肿瘤分子靶向治疗进展

随着对肿瘤细胞生长、增殖、凋亡的分子机制研究的深入,使人类靶向性治疗肿瘤成为可能.针对肿瘤的特异性分子靶点设计的治疗方案,具有治疗特异性强、基本不损伤正常组织的优点,是肿瘤治疗中最有前景的方案.目前,全球有80余种“靶向治疗”制剂已经或正在进行临床试验,以肿瘤血管生成和表皮生长因子受体（EGFR）为靶点的药物占总数的一半以上.     

晚期胃肠间质瘤联合靶向药物治疗进展

胃肠间质瘤（gastrointestinal stromal tumors,GIST）是消化道最常见的间叶源性肿瘤,起源于Cajal间质细胞。所有的GIST均被认为具有一定程度的恶性潜能。KIT/血小板衍生生长因子受体α（platelet-derived growth factor receptor alpha,PDGFRA）基因突变导致的受体酪氨酸激酶编码蛋白异常激活,是目前已知GIST最主要的发病机制。酪氨酸酸激酶抑制剂（tyrosine kinase inhibitor,TKI）是治疗的主要选择,目前单药TKI序贯治疗是GIST的标准治疗方案,但一线治疗耐药以后,后线治疗的疗效有限。因此,针对不同靶点的药物联合治疗是目前重要的探索方向。在此,本文结合了近年来关于GIST联合靶向治疗的研究进展,包括两种TKI联合治疗、TKI与下游通路抑制剂联合治疗等,旨在对晚期GIST联合治疗的有效性及安全性进行全面的分析和讨论。     

慢性粒细胞白血病靶向治疗研究进展

酪氨酸激酶抑制剂（TKI）的应用革命性地改善了慢性粒细胞白血病（CML）患者的治疗结果和生存。当前治疗CML的新目标是如何获得持续的深度分子生物学反应,以减少耐药复发,甚至实现无治疗的缓解维持和治愈。国际上已有4种TKI获批用于一线治疗初诊的慢性期CML,并且不断有新的药物和治疗方案在研发和临床研究中。文章结合第62届美国血液学会年会相关报道介绍CML靶向治疗研究进展。     

侵袭性纤维瘤的靶向治疗进展

侵袭性纤维瘤（aggressive fibromatosis,AF）,又称韧带样型纤维瘤病、韧带样肿瘤（desmoid tumor,DT）、肌肉腱膜纤维瘤病等。AF是一种介于良、恶性之间的肿瘤,虽然无包膜,局部浸润周围组织,可能是多灶性的,并且在术后易复发,但不易发生转移。目前,对于AF的治疗方法主要包括积极监测、手术、放疗、化疗、靶向治疗、内分泌与非甾体类药物治疗等。靶向治疗AF在过去的研究进展较为缓慢,疗效有限,因此通常被应用于其他常规治疗方法失败之后,作为补救治疗手段。但近年来随着靶向治疗基础研究的快速进展,一些新的靶向药物越来越多的用于AF的临床治疗,并且获得了较好的疗效。因此,如何预测这些靶向药物对AF治疗的疗效,其治疗机制又是如何,均是目前靶向治疗AF研究的热点。本文将就AF的靶向治疗新进展进行综述。      

卵巢癌靶向治疗研究进展

靶向治疗作为一种新的肿瘤治疗手段,能够提高药物对肿瘤细胞的杀伤力,而同时减少对正常组织器官的不良作用,已逐步应用于临床治疗,且在卵巢癌的治疗中较传统治疗方式显示出明显优势。本文分别从单克隆抗体、酪氨酸激酶、肿瘤血管生成、基因治疗、光动力学治疗五个侧面对靶向治疗在卵巢癌治的研究现况、治疗应用及前景进行了总结及瞻望。     

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。     

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。     

慢性粒细胞白血病靶向治疗和靶向鸡尾酒疗法研究进展

酪氨酸激酶抑制剂（TKI）的应用显著改善了慢性粒细胞白血病（CML）患者的预后,但目前单用 TKI 仍难以根治 CML。除更有效 TKI 类药物的研发及现有药物的精确使用外,CML 其他分子靶点的开发、针对 CML 肿瘤干细胞的治疗研究和联合用药为改进治疗和治愈 CML 带来新的希望。文章就相关研究进展进行综述。     

非小细胞肺癌靶向治疗研究进展

靶向针对表皮生长因子受体(EGFR)和血管内皮生长因子受体(VEGFR)的药物已取得临床获益,部分针对其他通路的新药也已在临床试验阶段.通过对患者生物标志物的测定,对其进行合理的靶向药物治疗将取得更大的临床获益.文章对非小细胞肺癌生物靶向治疗药物的研究进展及靶向药物的联合治疗进行综述.     

靶向药物在乳腺癌辅助治疗中的进展

随着肿瘤分子生物学研究的进展,以基因分子为靶点的靶向治疗成为乳腺癌辅助治疗的热点。其中以赫赛汀（herceptin）为代表的靶向药物已经被应用于临床,呈现出喜人前景。现就有关乳腺癌靶向治疗的新作用靶点和新型药物的研究,以及大规模前瞻性临床试验评价的结论作一综述。     

Targeted therapies for the treatment of breast cancer in the post-trastuzumab era

Targeted therapies for breast cancer are evolving rapidly. Trastuzumab has revolutionized breast cancer treatment and outcome, reducing the risk for recurrence and significantly increasing survival, at least for a subgroup of patients. Other targeted therapies, such as bevacizumab, a monoclonal antibody targeting angiogenesis, lapatinib, a dual human epidermal growth factor receptor (HER)‐1 and HER‐2 inhibitor, other small‐molecule tyrosine kinase inhibitors, and mammalian target of rapamycin inhibitors, have been developed in phase II and III clinical trials. Although there has been rapid approval of these new drugs by health authorities, some questions have emerged about their application in clinical practice. What is the appropriate drug or sequence of drugs? What is the ideal target? How should tumor response be evaluated? Are financial resources sufficient to treat patients? How do we design trials with these molecules? These are emerging as current dilemmas for clinical oncologists.     

Targeted therapies for renal cell carcinoma

Renal cell carcinoma (RCC) is the sixth leading cause of cancer-related deaths and is responsible for an estimated 95,000 deaths worldwide. Metastatic RCC is refractory to radiation therapy and traditional chemotherapy. Treatment of metastatic RCC with either interleukin 2 (IL-2) or interferon-alfa (IFN-α) has demonstrated a response rate of approximately 15%. Identification of and research into the von Hippel-Lindau (VHL) gene has led to the development of multi-kinase inhibitors and other novel molecular targeting therapies. Sunitinib and sorafenib are now commercially available agents that can improve progression-free survival. Additional targeting agents are currently under clinical investigation. Combination trials of molecular targeting agents and cytokines are ongoing in the metastatic setting as are trials using molecular targeting agents in the adjuvant setting. This review focuses on the recent advances of targeted therapy for RCC.     

Phase II trial of sunitinib for the therapy of progressive metastatic castration-refractory prostate cancer after previous docetaxel chemotherapy

Effective options are lacking for progressive castration-refractory prostate cancer (CRPC) after conventional chemotherapy. Sunitinib is an orally administered multitargeted tyrosine kinase inhibitor that is approved multinationally for renal cell carcinoma and gastrointestinal stromal tumors. A phase II trial was conducted to examine the efficacy and toxicities of sunitinib in metastatic CRPC progressing after 1-2 previous chemotherapy regimens including docetaxel. The primary objective was clinical progression-free survival (PFS) with a 12-week PFS > or = 30% assumed to be of interest. Secondary objectives included prostate-specific antigen (PSA) response, modulation of PSA kinetics, objective response, quality of life, pain, survival, and toxicities. Sunitinib 50 mg daily was administered orally on days 1-28 of each 6-week cycle. Patients were treated to a maximum of 8 cycles or until clinically progressive disease or intolerable toxicity.     

Review of therapeutic drug monitoring of anticancer drugs part two – Targeted therapies

Most of oral targeted therapies are tyrosine kinase inhibitors (TKIs). Oral administration generates a complex step in the pharmacokinetics (PK) of these drugs. Inter-individual PK variability is often large and variability observed in response is influenced not only by the genetic heterogeneity of drug targets, but also by the pharmacogenetic background of the patient (e.g. cytochome P450 and ABC transporter polymorphisms), patient characteristics such as adherence to treatment and environmental factors (drug–drug interactions). Retrospective studies have shown that targeted drug exposure, reflected in the area under the plasma concentration–time curve (AUC) correlates with treatment response (efficacy/toxicity) in various cancers. Nevertheless levels of evidence for therapeutic drug monitoring (TDM) are however heterogeneous among these agents and TDM is still uncommon for the majority of them. Evidence for imatinib currently exists, others are emerging for compounds including nilotinib, dasatinib, erlotinib, sunitinib, sorafenib and mammalian target of rapamycin (mTOR) inhibitors. Applications for TDM during oral targeted therapies may best be reserved for particular situations including lack of therapeutic response, severe or unexpected toxicities, anticipated drug–drug interactions and/or concerns over adherence treatment. Interpatient PK variability observed with monoclonal antibodies (mAbs) is comparable or slightly lower to that observed with TKIs. There are still few data with these agents in favour of TDM approaches, even if data showed encouraging results with rituximab, cetuximab and bevacizumab. At this time, TDM of mAbs is not yet supported by scientific evidence. Considerable effort should be made for targeted therapies to better define concentration–effect relationships and to perform comparative randomised trials of classic dosing versus pharmacokinetically-guided adaptive dosing.     

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。     

The role of autophagy in resistance to targeted therapies

Autophagy is a self-degradative cellular process, involved in stress response such as starvation, hypoxia, and oxidative stress. This mechanism balances macro-molecule recycling to regulate cell homeostasis. In cancer, autophagy play a role in the development and progression, while several studies describe it as one of the key processes in drug resistance. In the last years, in addition to standard anti-cancer treatments such as chemotherapies and irradiation, targeted therapy became one of the most adopted strategies in clinical practices, mainly due to high specificity and reduced side effects. However, similar to standard treatments, drug resistance is the main challenge in most patients. Here, we summarize recent studies that investigated the role of autophagy in drug resistance after targeted therapy in different types of cancers. We highlight positive results and limitations of pre-clinical and clinical studies in which autophagy inhibitors are used in combination with targeted therapies.     

Targeted therapies in the treatment of advanced/metastatic NSCLC

The treatment of advanced non-small cell lung cancer (NSCLC) has evolved substantially during the last years. Chemotherapy remains the cornerstone of treatment and prolongs survival with a positive impact on quality of life. However, we seem to have reached a plateau of activity in the treatment of NSCLC. Recently, the addition of bevacizumab or cetuximab to chemotherapy doublets has improved the outcome in selected patients with advanced NSCLC. Furthermore, the use of erlotinib and gefitinib is an alternative for second line treatment. Advances in our understanding of molecular biology of cancer and mechanisms of tumourigenesis have further enabled the discovery of several potential molecular targets and development of novel ‘targeted therapies’. The purpose of this study is to review current data on the role of targeted therapies in the treatment of advanced NSCLC.     

New targets and therapies for gastrointestinal stromal tumors

Introduction: The majority of gastrointestinal stromal tumors (GIST) are driven by an abnormal receptor tyrosine kinase (RTK) signaling, occurring mainly due to somatic mutations in KIT or platelet derived growth factor receptor alpha (PDGFRA). Although the introduction of tyrosine kinase inhibitors (TKIs) has revolutionized therapy for GIST patients, with time the vast majority of them develop TKI resistance. Advances in understanding the molecular background of GIST resistance allows for the identification of new targets and the development of novel strategies to overcome or delay its occurrence.

Areas covered: The focus of this review is on novel, promising therapeutic approaches to overcome heterogeneous resistance to registered TKIs. These approaches involve new TKIs, including drugs specific for a mutated form of KIT/PDGFRA, drugs with inhibitory effect against multiple RTKs, compounds targeting dysregulated downstream signaling pathways, drugs affecting KIT expression and degradation, inhibitors of cell cycle, and immunotherapeutics.

Expert commentary: As the resistance to standard TKI treatment can be heterogeneous, a combinational approach for refractory GIST could be beneficial. Moreover, the understanding of the molecular background of resistant disease would allow development of a more personalized approach for these patients and their response to targeted therapy could be monitored closely using ‘liquid biopsy’.     

Philadelphia Chromosome–like Acute Lymphoblastic Leukemia

Philadelphia chromosome–like acute lymphoblastic leukemia (Ph-like ALL) is a recently described B-cell precursor ALL with a gene expression profile and a high frequency of IKZF1 gene alteration similar to that of Ph-positive ALL. Its prevalence is approximately 12% in children, 21% in adolescents (16-20 years of age), and 20% to 24% in adults older than 40 years, with a peak (27%) in young adults 21 to 39 years old. It occurs more often in male individuals and patients with Down syndrome. Ph-like ALL is overrepresented in those with Hispanic ethnicity and is associated with inherited genetic variants in GATA3 (rs3824662). It is a clinically and biologically heterogeneous subtype of B-ALL. Although most patients with Ph-like ALL have positive minimal residual disease after remission induction and poor event-free survival, approximately 40% of pediatric patients responded well to chemotherapy and can be cured with relatively low intensity of treatment. The treatment outcome correlated negatively with increasing age at presentation. Ph-like ALL is characterized by a wide range of genetic alterations that dysregulate several cytokine receptor and kinase signaling pathways, including CRLF2 rearrangement in half of the cases and translocation of nonreceptor tyrosine kinases (predominantly ABL-class and Janus kinases). Patients with ABL-class fusions respond clinically to ABL1 tyrosine kinase inhibitors, whereas mutations activating the JAK-STAT pathway are amendable to treatment with JAK inhibitors in vitro or in preclinical models. Prospective studies are needed to determine if incorporation of tyrosine kinase inhibitor targeting kinase alterations into intensive chemotherapy regimens will improve outcome of patients with Ph-like ALL.