小细胞肺癌的靶向治疗

小细胞肺癌（SCLC）靶向治疗药物包括血管生成抑制剂、酪氨酸激酶抑制剂和信号通路抑制剂等。研究表明血管生成抑制剂如贝伐珠单抗疗效并不显著;酪氨酸激酶抑制剂如舒尼替尼等可能更适合单药治疗;信号通路抑制剂如 Amuvatinib、LDE225等正在进行Ⅰ、Ⅱ期临床试验。目前认为 SCLC对于靶向治疗不敏感,或更具有选择性和针对性,有待于进一步研究。     

小细胞肺癌的靶向治疗进展

近年来,小细胞肺癌（SCLC）靶向治疗药物的研究明显增加。靶向治疗药物包括血管生成抑制剂、酪氨酸和Src家族激酶抑制剂、重组分子、bcl-2抑制剂、sonichedgehog信号传导通路抑制剂等,其中,研究最为广泛的是血管生成抑制剂贝伐单抗（bevacizumab）、小分子酪氨酸激酶抑制剂和沙利度胺（thalidomide）。文章就一些主要的靶向药物治疗小细胞肺癌的情况作一综述。     

子宫内膜癌的分子靶向治疗新进展

随着对肿瘤分子靶向治疗研究的不断深入,越来越多的分子靶向药物在子宫内膜癌中得到应用,并取得了一定的疗效,包括酪氨酸激酶抑制剂、单克隆抗体和mTOR信号通路抑制剂等.但目前的研究多为Ⅱ期临床试验,缺乏大规模Ⅲ期随机对照临床试验的结果.本文对近年来子宫内膜癌的分子靶向治疗的进展情况进行综述.     

肾细胞癌分子靶向治疗进展

针对血管内皮生长因子受体和表皮生长因子受体信号传导通路发展的低分子量多靶点酪氨酸激酶抑制剂、抗血管生成单克隆抗体、哺乳动物雷帕霉素靶蛋白抑制剂等分子靶向药物二线治疗肾细胞癌有延长无进展生存优势;一线治疗在无进展生存期及总生存期方面优于传统细胞因子治疗。分子靶向药物联合应用及与细胞因子或传统化疗药物的联合应用正在研究中。     

肾细胞癌分子靶向治疗进展

针对血管内皮生长因子受体和表皮生长因子受体信号传导通路发展的低分子量多靶点酪氨酸激酶抑制剂、抗血管生成单克隆抗体、哺乳动物雷帕霉素靶蛋白抑制剂等分子靶向药物二线治疗肾细胞癌有延长无进展生存优势；一线治疗在无进展生存期及总生存期方面优于传统细胞因子治疗。分子靶向药物联合应用及与细胞因子或传统化疗药物的联合应用正在研究中。     

仑伐替尼联合免疫检查点抑制剂治疗恶性肿瘤协同效应的机制研究进展

抗血管生成靶向药物联合免疫检查点抑制剂(ICIs)有望通过协同效应提高ICIs或抗血管生成靶向药物的治疗效果.仑伐替尼是多靶点酪氨酸激酶抑制剂,具有强大的抗血管生成活性,并且能够与PD-1/PD-L1抑制剂发挥协同效应,从而增强PD-1/PD-L1抑制剂的抗肿瘤作用.仑伐替尼联合PD-1抑制剂组合疗法于2021年通过美...     

非小细胞肺癌中 HGF/c-Met 信号通路与 EGFR-TKI 获得性耐药的关系

表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）为首的靶向药物在晚期非小细胞肺癌患者治疗中取得巨大进展。然而,获得性耐药的出现是其不可避免的结果。肝细胞生长因子（HGF）／c-Met信号通路参与多种肿瘤细胞的形成、迁徙、血管生成等重要细胞进程。该信号通路的异常激活在EGFR-TKI 获得性耐药中发挥了重要作用。实验表明,HGF ／c-Met 信号通路抑制剂可使部分 EGFR-TKI获得性耐药患者临床获益。     

胰腺癌分子靶向治疗研究进展

目前,胰腺癌分子靶向治疗的研究主要集中于单克隆抗体、酪氨酸激酶抑制剂、法呢基转移酶抑制剂、基质金属蛋白酶抑制剂以及肿瘤疫苗等方面。单克隆抗体cetuximab和bevacizumab分别联合化疗药物治疗胰腺癌的Ⅱ期临床试验已初见成效。酪氨酸激酶抑制剂erlotinib联合吉西他滨疗效一般,但Grb7抑制物的临床前实验显示其能够抑制胰腺癌的侵袭和转移。肿瘤疫苗G17DT联合吉西他滨用于胰腺癌也已进入了Ⅲ期临床试验,SS1P的动物实验也显示其有一定的疗效。抗叶酸代谢药pemetrexed的Ⅱ期临床试验提示其疗效尚可。基质金属蛋白酶抑制剂和法呢基转移酶抑制剂则疗效欠佳。     

胰腺癌分子靶向治疗研究进展

目前,胰腺癌分子靶向治疗的研究主要集中于单克隆抗体、酪氨酸激酶抑制剂、法呢基转移酶抑制剂、基质金属蛋白酶抑制剂以及肿瘤疫苗等方面。单克隆抗体cetuximab和bevacizumab分别联合化疗药物治疗胰腺癌的Ⅱ期临床试验已初见成效。酪氨酸激酶抑制剂erlotinib联合吉西他滨疗效一般,但Grb7抑制物的115床前实验显示其能够抑制胰腺癌的侵袭和转移。肿瘤疫苗G17DT联合吉西他滨用于胰腺癌也已进入了Ⅲ期临床试验,SSIP的动物实验也显示其有一定的疗效。抗叶酸代谢药pemetrexed的Ⅱ期临床试验提示其疗效尚可。基质金属蛋白酶抑制剂和法呢基转移酶抑制剂则疗效欠佳。     

PS≥2的非小细胞肺癌的共识和挑战

 行为状态评分（PS）≥2的非小细胞肺癌患者受关注度低，传统治疗疗效不佳，治疗手段局限。新的靶向治疗包括表皮生长因子（EGFR）酪氨酸激酶抑制剂和血管生成（VEGF）抑制剂已经进入了Ⅱ／Ⅲ期临床试验，并已取得了一些临床数据，给这部分患者带来了希望。对PS≥2非小细胞肺癌患者的传统化疗和靶向治疗的现状和发展进行阐述。     

The potential of antiangiogenic therapy in non-small cell lung cancer.

The long-term prognosis for patients with advanced non-small cell lung cancer (NSCLC) remains poor despite the availability of several cytotoxic chemotherapy regimens. The use of targeted therapies, particularly those against the key mediator of angiogenesis vascular endothelial growth factor (VEGF), has the potential to improve outcomes for NSCLC patients. Bevacizumab, a recombinant humanized monoclonal anti-VEGF antibody, is the most clinically advanced antiangiogenic agent in NSCLC. In a phase III study, bevacizumab showed significantly improved overall and progression-free survival when used in combination with standard first-line chemotherapy in patients with advanced NSCLC. Bevacizumab was generally well tolerated in patients with NSCLC; however, tumor-related bleeding adverse events have been noted in some patients, predominantly those with squamous cell histology or centrally located tumors. Several small-molecule VEGF receptor tyrosine kinase inhibitors have also shown promise in phase I and II trials in NSCLC. This review summarizes the most important findings of angiogenesis inhibitors in NSCLC and discusses the potential for the use of these novel agents in different settings of NSCLC.     

Targeted therapy for small cell lung cancer

Small cell lung cancer (SCLC) is very aggressive clinically, and current cytotoxic therapy has only a limited impact on survival. The development of targeted therapy for SCLC has lagged behind that of non-small cell lung cancer. Current drugs under investigation include those targeting the angiogenetic, apoptotic, sonic hedgehog, and mammalian target of rapamycin (mTOR) pathways. Vaccines seem to be promising adjunctive therapies. This review will present the available data on these agents. Common genetic abnormalities seen in SCLC, which could serve as potential future targets are also discussed.     

The Insulin-Like Growth Factor Pathway in Lung Cancer

The insulin-like growth factor (IGF) pathway is involved in the normal control of fetal development, tissue growth, and metabolism. Two distinct ligands (insulin-like growth factor-1 [IGF-1] and IGF-2) plus insulin, and two receptors (insulin-like growth factor receptor-1 [IGF-1R] and the insulin receptor) capable of both homo- and heteropolymerization mediate the actions of this pathway. Cellular functions of IGF-regulated signaling are influenced by the expression of a variety of receptor docking proteins, including four different insulin receptor substrate proteins. Downstream signaling is primarily through the phosphatidylinositol-3 kinase-Akt pathway and the mitogen-activated protein kinase pathway, resulting in increased cell proliferation and apoptosis inhibition. Ligand-driven activation is influenced by upstream endocrine factors (particularly for IGF-1), imprinting (for IGF-2), by multiple circulating and tissue-based IGF-binding proteins/proteases, and by the expression of the IGF-2 clearance receptor (IGF-2R). Deregulation of IGF signaling has been described in several cancer types, including both small cell and non-small cell lung cancer. A number of IGF receptor inhibitors, including monoclonal antibodies and small molecule inhibitors are currently undergoing testing in clinical trials as both monotherapy, and in combination with chemotherapy, or with other targeted agents. Preliminary results from a randomized phase II trial of an anti-IGF-1R monoclonal antibody in combination with carboplatin/paclitaxel already suggest a potential efficacy benefit from targeting this pathway in the first line advanced non-small cell lung cancer setting.     

Antiangiogenic agents for the treatment of nonsmall cell lung cancer: characterizing the molecular basis for serious adverse events

Novel agents to reduce angiogenesis by targeting vascular endothelial growth factor and other proangiogenic signaling pathways are being developed for advanced nonsmall cell lung cancer. Antibody-based therapies (e.g., aflibercept) and multitargeted tyrosine kinase inhibitors (e.g., sorafenib, sunitinib, and BIBF 1120) are being evaluated in phase III clinical trials. Some antiangiogenic agents have demonstrated distinct profiles in producing a variety of nonhematologic toxicities, including bleeding/hemorrhage, venous and arterial thromboembolic events, gastrointestinal perforation, hypertension, and proteinuria. Elucidating the molecular basis of these toxicities may lead to clinical benefits by improving patient selection and allowing for the development of effective prevention and management strategies.     

Antiangiogenic agents in the management of non-small cell lung cancer: Where do we stand now and where are we headed?

Several therapies targeting angiogenesis are currently in development for non-small cell lung cancer (NSCLC). This review discusses results of recent clinical trials evaluating chemotherapy plus antiangiogenic therapy for NSCLC. Bevacizumab, an anti-VEGF antibody, is currently approved for the treatment of advanced NSCLC in combination with carboplatin and paclitaxel. Completed phase III trials evaluating bevacizumab plus chemotherapy have shown prolonged progression-free survival; however, not all trials showed significant improvement in overall survival (OS). Phase III trials of the tyrosine kinase inhibitors (TKIs) vandetanib and sorafenib and the vascular disrupting agent ASA404 also failed to improve OS compared with chemotherapy alone. Clinical trials are ongoing involving several new antiangiogenic therapies, including ramucirumab, aflibercept, cediranib, BIBF 1120, sunitinib, pazopanib, brivanib, ABT-869, axitinib, ABT-751, and NPI-2358; several of these agents have shown promising phase I/II results. Results from recently completed and ongoing phase III trials will determine if these newer antiangiogenic agents will be incorporated into clinical practice.     

Antiangiogenic agents as second-line therapy for advanced non-small cell lung cancer

With the approval of the antiangiogenic antibody bevacizumab in non-small cell lung cancer (NSCLC) and other malignancies, the tumor vasculature has emerged as a worthwhile therapeutic target. Second-line therapies have the potential to improve overall survival and quality of life over best supportive care alone. Accordingly, phase II and phase III studies are actively evaluating antiangiogenic treatments in the second-line setting in NSCLC, and results are awaited. Such therapies include antiangiogenic antibodies, small molecule inhibitors, and vascular-disrupting agents. This review will present the current landscape of angiogenesis inhibition in NSCLC, focusing on use as second-line therapy.     

Antiangiogenesis Therapy in Breast Cancer

Increased expression of the vascular endothelial growth factor (VEGF) is a poor prognostic factor in breast cancer, indicating that antiangiogenic therapies may improve outcomes. Novel antiangiogenic agents targeting the proangiogenic VEGF ligand and receptor tyrosine kinase inhibitors have been developed. Of these, bevacizumab, a humanized monoclonal antibody directed against VEGF, is very promising in breast cancer. A large phase 3 clinical trial demonstrated a statistically significant improvement in progression-free survival with the addition of bevacizumab to paclitaxel as first-line treatment of advanced breast cancer, establishing the benefit of antiangiogenic therapy in breast cancer. Additional studies of bevacizumab in the metastatic, adjuvant, and neoadjuvant settings are underway. Ongoing trials are also evaluating the efficacy of multitargeted tyrosine kinase inhibitors in advanced breast cancer. This article reviews the results of the key trials evaluating antiangiogenic agents in breast cancer with particular emphasis on bevacizumab and future directions of antiangiogenic therapy.     

Angiogenesis inhibitors: a rational strategy for radiosensitization in the treatment of non-small-cell lung cancer?

Angiogenesis is a precondition to invasion and metastasis for all solid tumors. Vascular endothelial growth factor (VEGF) and its family of receptors (VEGFR) play a critical role in cancer progression by promoting new blood vessel formation. Overexpression of VEGF and VEGFR has been correlated with poor prognosis in a variety of malignancies. In this era of targeted therapies for cancer, inhibiting angiogenesis through antiangiogenic and/or vascular targeting agents seems logical. Disturbing the angiogenesis process is an alternative or complementary strategy to inhibition of growth factor signaling. Blocking angiogenesis may enhance conventional anticancer treatments such as radiation therapy in situations where tumors are unresponsive to current antigrowth factor efforts. Compounds currently under investigation in cancer therapy include anti-VEGF/VEGFR antibodies, small molecule VEGFR tyrosine kinase inhibitors, antisense suppression of VEGF, immunotherapy, viral-directed targeting of VEGFR signaling, ribozymes, and various toxin conjugates. Preclinical investigations are exploring the benefits of combining angiogenic inhibitors with radiation. This article will provide an overview of these preclinical studies and the rationale for this therapeutic strategy in the treatment of non-small-cell lung cancer.     

Emerging antiangiogenic agents in lung cancer

The success of the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab in numerous tumor types including non-small-cell lung cancer (NSCLC) has spurred the development of additional novel antiangiogenic agents with distinct mechanisms of action. These include the small-molecule receptor tyrosine kinase (TK) inhibitors ZD6474, sorafenib, sunitinib malate, and AG-013736, all of which inhibit VEGF receptor TK activity. Because of the structural similarity of the different receptor TKs, these receptor TK inhibitors inhibit multiple receptors in addition to VEGF receptor. Vascular endothelial growth factor Trap, a novel, high-affinity molecule with specificity to the VEGF molecule, was generated as a fusion molecule of the VEGF receptor extracellular domain and the Fc portion of immunoglobulin (Ig) G1. Data from phase I/II trials have indicated the clinical feasibility of these agents, which are currently being investigated in phase II/III trials.     

Update on antiangiogenic treatment of advanced non-small cell lung cancer (NSCLC)

Bevacizumab is a monoclonal antibody that specifically inhibits vascular endothelial growth factor, and is the first antiangiogenic agent to be approved for first-line treatment of advanced non-small cell lung cancer (NSCLC). Evidence from two large phase III trials demonstrates that bevacizumab combined with chemotherapy improves outcomes for patients with non-squamous NSCLC. In patients with adenocarcinoma without epidermal growth factor receptor (EGFR) mutation, a median overall survival of 18.0 months is achieved. Several post-registration phase IV studies have confirmed bevacizumab’s efficacy and tolerability profile and have clarified the eligibility criteria. Clinical research is still ongoing to define the role of bevacizumab in different settings, such as single-agent bevacizumab for continuation maintenance therapy in advanced disease, treatment beyond disease progression, adjuvant therapy in early-stage NSCLC, or bevacizumab in combination with other targeted agents. A number of antiangiogenic tyrosine kinase inhibitors (TKI) have also been investigated in phase II and III trials. None of these drugs has proven significant clinical benefit in unselected patient populations. This article reviews the extensive information from randomized trials and large observational studies for bevacizumab in advanced NSCLC, and shortly describes the current clinical development of antiangiogenic monoclonal antibodies, TKIs and related compounds.