Correlation of genes associated with drug response to prognosis of large cell lung carcinoma

Platinum-based chemotherapy remains the main treatment of advanced lung cancer. However, platinum resistance has become a major treatment obstacle. Novel therapies, particularly tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR-TKI) and agents that target vascular endothelial growth factor (VEGF), have improved the treatment. Both chemotherapy and targeted therapy have their molecular mechanisms. This study aimed to determine the mutation, amplification, or expression status and inter...     

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。     

乳腺癌的靶向治疗

乳腺癌靶向治疗基于分子分型为乳腺癌患者提供了一个有效和个性化治疗的选择.目前用于乳腺癌靶向治疗的药物包主要括以人表皮生长因子受体2(HER2)为靶点的药物曲妥珠单抗、帕妥珠单抗、拉帕替尼、T-DM1和以血管内皮生长因子(VEGF)为靶点的贝伐珠单抗以及以雷帕霉素靶蛋白(mTOR)为靶点的依维莫司,多项研究表明靶向治疗联合化疗能显著提高患者的无进展生存期及总生存时间.     

Novel Therapeutic Targets in Non-small Cell Lung Cancer

The development of personalized medicine with a focus on novel targeted therapies has supplanted the one-size-fits-all approach to the treatment of many cancers, including non-small cell lung cancer. Targeted therapies, if given to a patient subpopulation enriched by the presence of relevant molecular targets, can often abrogate cell signaling that perpetuates cancer progression. Critical targets activating procancer pathways include, but are not limited to, epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (MET), vascular endothelial growth factor (VEGF), VEGF receptor, GTPase KRAS (KRAS), receptor tyrosine protein kinase erbB-2 (HER2), echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA), serine/threonine-protein kinase B-raf (BRAF), and insulin-like growth factor 1 receptor (IGF-1R). Some target-directed therapies, such as epidermal growth factor receptor tyrosine kinase inhibitors and anti-VEGF monoclonal antibody, have already been approved for clinical use. Others, such as those targeted to MET, VEGFR, HER2, PIK3CA, and IGF-1R, are in clinical testing. This review describes molecular targets in non-small cell lung cancer that are in development or being clinically applied and their implications for developing novel anticancer therapies for this previously refractory malignancy.     

New therapies in HER2-positive breast cancer: A major step towards a cure of the disease?

Overexpression of the human epidermal growth factor receptor 2 (HER2) predicts a poor prognosis in metastatic breast cancer. While the introduction of HER2-targeted therapies, such as the monoclonal antibody trastuzumab and the small-molecule tyrosine kinase inhibitor lapatinib, has significantly improved outcomes in HER2+ breast cancer compared with previously available therapies, use of these targeted therapies is often limited by the development of drug resistance and tolerability issues. These limitations create the need for further development and investigation of new targeted therapies that show potent and selective inhibition of these targets or closely connected molecular pathways. Recently, several agents have demonstrated promising activity in HER2+ metastatic breast cancer, either as monotherapy or in combination therapy, including the tyrosine-kinase inhibitors neratinib (HKI-272) and afatinib (BIBW-2992) and the anti-HER2 monoclonal antibodies pertuzumab and trastuzumab-DM1 (T-DM1). Agents that target other molecular pathways, such as the vascular endothelial growth factor receptor, mammalian target of rapamycin, PI3-kinases, insulin-like growth factor (IGFR), HSP-90, and other kinases also have potential, in combination with anti-HER2 and/or other systemic therapies, to be active in this subtype of breast cancer. Innovative clinical studies are required in well-characterized patient populations to define the true clinical value of these emerging new approaches.     

Present and future evolution of advanced breast cancer therapy

Although the introduction of novel therapies and drug combinations has improved the prognosis of metastatic breast cancer, the disease remains incurable. Increased knowledge of the biology and the molecular alterations in breast cancer has facilitated the design of targeted therapies. These agents include receptor and nonreceptor tyrosine kinase inhibitors (epidermal growth factor receptor family), intracellular signaling pathways (phosphatidylinositol-3-kinase, AKT, mammalian target of rapamycin) angiogenesis inhibitors and agents that interfere with DNA repair (poly(ADP-ribose) polymerase inhibitors). In the present review, we present the most promising studies of these new targeted therapies and novel combinations of targeted therapies with cytotoxic agents.     

肝癌靶向治疗的研究进展

随着分子靶向药物的研发和临床应用,肿瘤的分子靶向治疗已成为肿瘤内科的研究热点。现有的研究结果已表明,肿瘤分子靶向治疗具有较好的安全性和有效性,尤其以多靶点Raf激酶抑制剂,表皮生长因子受体（EGFR）和血管内皮生长因子受体（VEGF）为靶点的治疗药物,已在临床中取得较好的疗效。本文就这几种治疗中具有代表性的药物进行综述,并提出今后的分子靶向治疗可能发展的方向。     

Challenges for patient selection with VEGF inhibitors

As targeted therapies for cancer become increasingly integrated into standard practice, appropriate selection of the patients most likely to benefit from these therapies is now receiving critical scrutiny. Early experience with therapies directed at targets that are definitively overactive (e.g. the bcr-abl tyrosine kinase targeted by imatinib) or over-expressed [e.g. the human epidermal growth factor receptor 2 (HER2) targeted by trastuzumab] has generated the perception that pre-treatment target assessment is a pre-requisite for therapy with all targeted agents. However, emerging evidence suggests that this is not presently feasible for anti-angiogenic agents. Despite considerable evidence for the association of intratumoral and/or plasma vascular endothelial growth factor (VEGF) levels with tumor progression and/or poor prognosis, pre-treatment VEGF levels do not appear to be predictive of response to anti-angiogenic therapy. This may possibly be due to the complexity of the angiogenic pathways and the limitations associated with current methods of VEGF detection and quantification; e.g. low assay sensitivity and lack of standardized methods could prevent detection of very small increases in VEGF, which may be clinically important in patients with tumors that are highly dependent on this growth factor. In addition to a general lack of agreement as to the relative clinical relevance of circulating versus tumor VEGF levels, the absence of a 'gold standard' VEGF detection assay and the lack of a predefined, clinically relevant cut-off pose a significant hindrance to the clinical utility of VEGF measurements for therapy selection. Given the fundamental importance of angiogenesis for tumor growth and progression, and the key role of VEGF in these processes, presently it seems appropriate to view anti-VEGF agents such as bevacizumab (Avastin) as having potential utility, independently of pre-treatment screening. Further research is needed to define the relationship between potential surrogate markers of VEGF pathway activity and clinical outcomes.     

Review of the current targeted therapies for non-small-cell lung cancer

The last decade has witnessed the development of oncogene-directed targeted therapies that have significantly changed the treatment of non-small-cell lung cancer (NSCLC). In this paper we review the data demonstrating efficacy of gefitinib, erlotinib, and afatinib, which target the epidermal growth factor receptor (EGFR), and crizotinib which targets anaplastic lymphoma kinase (ALK). We discuss the challenge of acquired resistance to these small-molecular tyrosine kinase inhibitors and review promising agents which may overcome resistance, including the EGFR T790M-targeted agents CO-1686 and AZD9291, and the ALK-targeted agents ceritinib (LDK378), AP26113, alectinib (CH/RO5424802), and others. Emerging therapies directed against other driver oncogenes in NSCLC including ROS1, HER2, and BRAF are covered as well. The identification of specific molecular targets in a significant fraction of NSCLC has led to the personalized deployment of many effective targeted therapies, with more to come.     

Integrating new targeted agents into the treatment of non-small-cell lung cancer

Lung cancer is the most common cause of cancer-related deaths worldwide, and the discovery and implementation of more effective therapy remains challenging. The development of agents that target the epidermal growth factor receptor/human epidermal growth factor receptor 1 (EGFR/HER1) signal transduction pathway have provided a class of novel targeted therapies that are applicable in the treatment of non-small-call lung cancer (NSCLC). Current challenges include the determination of how best these promising new agents can be integrated into current methods of treatment for patients with NSCLC, and clarification of the extent to which early lines of treatment can influence outcome in the later stages.     

Molecular profiling to optimize treatment in non-small cell lung cancer: a review of potential molecular targets for radiation therapy by the translational research program of the radiation therapy oncology group

Therapeutic decisions in non-small cell lung cancer (NSCLC) have been mainly based on disease stage, performance status, and co-morbidities, and rarely on histological or molecular classification. Rather than applying broad treatments to unselected patients that may result in survival increase of only weeks to months, research efforts should be, and are being, focused on identifying predictive markers for molecularly targeted therapy and determining genomic signatures that predict survival and response to specific therapies. The availability of such targeted biologics requires their use to be matched to tumors of corresponding molecular vulnerability for maximum efficacy. Molecular markers such as epidermal growth factor receptor (EGFR), K-ras, vascular endothelial growth factor (VEGF), mammalian target of rapamycin (mTOR), and anaplastic lymphoma kinase (ALK) represent potential parameters guide treatment decisions. Ultimately, identifying patients who will respond to specific therapies will allow optimal efficacy with minimal toxicity, which will result in more judicious and effective application of expensive targeted therapy as the new paradigm of personalized medicine develops.     

Added value of molecular targeted agents in oncology

The treatment of certain cancers has been revolutionised in recent years by the introduction of novel drugs designed to target specific molecular factors implicated in tumour growth. Notable examples include trastuzumab, a humanised monoclonal antibody (mAb) against human epidermal growth factor receptor (HER)-2 in women with HER2-positive breast cancer; rituximab, an anti-CD20 mAb in patients with non-Hodgkin's lymphoma; imatinib, a tyrosine kinase inhibitor in KIT-positive gastrointestinal stromal tumours and sunitinib, another tyrosine kinase inhibitor, in metastatic renal cell carcinoma. For regulatory reasons, new molecular targeted agents are first evaluated in advanced and metastatic disease, wherein they prolong survival. However, their most profound impact has been observed in the adjuvant setting, where they may contribute to curative therapy rather than mere palliation. Expansion in the use of molecular targeted therapies will have important cost implications for health care systems. Although expensive, on a monthly basis, molecular targeted therapies may not be more costly than treatments for other major chronic diseases, especially considering the contribution of cancer to the global disease burden, the associated socioeconomic costs and the long-term benefits of therapy. Nevertheless, the use of these agents must be optimised, in part using molecular biomarkers associated with drug response.     

Inhibition of angiogenesis in the treatment of non-small cell lung cancer

Angiogenesis and its role in the growth and development of metastases has become a topic of increasing importance. In non-small cell lung cancer (NSCLC), vascular endothelial growth factor (VEGF) plays an important role in angiogenesis, growth of the primary tumor, and development of metastases. In addition, elevated expression in tissue samples is a negative prognostic feature. For these reasons, VEGF is a worthy target for novel therapies. Recent clinical trials have shown that the anti-VEGF monoclonal antibody bevacizumab adds to the effect of chemotherapy in the metastatic setting. Hypertension and proteinuria are, as expected, commonly seen in this patient population, but the unexpected toxicity of life-threatening hemoptysis has also been observed. This makes careful patient selection especially important for this class of drugs. Our understanding of the VEGF pathway is increasing, as are the number of available targeted agents. In addition to the monoclonal antibody, bevacizumab, VEGF receptor tyrosine kinase inhibitors, multitargeted kinase inhibitors, and combination VEGF and epidermal growth factor receptor (EGFR) inhibition, are all being evaluated in NSCLC. Small phase I and II trials have suggested modest benefit when used alone; however, we now know that the anti-angiogenic therapies work best in combination with chemotherapy. The results of ongoing trials using these agents in combination with standard therapy will provide more insight into their potential benefit. As it is known that small tumors require angiogenesis to grow and metastasize, the use of anti-angiogenic therapies in the adjuvant setting may provide even greater benefit, and increase the potential cure rate in this population of patients. The results of well-designed phase III trials will be required to truly understand how to best use this class of targeted therapies in resectable and metastatic NSCLC. ( Cancer Sci 2007; 98: 1825–1830)     

Vascular endothelial growth factor: regulation in the mouse skin carcinogenesis model and use in antiangiogenesis cancer therapy

Of the various mechanisms responsible for tumor neovascularization, the angiogenesis process, in particular vascular endothelial growth factor (VEGF), is described here as a target for cancer therapy. While hypoxia is a trigger of tumor angiogenesis, various alterations in oncogenes and tumor suppressor genes also have been reported to induce VEGF expression in tumors. The regulation of VEGF has been investigated in chemically induced mouse squamous cell carcinoma of the skin. In this cancer model, VEGF expression appears to be dependent on ras oncogene activation as well as the epidermal growth factor receptor. Thus, in addition to VEGF, oncogene signaling pathways may be relevant targets in antiangiogenesis cancer therapies. The central role of VEGF in angiogenesis has led to the development of several drugs targeting the pathway of this growth factor. The present paper provides an overview of these drugs and their stage of development. In the near future, clinical trials using anti-VEGF drugs and other antiangiogenic agents, such as endostatin and angiostatin, will yield valuable information about their potential for cancer therapy.     

Current management of advanced non-small cell lung cancer: targeted therapy

Lung cancer is one of the most frequent causes of cancer-related death in the United States. For patients with advanced non-small cell lung cancer (NSCLC), chemotherapy, alone or in combination with radiation therapy, is considered the standard treatment. Although this treatment may result in a modest improvement in patient survival, overall prognosis of these patients remains dismal, and the treatment is nonspecific, nonselective, and toxic. Therefore, new therapeutic strategies are needed. During the past decade, several molecules that contribute to lung cancer progression and metastasis have been identified. Growth factors and proangiogenic factors have been the focus of intense research in cancer since therapeutic approaches for their inhibition do exist. The role of these factors was studied in different organs and tumors and was found to be phenotypically distinct. Several molecular targeted therapies have shown efficacy and had been approved for treatment of specific cancers. Most advanced in clinical research for lung cancer are targeted therapies that inhibit the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) signaling pathways. Others are signaling pathway inhibitors. The first targeted therapy for lung cancer is gefitinib, an EGFR inhibitor, which was approved in several countries in 2003. Goals of molecular targeted therapy studies include the following: better understanding of the exact role of particular growth factors in specific tumors; establishment of new clinical study designs for biological agents; and tailoring appropriate combinations of conventional chemotherapy and/or radiotherapy with biological therapy for specific patients. Achievement of these goals will hopefully lead to incorporation of biological therapy into the current anticancer arsenal, for the benefit of lung cancer patients.     

Genomic Alterations in Advanced Esophageal Cancer May Lead to Subtype‐Specific Therapies

The development of targeted agents for metastatic esophageal or gastroesophageal junction (GEJ) tumors has been limited when compared with that for other common tumors. To date, the anti‐human epidermal growth factor receptor‐2 (HER‐2) antibody, trastuzumab, in combination with chemotherapy, is the only approved novel agent for these cancers, and its use is limited to the small population of patients whose tumors overexpress HER‐2. Despite recent progress in the field, median overall survival remains only 8–12 months for patients with stage IV esophageal or GEJ cancer. In this article, we examine the molecular aberrations thought to drive the development and spread of esophageal cancer and identify promising targets for specific tumor inhibition. Data from clinical studies of targeted agents are reviewed, including epidermal growth factor receptor antibodies, tyrosine kinase inhibitors, HER‐2, and vascular endothelial growth factor‐directed therapy. Current and future targets include MET, fibroblast growth factor receptor, and immune‐based therapies. Evidence from trials to date suggests that molecularly unselected patient cohorts derive minimal benefit from most target‐specific agents, suggesting that future collaborative investigation should focus on preselected molecular subgroups of patients with this challenging heterogeneous disease.     

Reappraisal of the role of bevacizumab in the therapeutic strategy in advanced renal cell carcinoma

Increased understanding of the molecular pathophysiology of metastatic renal cell carcinoma (mRCC) has led to development of antiangiogenic therapies in the past 5 years that significantly improved the prognosis. Vascular endothelial growth factor (VEGF) is a major growth factor in tumor angiogenesis and is implicated in tumor progression of several types of cancer, including mRCC. Use of 2 distinct approaches resulted in clinical efficacy in blocking the VEGF pathway: small molecule tyrosine kinase inhibitors (sunitinib, sorafenib, axitinib, pazopanib) and the humanized anti-VEGF monoclonal antibody bevacizumab that binds circulating VEGF and prevents activation of the VEGF receptor. In the 2 large phase III trials AVOREN and CALGB 90206, bevacizumab combined with interferon alfa demonstrated its efficacy as a first-line therapy in terms of progression-free survival. Nevertheless, in the era of targeted therapies, other studies are still needed to better obtain the maximal clinical benefit of bevacizumab. The aim of this overview is to report the current role of bevacizumab in the treatment of metastatic kidney cancer and to highlight possible combinations or sequential strategies that involve other targeted agents.     

Novel targeted therapeutics for metastatic castration-resistant prostate cancer

Virtually all patients that succumb to prostate cancer die of metastatic castration-resistant disease. Although docetaxel is the standard of care for these patients and is associated with a modest prolongation of survival, there is an urgent need for novel treatment strategies for metastatic prostate cancer. In the last several years, great strides have been made in our understanding of the biological and molecular mechanisms driving prostate cancer growth and progression, and this has resulted in widespread clinical testing of numerous new targeted therapies. This review discusses some of the key therapeutic agents that have emerged for the treatment of metastatic castration-resistant prostate cancer in the last 5 years, with an emphasis on both molecular targets and clinical trial design. These agents include mammalian target of rapamycin (mTOR) pathway inhibitors, anti-angiogenic drugs, epidermal growth factor receptor (EGFR) inhibitors, insulin-like growth factor (IGF) pathway inhibitors, apoptosis-inducing drugs, endothelin receptor antagonists, receptor activator of nuclear factor κB (RANK) ligand inhibitors, vitamin D analogues, cytochrome P17 enzyme inhibitors, androgen receptor modulators, epigenetic therapies, vaccine therapies, and cytotoxic T lymphocyte-associated antigen (CTLA)-4 blocking agents.     

Targeted therapy of metastatic breast cancer

Breast cancer is a heterogeneous disease characterised by a dysregulation of multiple pathways related to cell differentiation, cell cycle control, apoptosis, angiogenesis and development of metastasis. Acting against these pathways provides therapeutic targets for new targeted biologic therapies, which, in the future, might constitute a key for fighting cancer. The development of molecular technology in recent years has allowed a further comprehension of these mutations and dysregulated pathways leading to oncogenesis. New targeted biologic therapies will block essential functions of cancer cells and tumour stroma. A growing number of therapy options, alone or in combination with background treatments (chemotherapy, hormone therapy, radiotherapy), will allow oncologists a better adaptation of treatment to patients and disease characteristics. Examples of approved targeted agents in breast cancer include agents targeting the human epidermal growth factor receptor 2 (HER2), such as trastuzumab, lapatinib and the anti-VEGF bevacizumab. In addition, there are other therapy classes under evaluation, including novel antiEGFR or antiHER2 therapies; agents fighting other tyrosine kinases, including the Src and the insulin-like growth factor receptor; agents interfering critically relevant pathways, such as PI3K/AKT/mTOR inhibitors; and agents promoting apoptosis, such as PARP inhibitors (for particular breast cancer subtypes, such as basal-like, or breast cancer with BRCA mutations) and others. The better selectivity against malignant cells of these therapies, when compared to conventional chemotherapy, gives, a priori, at least two advantages to biologic treatments: fewer side effects and a more individualised treatment of cancer depending on the tumour’s molecular characteristics. The ability to identify patients’ subgroups and response predicting factors will be crucial in obtaining the greatest benefit with minimal toxicity levels. Unsolved questions remain, such as appropriate patient selection based on the expression of the therapeutic target in the tumour, the study of the efficacy of the drug in not so extensively pretreated populations and with a greater chance of response, the use of new pharmacodynamic models to help to define new response predicting factors for a specific new biologic therapy, the combined and rational use of different biologic therapies having different molecular targets and fighting the same target through a complementary mechanism of action that might improve clinical efficacy.     

Molecularly Targeted Therapy for Metastatic Colon Cancer: Proven Treatments and Promising New Agents

There has been a dramatic upsurge in the investigation of molecularly targeted therapy in colorectal cancer over the past two decades, with the first success being bevacizumab, a monoclonal antibody directed at vascular endothelial growth factor (VEGF). The latest additions to our armament are epidermal growth factor receptor (EGFR) inhibitors and the discovery of K-ras mutation’s impact on treatment efficacy. This review summarizes the new therapies targeting established pathways, such as VEGF and EGFR, and introduces tyrosine kinase inhibitors and monoclonal antibodies, as well as exciting novel agents targeting insulin-like growth factor, tumor necrosis factor, the Sonic Hedgehog pathway, Src kinase, mammalian target of rapamycin, and protein kinase C, which already have shown activity in other cancers and are currently being studied in phase 1/2 trials in metastatic colorectal cancer.