metalloproteinase inhibitors (MMPIs).
(1) VEGF/VEGFR-targeted drugs Because vascular endothelial growth factor and its receptor (VEGFR) play a central role in this tumor angiogenesis process, the drugs currently developed for VEGFR and entered clinical research are mainly divided into two. Classes: (1) Synthetic monoclonal antibodies (MAbs) that bind to the extracellular domain of VEGFR to block the activation of VEGFR-dependent ligands; (2) VEGFR tyrosine kinase inhibitors (VEGFR-TKIs), which inhibit VEGFR Intracellular region tyrosine kinase activity.
1. Anti-VEGF / VEGFR monoclonal antibody (MAb): Bevacizumab (trade name: Avastin) is an anti-VEGF recombinant humanized monoclonal antibody (rhuMAb VEGF) that blocks VEGF binding to its receptor and inhibits VEGF biological activity, inhibition of tumor neovascularization. Phase II randomized clinical trials in patients with stage IIIB or IV NSCLC who were approved by the US FDA in February 2004, showed bevacizumab (7.5 mg or 15 mg/kg) and chemotherapy (carboplatin + paclitaxel) Compared with chemotherapy alone (carboplatin + paclitaxel), the response rate in the 15 mg/kg group was 10% higher than that in the chemotherapy group alone (31.5%, 18.8%, respectively), and the tumor progression time was 3 months longer than the latter. (7.4 months, 4.2 months, respectively), the survival period also has a tendency to extend (distribution is 17.7 months, 14.9 months). Common adverse reactions include hypertension, proteinuria, thrombosis, nosebleeds, etc. Severe adverse reactions are tumor-related hemorrhage, such as hemoptysis and hematemesis; squamous cell carcinoma is most prone to massive hemoptysis, because squamous cell carcinoma is prone to necrosis and cavities. And the location of the mass is often close to the large blood vessels. A subsequent phase III randomized clinical trial compared the efficacy of bevacizumab with chemotherapy (carboplatin plus paclitaxel) in combination with chemotherapy alone in patients with advanced non-squamous cell NSCLC, and found that the bevacizumab group was significantly prolonged. The median survival of patients (12.5 months vs. 10.2 months), increased response rate (27% vs. 10%), and prolonged progression-free survival (6.4 months vs. 4.5 months), this is the first demonstration of targeted therapy combined with chemotherapy Clinical trials that produce better efficacy with NSCLC. The above studies suggest that bevacizumab is better in patients with pathological type of squamous cell carcinoma, but the risk of hemoptysis is also significantly higher, so it can be used after surgical removal of the primary lesion of squamous cell carcinoma. The use of bevacizumab in patients with non-squamous cell carcinoma before surgery and in patients with squamous cell carcinoma/non-squamous cell carcinoma after surgery can achieve better results.
2. VEGFR tyrosine kinase inhibitor: ZD6474 is an oral KDR (VEGFR-2) tyrosine kinase inhibitor that also inhibits EGFR tyrosine kinase and ret tyrosine kinase, hence the name multi-target Tyrosine kinase inhibitor. In a phase II randomized clinical trial of advanced chemotherapy with failed NSCLC, patients with ZD6474 (300 mg/d) had significantly longer progression-free survival (TTP) compared with gefitinib (250 mg/d) (11.9, respectively) Weeks and 8.1 weeks); while ZD6474 has mild side effects, mainly rash, diarrhea, and asymptomatic QT interval prolongation. Another phase II randomized clinical trial in 127 patients with advanced NSCLC showed a median TTP of 12 weeks in the docetaxel + placebo group, docetaxel + ZD6474 100 mg group, and docetaxel + ZD6474 300 mg group, respectively. 18.7 weeks and 17 weeks. Due to the small side effects of ZD6474, it may be the best candidate for first-line treatment of elderly patients with NSCLC. Other VEGFR-TKIs that are still undergoing Phase I/II clinical studies include AZD2171, SU11248, PTK787/vatalanib, AG013736, AMG706, GW-786034, BAY43-9006/sorafenib, and ZD4190.
(2) Drugs targeting vascular endothelial cells
Vascular endothelial cell proliferation is the first step in tumor angiogenesis. Therefore, anti-tumor angiogenesis therapy with proliferating vascular endothelial cells has a good application prospect.
Endostatin is an endogenous anti-angiogenic factor that specifically inhibits vascular endothelial proliferation, migration, and angiogenesis. The phase III clinical study of recombinant human endostatin (YH-16) combined with vinorelbine plus cisplatin (NP) in the treatment of NSCLC in China showed that the NP/YH-16 regimen and the NP/placebo regimen Compared with the two groups, the effective rates were 35.4% and 19.5%, the median TTP was 6.3 and 3.6 months, and the clinical benefit rates were 73.3% and 64%, respectively, which were statistically significant. There were no significant differences in reactions such as neutropenia, anemia, nausea and vomiting. Other drugs such as recombinant human angiostatin, endothins (atrasentan), etc. have been confirmed to be tolerable and effective by Phase I and II clinical trials, and an expanded case study is currently underway.
(III) Matrix metalloproteinase inhibitors Matrix metalloproteinases (MMPs) are zinc-dependent proteases that degrade extracellular matrix (ECM) and vascular basement membrane, promote tumor angiogenesis, and tumor growth and metastasis. Prinomastat is a selective matrix metalloproteinase inhibitor (MMPI), a phase III randomized clinical trial in patients with advanced NSCLC who showed that the prinomastat + carboplatin + paclitaxel group compared with the carboplatin + paclitaxel group The efficiencies (27% and 26%, respectively) and median survival (11.5 months and 10.8 months, respectively) were not statistically significant. Because prinomastat was found to be more toxic in the trial, it was not suitable for long-term use. BMS-275291 is a broad-spectrum MMPI. Phase III randomized clinical trials in patients with advanced NSCLC showed that the BMS-275291+carboplatin + paclitaxel group was more effective than the carboplatin + paclitaxel group (25.8, respectively). The median survival (% and 33.7%) and median survival (8.6 months and 9.2 months, respectively) were not statistically significant. The combination of BMS-275291 only increased toxicity without increasing efficacy.
The shark cartilage extract neovastat not only inhibits MMP-2, MMP-9 and MMP-12, but also inhibits VEGF signaling and promotes endothelial cell apoptosis. In a phase I/II clinical trial, neovastat monotherapy was advanced. No dose-limiting toxicity was observed in NSCLC, and phase III clinical trials of neovastat combined with chemoradiotherapy for stage III NSCLC are currently underway.
Third, other targeted therapeutic drugs
Other tumor target therapeutic agents include cyclin-dependent protein kinase (CDKs) inhibitors such as selicicilib, protein kinase C inhibitors such as affinitak, Faginy protein transferase inhibitors such as lonafarnib, ubiquitin-proteasome inhibitor bortizomib, Cyclooxygenase-2 inhibitors such as meloxicam, RXR (retinoid X receptor) receptor binding agents such as bexarotene, etc. are undergoing preclinical or clinical trial studies.
Fourth, the prospects
With the deepening of the understanding of molecular mechanisms in the process of tumorigenesis, development, metastasis, etc., tumor therapy strategies represented by molecular targeted therapeutic drugs have shown attractive prospects, a variety of new target discoveries, and a variety of novel molecules. Targeted drugs continue to emerge, bringing new hope for the treatment of lung cancer. But how do you accurately identify the "targeted therapy" patients who are most likely to benefit? How to improve the efficacy of targeted therapy combined with surgery, radiotherapy and chemotherapy? How to use molecular targeted therapeutic drugs as an opportunity to truly realize the individualization of treatment for cancer patients? Both require more in-depth basic and clinical research to answer these questions. ——Midi Medical Network
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