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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 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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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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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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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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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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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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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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Platelet membrane-based and tumor-associated platelet- targeted drug delivery systems for cancer therapy

Yinlong Zhang, Guangna Liu, Jingyan Wei, Guangjun Nie

《医学前沿（英文）》 2018年第12卷第6期页码 667-677 doi: 10.1007/s11684-017-0583-y

摘要： Platelets have long been known to play critical roles in hemostasis by clumping and clotting blood vessel injuries. Recent experimental evidence strongly indicates that platelets can also interact with tumor cells by direct binding or secreting cytokines. For example, platelets have been shown to protect circulating cancer cells in blood circulation and to promote tumor metastasis. In-depth understanding of the role of platelets in cancer progression and metastasis provides promising approaches for platelet biomimetic drug delivery systems and functional platelet-targeting strategies for effective cancer treatment. This review highlights recent progresses in platelet membrane-based drug delivery and unique strategies that target tumor-associated platelets for cancer therapy. The paper also discusses future development opportunities and challenges encountered for clinical translation.

关键词： platelet-mimicking delivery systems tumor-associated platelets cancer therapy EPR effect

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Overcoming resistance to endocrine therapy in hormone receptor-positive human epidermal growth factor

Wenjie Zhu, Binghe Xu

《医学前沿（英文）》 2021年第15卷第2期页码 208-220 doi: 10.1007/s11684-020-0795-4

摘要： New targeted therapies have been developed to overcome resistance to endocrine therapy (ET) and improve the outcome of HR /HER2 advanced breast cancer (ABC). We conducted a meta-analysis and systemic review on randomized controlled trials evaluating various targeted therapies in combination with ET in HR /HER2 ABC. PUBMED and EMBASE databases were searched for eligible trials. Hazard ratios (HRs) for progression-free survival (PFS), odds ratios (ORs) for objective response rate (ORR), clinical benefit rate (CBR), and toxicity were meta-analyzed. Twenty-six studies with data on 10 347 patients were included and pooled. The addition of cyclin-dependent kinase 4/6 inhibitors to ET significantly improved median PFS (pooled HR= 0.547, <0.001), overall survival (pooled HR= 0.755, <0.001), and tumor response rates (ORR, pooled OR= 1.478, <0.001; CBR, pooled OR= 1.201, <0.001) with manageable toxicities (pooled OR= 3.280, <0.001). The mammalian targets of rapamycin inhibitors and exemestane were not clinically beneficial for this pooled population including ET-naïve and ET-resistant patients. Moderate improvement in PFS (pooled HR= 0.686, <0.001) yet pronounced toxicities (pooled OR= 2.154, <0.001) were noted in the combination of phosphatidylinositol-4,5-bisphosphate 3-kinase inhibitors with fulvestrant. Future studies are warranted to optimize the population and the dosing sequence of these available options.

关键词： endocrine-resistant HR⁺/HER2^- advanced breast cancer randomized clinical trials meta-analysis targeted therapy

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Taking advantage of drug resistance, a new approach in the war on cancer

null

《医学前沿（英文）》 2018年第12卷第4期页码 490-495 doi: 10.1007/s11684-018-0647-7

摘要：

Identification of the driver mutations in cancer has resulted in the development of a new category of molecularly targeted anti-cancer drugs. However, as was the case with conventional chemotherapies, the effectiveness of these drugs is limited by the emergence of drug-resistant variants. While most cancer therapies are given in combinations that are designed to avoid drug resistance, we discuss here therapeutic approaches that take advantage of the changes in cancer cells that arise upon development of drug resistance. This approach is based on notion that drug resistance comes at a fitness cost to the cancer cell that can be exploited for therapeutic benefit. We discuss the development of sequential drug therapies in which the first therapy is not given with curative intent, but to induce a major new sensitivity that can be targeted with a second drug that selectively targets the acquired vulnerability. This concept of collateral sensitivity has hitherto not been used on a large scale in the clinic and holds great promise for future cancer therapy.

关键词： cancer drug resistance genetic screens senescence targeted therapy

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Chinese expert consensus on oral drugs for the treatment of mature B-cell lymphomas (2020 edition)

《医学前沿（英文）》 2022年第16卷第5期页码 815-826 doi: 10.1007/s11684-021-0891-0

摘要： Oral drugs such as ibrutinib play an important role in the treatment of mature B-cell lymphoma (BCL) due to their reliable efficacy, manageable safety, high accessibility, and convenience for use. Still, no guidelines or consensus focusing on oral drug therapies for BCL is available. To provide a reference of oral agent-based treatment for mature BCL, a panel of experts from the Lymphocyte Disease Group, Chinese Society of Hematology, Chinese Medical Association conducted an extensive discussion and reached a consensus on oral drugs for Chinese BCL patients on the basis of the current application status of oral drugs in China, combined with the latest authoritative guidelines in the world and current research reports. This consensus reviewed the application of oral drugs in the treatment of BCL and the latest research and provided appropriate recommendations on the use of oral drugs for indolent or aggressive BCL patients. With the deepening of research and the development of standardized clinical applications, oral medications will bring better treatment to BCL patients, enabling more patients to benefit from them.

关键词： B-cell lymphoma oral drug targeted therapy immunotherapy COVID-19 pandemic

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标题作者时间类型操作

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 classification and molecular targeted therapy of cancer

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

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

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

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

Precision medicine in acute lymphoblastic leukemia

Ching-Hon Pui

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

Platelet membrane-based and tumor-associated platelet- targeted drug delivery systems for cancer therapy

Yinlong Zhang, Guangna Liu, Jingyan Wei, Guangjun Nie

期刊论文

Overcoming resistance to endocrine therapy in hormone receptor-positive human epidermal growth factor

Wenjie Zhu, Binghe Xu

期刊论文

Taking advantage of drug resistance, a new approach in the war on cancer

null

期刊论文

Chinese expert consensus on oral drugs for the treatment of mature B-cell lymphomas (2020 edition)

期刊论文

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