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Molecular classification of non-small-cell lung cancer: diagnosis, individualized treatment, and prognosis

null

《医学前沿（英文）》 2013年 第7卷 第2期   页码 157-171 doi: 10.1007/s11684-013-0272-4

摘要：

Non-small-cell lung cancer (NSCLC) is the most common cause of premature death among the malignant diseases worldwide. The current staging criteria do not fully capture the complexity of this disease. Molecular biology techniques, particularly gene expression microarrays, proteomics, and next-generation sequencing, have recently been developed to facilitate effectively its molecular classification. The underlying etiology, pathogenesis, therapeutics, and prognosis of NSCLC based on an improved molecular classification scheme may promote individualized treatment and improve clinical outcomes. This review focuses on the molecular classification of NSCLC based on gene expression microarray technology reported during the past decade, as well as their applications for improving the diagnosis, staging and treatment of NSCLC, including the discovery of prognostic markers or potential therapeutic targets. We highlight some of the recent studies that may refine the identification of NSCLC subtypes using novel techniques such as epigenetics, proteomics, or deep sequencing.

关键词： non-small-cell lung cancer     molecular typing     individualized medicine     molecular-targeted therapy     gene expression profiling    

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Molecular classification and molecular targeted therapy of cancer

null

《医学前沿（英文）》 2013年 第7卷 第2期   页码 147-149 doi: 10.1007/s11684-013-0274-2

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Molecular markers and pathogenically targeted therapy in non-small cell lung cancer

Bo PENG BA , Jinnong ZHANG MD , Jamile S. WOODS MD , Wei PENG MD, PhD

《医学前沿（英文）》 2009年 第3卷 第3期   页码 245-255 doi: 10.1007/s11684-009-0044-3

摘要： Lung cancer is one of the most common human cancers and the number one cancer killer in the United States. In general, lung cancer includes small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), but NSCLC accounts for approximately 90% of lung cancer. The early diagnosis and therapy of lung cancer still presents a big challenge because validated screening tools, which can improve current early detection to reduce mortality from lung cancer, do not exist. Over the last decade, molecular genetic abnormalities have been described in NSCLC, including chromosomal aberrations, overexpression of oncogenes, and deletion and/or mutations in tumor suppressor genes. These molecular markers in NSCLC demonstrated close associations with the development of lung cancer such as Ras, the epidermal growth factor receptor (EGFR, or c-erbB-1), HER2 (c-erbB-2), c-Met, and Bcl-2. Therefore, this information may be applied for early cancer detection, classification, novel targeted therapy, and prognosis in NSCLC. Recent clinical data have revealed that targeted therapy might be the second-line therapy as an alternative approach. Currently, the targeted therapies are mainly focused on two lung cancer pathways, the EGFR and the vascular endothelial growth factor (VEGF) pathways. Some clinical trials are very encouraging, but some of them are not. However, these trials have not identified a subgroup of NSCLC with biomarkers. Therefore, it is very important to select NSCLC patients with biomarkers to match targeted agents so that we can further identify effectiveness of targeted therapy in the future.

关键词： lung cancer     carcinoma     non-small cell lung cancer     molecular markers     targeted therapy    

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Molecular targeted therapy of gynecological malignant tumors: the development and challenge, from laboratory

Pengming SUN PhD, MD , Jalid SEHOULI PhD, MD , Lihui WEI BM ,

《医学前沿（英文）》 2009年 第3卷 第3期   页码 256-264 doi: 10.1007/s11684-009-0052-3

摘要： More and more molecular drugs based on targeted therapy have been utilized in the treatment of gynecologic cancer, especially in ovarian cancer. In this article, we systematically review the current targeted therapeutic trials running in clinic. Large, randomized trials have been conducted in the treatment of ovarian cancer, endometrial cancer and cervical cancer by using small molecule, antisense, mutational gene as well as antibodies. Other planned or ongoing trials currentlytargeted at molecular markers which may play important roles in gynecological carcinogenesis andprogression suggest that combination chemotherapy with molecular targeted therapy will ultimately be an importantoption.

关键词： target therapy     gynecologic malignant tumors     clinical trail     molecular medicine    

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Synthesis and application of superparamagnetic iron oxide nanoparticles in targeted therapy and imaging

Liangqian Tong, Ming Zhao, Shu Zhu, Jing Chen

《医学前沿（英文）》 2011年 第5卷 第4期   页码 379-387 doi: 10.1007/s11684-011-0162-6

摘要： Superparamagnetic iron oxide (SPIO) nanoparticles have become a popular strategy of cancer treatment and molecular imaging because of their versatile properties and biocompatibility. A variety of studies have shown the exciting potential of functionalized SPIO nanoparticles, such as surface-coated, targeted ligand-conjugated, and/or drug-loaded SPIO nanoparticles, as powerful tools for targeted imaging and therapy. Moreover, the applications of SPIO nanoparticles that integrate diagnosis and therapy in SPIO nanoparticles facilitate the monitoring of therapeutic efficacy during treatment. In the present review, we primarily concentrate on the recent advancements in the field of SPIO nanoparticles in terms of synthesis, targeted therapy, and cancer imaging.

关键词： nanoparticles     superparamagnetic iron oxide     targeted therapy     molecular imaging     cancer    

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Precision medicine in acute lymphoblastic leukemia

Ching-Hon Pui

《医学前沿（英文）》 2020年 第14卷 第6期   页码 689-700 doi: 10.1007/s11684-020-0759-8

摘要： The cure rate of childhood acute lymphoblastic leukemia (ALL) has exceeded 90% in some contemporary clinical trials. However, the dose intensity of conventional chemotherapy has been pushed to its limit. Further improvement in outcome will need to rely more heavily on molecular therapeutic as well as immuno- and cellular-therapy approaches together with precise risk stratification. Children with or hyperdiploid>50 ALL who achieve negative minimal residual disease during early remission induction are suitable candidates for reduction in treatment. Patients with Philadelphia chromosome (Ph)-positive or Ph-like ALL with ABL-class fusion should be treated with dasatinib. BH3 profiling and other preclinical methods have identified several high-risk subtypes, such as hypodiplod, early T-cell precursor, immature T-cell, -rearranged, Ph-positive and -positive ALL, that may respond to BCL-2 inhibitor venetoclax. There are other fusions or mutations that may serve as putative targets, but effective targeted therapy has yet to be established. For other high-risk patients or poor early treatment responders who do not have targetable genetic lesions, current approaches that offer hope include blinatumomab, inotuzumab and CAR-T cell therapy for B-ALL, and daratumumab and nelarabine for T-ALL. With the expanding therapeutic armamentarium, we should start focus on rational combinations of targeted therapy with non-overlapping toxicities.

关键词： acute lymphoblastic leukemia     molecular therapeutics     targeted therapy     tyrosine kinase inhibitors     immunotherapy     CAR T-cell therapy    

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Resistance to receptor tyrosine kinase inhibition in cancer: molecular mechanisms and therapeutic strategies

null

《医学前沿（英文）》 2015年 第9卷 第2期   页码 134-138 doi: 10.1007/s11684-015-0396-9

摘要：

Drug resistance is a major factor that limits the efficacy of targeted cancer therapies. In this review, we discuss the main known mechanisms of resistance to receptor tyrosine kinase inhibitors, which are the most prevalent class of targeted therapeutic agent in current clinical use. Here we focus on bypass track resistance, which involves the activation of alternate signaling molecules by tumor cells to bypass inhibition and maintain signaling output, and consider the problems of signaling pathway redundancy and how the activation of different receptor tyrosine kinases translates into intracellular signal transduction in different cancer types. This information is presented in the context of research strategies for the discovery of new targets for pharmacological intervention, with the goal of overcoming resistance in order to improve patient outcomes.

关键词： targeted therapy     drug resistance     receptor tyrosine kinases     cancer    

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mTOR-targeted cancer therapy: great target but disappointing clinical outcomes, why?

Shi-Yong Sun

《医学前沿（英文）》 2021年 第15卷 第2期   页码 221-231 doi: 10.1007/s11684-020-0812-7

摘要： The mammalian target of rapamycin (mTOR) critically regulates several essential biological functions, such as cell growth, metabolism, survival, and immune response by forming two important complexes, namely, mTOR complex 1 (mTORC1) and complex 2 (mTORC2). mTOR signaling is often dysregulated in cancers and has been considered an attractive cancer therapeutic target. Great efforts have been made to develop efficacious mTOR inhibitors, particularly mTOR kinase inhibitors, which suppress mTORC1 and mTORC2; however, major success has not been achieved. With the strong scientific rationale, the intriguing question is why cancers are insensitive or not responsive to mTOR-targeted cancer therapy in clinics. Beyond early findings on induced activation of PI3K/Akt, MEK/ERK, and Mnk/eIF4E survival signaling pathways that compromise the efficacy of rapalog-based cancer therapy, recent findings on the essential role of GSK3 in mediating cancer cell response to mTOR inhibitors and mTORC1 inhibition-induced upregulation of PD-L1 in cancer cells may provide some explanations. These new findings may also offer us the opportunity to rationally utilize mTOR inhibitors in cancer therapy. Further elucidation of the biology of complicated mTOR networks may bring us the hope to develop effective therapeutic strategies with mTOR inhibitors against cancer.

关键词： mTOR     cancer therapy     resistance     GSK3     protein degradation     E3 ubiquitin ligase     PD-L1    

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Targeted therapy of desmoid-type fibromatosis: mechanism, current situation, and future prospects

Zhen Wang, Jianhui Wu, Xiuyun Tian, Chunyi Hao

《医学前沿（英文）》 2019年 第13卷 第4期   页码 427-437 doi: 10.1007/s11684-018-0672-6

摘要： Desmoid-type fibromatosis (DF) is a rare monoclonal fibroblastic proliferation that is characterized by locally infiltrative but rarely metastatic lesions. Tyrosine kinase and γ-secretase inhibitors are primarily used in the targeted therapy of DF. The use of these drugs, however, is mainly based on the recommendations of retrospective studies with small sample sizes. Previous studies that focused on the mechanism, efficacy, and safety of targeted therapy for DF were reviewed to provide references for clinical applications and research. The efficacy and safety of targeted therapy were compared with those of other systemic therapy options. Targeted therapy does not provide considerable advantages in efficacy and safety over other medical treatments and is usually applied after the failure of antihormonal therapies, nonsteroidal anti-inflammatory drugs, and chemotherapy. Further studies are required to explore the mechanism, indications, and appropriate drug dosage of the targeted therapy of DF.

关键词： targeted therapy     desmoid-type fibromatosis     tyrosine kinase inhibitor     γ-secretase inhibitor    

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Progress and challenges in RET-targeted cancer therapy

《医学前沿（英文）》 2023年 第17卷 第2期   页码 207-219 doi: 10.1007/s11684-023-0985-y

摘要： The rearranged during transfection (RET) is a receptor protein tyrosine kinase. Oncogenic RET fusions or mutations are found most often in non-small cell lung cancer (NSCLC) and in thyroid cancer, but also increasingly in various types of cancers at low rates. In the last few years, two potent and selective RET protein tyrosine kinase inhibitors (TKIs), pralsetinib (BLU-667) and selpercatinib (LOXO-292, LY3527723) were developed and received regulatory approval. Although pralsetinib and selpercatinib gave high overall response rates (ORRs), < 10% of patients achieved a complete response (CR). The RET TKI-tolerated residual tumors inevitably develop resistance by secondary target mutations, acquired alternative oncogenes, or MET amplification. RET G810 mutations located at the kinase solvent front site were identified as the major on-target mechanism of acquired resistance to both selpercatinib and pralsetinib. Several next-generation of RET TKIs capable of inhibiting the selpercatinib/pralsetinib-resistant RET mutants have progressed to clinical trials. However, it is likely that new TKI-adapted RET mutations will emerge to cause resistance to these next-generation of RET TKIs. Solving the problem requires a better understanding of the multiple mechanisms that support the RET TKI-tolerated persisters to identify a converging point of vulnerability to devise an effective co-treatment to eliminate the residual tumors.

关键词： pralsetinib     selpercatinib     RET-alteration     lung cancer     thyroid cancer     tumor-agnostic therapy     drug resistance    

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Potential unreliability of ALK variant allele frequency in the efficacy prediction of targeted therapy

《医学前沿（英文）》 2023年 第17卷 第3期   页码 493-502 doi: 10.1007/s11684-022-0946-x

摘要： Anaplastic lymphoma kinase (ALK) is the most common fusion gene involved in non-small cell lung cancer (NSCLC), and remarkable response has been achieved with the use of ALK tyrosine kinase inhibitors (ALK-TKIs). However, the clinical efficacy is highly variable. Pre-existing intratumoral heterogeneity (ITH) has been proven to contribute to the poor treatment response and the resistance to targeted therapies. In this work, we investigated whether the variant allele frequencies (VAFs) of ALK fusions can help assess ITH and predict targeted therapy efficacy. Through the application of next-generation sequencing (NGS), 7.2% (326/4548) of patients were detected to be ALK positive. On the basis of the adjusted VAF (adjVAF, VAF normalization for tumor purity) of four different threshold values (adjVAF < 50%, 40%, 30%, or 20%), the association of ALK subclonality with crizotinib efficacy was assessed. Nonetheless, no statistical association was observed between median progression-free survival (PFS) and ALK subclonality assessed by adjVAF, and a poor correlation of adjVAF with PFS was found among the 85 patients who received first-line crizotinib. Results suggest that the ALK VAF determined by hybrid capture-based NGS is probably unreliable for ITH assessment and targeted therapy efficacy prediction in NSCLC.

关键词： ALK fusion     next-generation sequencing     fluorescence in situ hybridization     immunohistochemistry     variant allele frequency     intratumoral heterogeneity     targeted therapy    

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A small-molecule pan-HER inhibitor alone or in combination with cisplatin exerts efficacy against nasopharyngeal carcinoma

《医学前沿（英文）》 2023年 第17卷 第2期   页码 275-289 doi: 10.1007/s11684-022-0945-y

摘要： The abnormal activation of HER family kinase activity is closely related to the development of human malignancies. In this study, we used HER kinases as targets for the treatment of nasopharyngeal carcinoma (NPC) and explored the anti-tumor effects of the novel pan-HER inhibitor HM781-36B, alone or in combination with cisplatin. We found that HER family proteins were positively expressed in tumor tissues of some NPC patients, and the high levels of those proteins were significantly related to poor prognosis. HM781-36B inhibited NPC in vitro and in vivo. HM781-36B exerted synergistic effects with cisplatin on inhibiting proliferation and promoting apoptosis of NPC cells. In NPC xenograft models in nude mice, HM781-36B and cisplatin synergistically inhibited tumor growth. Downregulating the activity of HER family proteins and their downstream signaling pathways and regulating tumor microenvironment may explain the synergistic anti-tumor effects of HM781-36B and cisplatin. In conclusion, our study provides evidence for HER family proteins as prognostic biomarkers and potential therapeutic targets for NPC. The pan-HER inhibitor HM781-36B alone or in combination with cisplatin represents promising therapeutic effects for the treatment of NPC patients, which provides a new idea for the comprehensive treatment of NPC.

关键词： epidermal growth factor receptor     ErbB receptors     HM781-36B     nasopharyngeal carcinoma     molecular targeted therapy     cisplatin    

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Progress in systemic therapy for triple-negative breast cancer

Hongnan Mo, Binghe Xu

《医学前沿（英文）》 2021年 第15卷 第1期   页码 1-10 doi: 10.1007/s11684-020-0741-5

摘要： Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a heterogeneous genetic profile. Chemotherapy exhibits substantial activity in a small subset of these patients. Drug resistance is inevitable. Major progress has been made in the genetic analysis of TNBC to identify novel targets and increase the precision of therapeutic intervention. Such progress has translated into major advances in treatment strategies, including modified chemotherapy approaches, immune checkpoint inhibitors, and targeted therapeutic drugs. All of these strategies have been evaluated in clinical trials. Nevertheless, patient selection remains a considerable challenge in clinical practice.

关键词： triple-negative breast cancer     immunotherapy     targeted therapy    

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Influence of Survivin-targeted siRNA on the biological features of colorectal carcinoma cells

XIONG Ying, GUO Wen, LI Ting, LI Ke

《医学前沿（英文）》 2007年 第1卷 第3期   页码 304-307 doi: 10.1007/s11684-007-0058-7

摘要： The transient transfection of survivin-targeted siRNA to Lovo cells and its influence on the biological features were studied. Two pairs of 19 base pairs (bp) siRNA-specific targeted survivin gene were designed and synthesized by transcription (Survivin-1, Survivin-2). After transient transfection of the two survivin-targeted siRNAs to Lovo cells by Lipofectamine™ 2000, the expression of survivin mRNA was detected by reverse transcription-polymerase chain reaction (RT-PCR). Apoptosis was detected by flow cytometry and cell proliferation was evaluated by MTT assay. We found that the expression levels of survivin mRNA of the two RNAi groups (Survivin-1 group and Survivin-2 group) respectively decreased by 70% and 39.1% compared with the control Lovo’s. Seventy-two hours after transfection, apoptosis rates of the two RNAi groups were 21.51% and 26.28%, both of which were higher than control Lovo’s (9.03%). The results at 72 h after transfection were that the optical density (OD) at 490 nm of the two RNAi groups was 0.581±0.070 and 0.681±0.104, both of which were much lower than the control Lovo’s (2.060±0.272). Based on the results, we can draw a conclusion that the two survivin-targeted siRNAs successfully suppressed the expression of survivin mRNA, inhibited cell growth and induce cell apoptosis. It provides a powerful evidence for colorectal carcinoma gene therapy.

关键词： control     therapy     influence     Survivin-1     colorectal carcinoma    

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抑制FLT3 ——急性髓系白血病分子靶向治疗的原型 Review

Meira Yisraeli Salman, Jacob M. Rowe, Nir Weigert

《工程（英文）》 2021年 第7卷 第10期   页码 1354-1368 doi: 10.1016/j.eng.2021.05.020

摘要：

急性髓系白血病（AML）的现代治疗始于1973年，首例柔红霉素和阿糖胞苷联合治疗法的成功随后拯救了大约45%的患者。准确的AML诊断依赖于形态学方法，其最初仅由细胞化学手段辅助。与急性淋巴细胞白血病（ALL）不同，至少在20世纪70年代和80年代，免疫分型在AML的诊断中几乎不起作用。可靠的细胞遗传学方法的出现为AML的预后发展带来了翻天覆地的变化。通过核型分析，可以对不同的AML实现分类与分层，以进行各种治疗。借助细胞上抗原标记物的免疫表型鉴定，独特的突变图谱可以里程碑式地进一步对 AML 患者进行分类。所有的这些进展都随着对肿瘤负荷[即微小残留病变（minimal residual disease, MRD）]的重要性的理解而成为AML患者管理的关键。MRD的疗效在过去10年迅速发展，其特异性从免疫分型的10-3发展到聚合酶链反应（PCR）的10-4（且仅对于部分AML患者有效），并最终在具有下一代测序（NGS）技术的灵敏度极高的细胞中发展至10-5甚至10-6。所有这些进步都促进了个性化医疗概念的发展，并带来了可以准确用于特定诊断亚型的靶向药物。可以精准预测与测量其响应。这些靶向药物现已成为AML管理的基础，其疗效显著提高，而毒性则显著下降。本文的重点是研究最为深入的AML靶向药物之一——FMS样酪氨酸激酶3（FLT3）抑制剂，它影响了AML的预后与治疗。作为已被批准的其他新兴靶向药物以及目前正在开发的靶向药物的原型，本文将选择性地对FLT3抑制剂展开详细讨论。

关键词： 急性髓系白血病     靶向治疗     FLT3抑制剂     米哚妥林     吉瑞替尼     奎扎替尼     索拉非尼    

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标题 作者 时间 类型 操作

Molecular classification of non-small-cell lung cancer: diagnosis, individualized treatment, and prognosis

null

期刊论文

Molecular classification and molecular targeted therapy of cancer

null

期刊论文

Molecular markers and pathogenically targeted therapy in non-small cell lung cancer

Bo PENG BA , Jinnong ZHANG MD , Jamile S. WOODS MD , Wei PENG MD, PhD

期刊论文

Molecular targeted therapy of gynecological malignant tumors: the development and challenge, from laboratory

Pengming SUN PhD, MD , Jalid SEHOULI PhD, MD , Lihui WEI BM ,

期刊论文

Synthesis and application of superparamagnetic iron oxide nanoparticles in targeted therapy and imaging

Liangqian Tong, Ming Zhao, Shu Zhu, Jing Chen

期刊论文

Precision medicine in acute lymphoblastic leukemia

Ching-Hon Pui

期刊论文

Resistance to receptor tyrosine kinase inhibition in cancer: molecular mechanisms and therapeutic strategies

null

期刊论文

mTOR-targeted cancer therapy: great target but disappointing clinical outcomes, why?

Shi-Yong Sun

期刊论文

Targeted therapy of desmoid-type fibromatosis: mechanism, current situation, and future prospects

Zhen Wang, Jianhui Wu, Xiuyun Tian, Chunyi Hao

期刊论文

Progress and challenges in RET-targeted cancer therapy

期刊论文

Potential unreliability of ALK variant allele frequency in the efficacy prediction of targeted therapy

期刊论文

A small-molecule pan-HER inhibitor alone or in combination with cisplatin exerts efficacy against nasopharyngeal carcinoma

期刊论文

Progress in systemic therapy for triple-negative breast cancer

Hongnan Mo, Binghe Xu

期刊论文

Influence of Survivin-targeted siRNA on the biological features of colorectal carcinoma cells

XIONG Ying, GUO Wen, LI Ting, LI Ke

期刊论文

抑制FLT3 ——急性髓系白血病分子靶向治疗的原型

Meira Yisraeli Salman, Jacob M. Rowe, Nir Weigert

期刊论文