Molecular targeted therapy for prostate cancer

Once, prostate cancer becomes hormone-refractory, there are only a few effective therapies such as docetaxel-based chemotherapies. Several molecular targeted therapeutic drugs have been tested for prostate cancer such as endothelin-A receptor antagonist, endothelial growth factor receptor or platelet derived growth factor receptor inhibitor. Nuclear factor kappa B (NFkappaB) is a key molecule for the growth of prostate cancer. Therefore, NFkappaB can be a good target for the therapy. In fact, a couple of NFkappaB inhibitors have been clinically or pre-clinically tested. Among them, Bortezomib and thalidomide showed little clinical efficacy as a single therapeutic agent. However, these drugs exerted clinical benefits to some extent when used with other chemotherapeutic drugs. Dexamethasone is also an NFkappaB inhibitor. Its clinical efficacy is through suppressing the adrenal androgen level. Besides adrenal androgen blockade, dexamethasone suppresses the growth of prostate cancer via NFkappaB inactivation, and also via the inhibition of interleukin-6 production which is reportedly important for the growth of prostate cancer. One of the clinical benefits of dexamethasone treatment is the improvement in anemia.     

Molecular targeted therapy for renal cell carcinoma

Renal cell carcinoma (RCC) accounts for approximately 2% of all cancer cases worldwide. Metastatic disease is often present at the time of diagnosis of RCC and its poor response to chemotherapy and radiotherapy causes poor prognosis. Immunotherapy is relatively effective for RCC, but the response rate is approximately 15-20%. Therefore, new therapeutic approaches are necessary for these patients with metastatic RCC. Recently, the mechanisms responsible for the growth of RCC have been clarified, and molecular targeted therapy has been developed. In this paper, we review the new molecular targeted therapeutic agents effective for RCC.     

Molecular targeted therapy and tailor-made therapy for lung cancer

Somatically acquired mutations in the epidermal growth factor receptor (EGFR) gene in lung cancer are associated with significant clinical responses to gefitinib, a tyrosine kinase inhibitor (TKI) that targets EGFR. In our previous report, 42.2% of adenocarcinoma patients has EGFR mutations, and these mutations were more frequently found in women than in men, in well differentiated tumors than poorly differentiated tumors, and in patients who were never smokers than in patients who were current/former smokers. Retrospectively, we screened the EGFR gene of tumors in 37 NSCLC patients who had been treated with gefitinib. EGFR mutations were found in 22 patients. Gefitinib was effective (CR/PR) in 15 of 22 (68.2%) patients with mutations compared with none of 15 patients without mutations. Patients with EGFR mutations survived for a longer period than without the mutations after initiation of gefitinib treatment (p = 0.0005). Gefitinib was not effective in 3 patients with K-ras mutations. Three of 4 tumors obtained from patients with acquired resistant to gefitinib, had a secondary T790M mutation. No T790M mutation was detected in pretreatment tumors. Molecular targeted therapy using TKI indicates an effective therapy specifically in lung cancer patients with EGFR mutations, and analyses of mechanisms of resistance to TKI are necessary for establishment of tailor-made therapy.     

肝癌的分子靶向治疗

<正>原发性肝癌是最常见的恶性肿瘤之一,具有发病率高、病程短、恶性程度大、预后差等特点。近年来,其发病率有明显增高趋势。肝癌常规的治疗方     

前列腺癌的分子靶向治疗

前列腺癌的雄激素非依赖性进展是目前制约前列腺癌疗效的主要瓶颈。分子靶向治疗在诸多肿瘤治疗领域取得了突破性和革命性的进展。近年来,分子靶向方法在治疗晚期前列腺癌方面进行了诸多卓有成效的临床研究,本文对此进行了总结。     

Combining a targeted radiotherapy and gene therapy approach for adenocarcinoma of prostate

A targeted radiotherapy/gene therapy approach for prostate cancer, using the radiopharmaceutical [(131)I]meta-iodobenzylguanidine ([(131)I]MIBG), would restrict the effects of radiotherapy to malignant cells, thereby increasing efficacy and decreasing morbidity of radiotherapy. Prostate cancer cells were transfected with a transgene encoding the noradrenaline transporter (NAT) under the control of tumour-specific telomerase promoters, enabling them to actively take up [(131)I]MIBG. This led to tumour-specific cell kill. This strategy has the advantage of generating a radiological bystander effect, leading to the destruction of neighbouring tumour cells that have escaped transfection. This targeted approach could be a promising tumour-specific treatment option for prostate cancer.     

进展期胃癌分子靶向治疗

胃癌是消化系统最常见的恶性肿瘤,在世界范围内,死亡率位居第二位.与日本等国家不同的是,我国90%以上的胃癌患者在就诊时处于进展期.外科手术和围手术期化疗是进展期胃癌治疗的主要手段.标准D2手术和新型化疗药物的出现在一定程度上改善了胃癌治疗效果,但仍然未能达到人们的期望.     

局部转移性晚期甲状腺癌分子靶向药物治疗

晚期碘难治性甲状腺癌(radioactive iodine-refractory DTC,RAIR DTC)、甲状腺未分化癌和晚期髓样癌目前仍缺少有效治疗方法,一旦发生局部复发或远处转移,严重威胁病人的生命。随着甲状腺癌分子生物学研究的蓬勃发展,许多有效的药物分子作用靶标相继被发现。基于一个或多个靶点研发出分子靶向药物已经完成或正在进行治疗甲状腺癌的临床试验,展现出良好的发展和应用前景。索拉非尼、凡德尼布、乐伐替尼以及卡博替尼已被美国食品药品监督管理局(FDA)批准用于进展期甲状腺癌的治疗;阿西替尼、司美替尼等分子靶向抑制剂已通过Ⅱ/Ⅲ期临床试验,这些药物的出现为晚期甲状腺癌以及进展期髓样癌的治疗提供了全新的选择。这些靶向药物具有特异性强、副反应较小、疗效好等优点,在甲状腺癌的治疗中具有广阔的前景。     

胃肠道间质瘤的分子靶向治疗

分子靶向药物的出现,改变了胃肠道间质瘤(GIST)的治疗模式.伊马替尼400 mg/d被推荐为转移性GIST的标准一线治疗方案.伊马替尼标准剂量治疗失败后,增加伊马替尼剂量或换用舒尼替尼治疗可进一步延长患者生存时间,同时新的分子靶向药物显示出了治疗GIST的潜在活性.GIST完整切除术后,伊马替尼辅助治疗可改善中高度复发风险患者的无复发生存率.伊马替尼术前治疗可提高手术切除率,但是否使患者生存获益尚未得到最终证实.c-kit和(或)血小板源性生长因子受体α(PDGFRα)基因突变可以预测伊马替尼与舒尼替尼的疗效,同时亦有助于辅助治疗获益人群的筛选.     

食管胃结合部腺癌分子靶向治疗的研究进展

食管胃结合部腺癌是一种特殊类型的肿瘤,不仅在部位比较特别,而且在生物学特性和临床表现上也独具特点.手术治疗是主要的治疗手段,但单独手术治疗有时效果不佳,患者往往预后较差.分子靶向治疗作为肿瘤治疗的新方向,正在发挥着越来越大的作用.一些分子靶点如血管表皮生长因子、肝细胞生长因子受体、表皮生长因子受体、成纤维细胞生长因子受体2、人表皮生长因子受体-2在治疗食管胃结合部腺癌方面展现出广阔的前景.本文收集近期相关国内外文献对食管胃结合部腺癌分子靶向治疗的现状与进展进行综述.     

分子靶向治疗胆道恶性肿瘤：靶点的确定

胆道恶性肿瘤是少见的疾病,在美国每年大约有9 000人被诊断为此病[1],但大多数患者确诊时已是晚期.小部分患者虽然可以切除治疗,但许多患者切除后仍会复发,所以多学科的综合治疗显得尤为重要[2].传统的药物治疗对于虽局限但已属晚期肿瘤或已发生转移的肿瘤效果差.然而,最近ABC-02试验显示吉西他滨和顺铂联合用药较吉西他滨单药治疗患者的生存期明显延长(11.7个月vs.8.1个月,P＜0.0001),并以此作为晚期胆道肿瘤的标准治疗[3].虽然这项试验向正确的研究方向迈出了一步,但我们必须承认仅依靠一两种药物不足以治疗这些肿瘤.随着肿瘤的分子生物学基础的不断研究,分子靶向治疗的临床应用也逐渐发展起来.     

Notch信号转导通路与肿瘤分子靶向治疗研究进展

Notch信号转导通路与细胞增生、分化、凋亡密切相关,与肿瘤的关系日益受到关注,以Notch通路为靶点的肿瘤治疗策略显示了其广阔的应用前景.本文将从肿瘤中Notch通路的调控、分子靶向治疗机制及应用进展方面做一综述.     

Notch信号转导通路与肿瘤分子靶向治疗研究进展

Notch信号转导通路与细胞增生、分化、凋亡密切相关,与肿瘤的关系日益受到关注,以Notch通路为靶点的肿瘤治疗策略显示了其广阔的应用前景.本文将从肿瘤中Notch通路的调控、分子靶向治疗机制及应用进展方面做一综述.     

Neoadjuvant therapy reduces the incidence of nodal micrometastases in esophageal adenocarcinoma

Background

We evaluated the impact of neoadjuvant chemoradiotherapy (CRT) on nodal micrometastases (NMMs) in esophageal adenocarcinoma (EAC) patients with histologically negative nodes ([y]pN0).

Methods

Of 48 consecutively treated patients with neoadjuvant CRT, we selected 20 EAC ypN0 patients (group 1). These patients were matched with 20 pN0 EAC patients who had surgery alone (group 2). Harvested (y)pN0 lymph nodes were examined immunohistochemically (anti-CK8/18 [CAM 5.2]) according to a validated sentinel node protocol. A 3rd group (n = 11) staged as ypN1 after neoadjuvant CRT was used as the control group.

Results

Upstaging to NMM+ occurred in 2 patients (10%) in group 1 and in 8 patients (40%) in group 2 (P = .028). Disease-free and overall survival rates in NMM+ patients in group 1 were worse compared with NMM− patients (P = .014 and P = .003, respectively) but comparable with ypN1 patients (n = 11).

Conclusions

A 30% reduction of NMM+ was obtained after neoadjuvant treatment in (y)pN0 patients. NMM+ after CRT had a negative impact on survival in ypN1 patients. These data warrant further investigation in larger prospective datasets.     

Molecular determinants of susceptibility to oncolytic vesicular stomatitis virus in pancreatic adenocarcinoma

Background

M protein mutant vesicular stomatitis virus (M51R-VSV) has oncolytic properties against many cancers. However, some cancer cells are resistant to M51R-VSV. Herein, we evaluate the molecular determinants of vesicular stomatitis virus (VSV) resistance in pancreatic adenocarcinoma cells.

Methods

Cell viability and the effect of β-interferon (IFN) were analyzed using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. Gene expression was evaluated via microarray analysis. Cell infectability was measured by flow cytometry. Xenografts were established in athymic nude mice and treated with intratumoral M51R-VSV.

Results

Four of five pancreatic cancer cell lines were sensitive to M51R-VSV, whereas Panc 03.27 cells remained resistant (81 ± 3% viability 72 h after single-cycle infection). Comparing sensitive MiaPaCa2 cells with resistant Panc 03.27 cells, significant differences in gene expression were found relating to IFN signaling (P = 2 × 10⁻⁵), viral entry (P = 3 × 10⁻⁴), and endocytosis (P = 7 × 10⁻⁴). MiaPaCa2 cells permitted high levels of VSV infection, whereas Panc 03.27 cells were capable of resisting VSV cell entry even at high multiplicities of infection. Extrinsic β-IFN overcame apparent defects in IFN-mediated pathways in MiaPaCa2 cells conferring VSV resistance. In contrast, β-IFN decreased cell viability in Panc 3.27 cells, suggesting intact antiviral mechanisms. VSV-treated xenografts exhibited reduced tumor growth relative to controls in both MiaPaCa2 (1423 ± 345% versus 164 ± 136%; P < 0.001) and Panc 3.27 (979 ± 153% versus 50 ± 56%; P = 0.002) tumors. Significant lymphocytic infiltration was seen in M51R-VSV–treated Panc 03.27 xenografts.

Conclusions

Inhibition of VSV endocytosis and intact IFN-mediated defenses are responsible for M51R-VSV resistance in pancreatic adenocarcinoma cells. M51R-VSV treatment appears to induce antitumor cellular immunity in vivo, which may expand its clinical efficacy.     

Management of esophageal adenocarcinoma

The incidence of esophageal adenocarcinoma is increasing in Western countries with a tendency to exceed that of squamous-cell carcinoma. Prognosis is unfavorable with 5-year survival less than 15%, irrespective of treatment and the stage. At the time of diagnosis, more than two thirds of patients have a non-operable cancer because of extension or associated co-morbidities. Most studies have included different tumoral locations (esophagus and stomach) and different histological types (adenocarcinoma and squamous-cell carcinoma), making it difficult to interpret results. Surgery is currently the standard treatment for small tumors. Surgery should be preceded by neo-adjuvant treatment for patients with locally advanced resectable tumors, either preoperative chemotherapy or preoperative chemoradiation therapy. The therapeutic choice should be decided during multidisciplinary meetings according to patient and tumor characteristics and the expertise of the center. For patients with contraindications to surgery, exclusive chemoradiation therapy is recommended. Herein we reviewed and synthesized the different therapeutic strategies for esophageal adenocarcinoma.