Drug development in pancreatic cancer: finally,biology begets therapy

Pancreatic cancer is rarely curable, and only 5% of patients achieve long-term survival. The vast majority of patients present with metastatic or unresectable disease. Standard chemotherapy with gemcitabine provides clinical benefit to only a small minority of patients. Thus, the development and investigation of new therapies is clearly needed. As knowledge of the underlying biology of pancreatic cancer has increased, targeted therapies based upon preclinical laboratory work have been developed, and are entering clinical trials. Some of these agents lack traditional dose-limiting toxicities (DLTs) at biologically active doses, and therefore clinical evaluation may not follow traditional guidelines for cytotoxic drug development. This article focuses on targeted therapies currently undergoing clinical evaluation in pancreatic cancer. Classes of therapeutics reviewed include those targeting tumor-microenvironment interactions (matrix metalloproteinase inhibitors, vascular endothelial growth-factor blockade), signal transduction (e.g., farnesyltransferase inhibitors), growth-factor receptors (epidermal growth-factor receptor blockade, Her-2/neu, gastrin), and vaccine approaches. Currently, there is a renewed optimism that the clinical application of biologic understanding will lead to an improved outcome for patients with pancreatic cancer.     

Targeted therapies in gastric cancer and future perspectives

Advanced gastric cancer(AGC) is associated with a high mortality rate and, despite multiple new chemotherapy options, the survival rates of patients with AGC remains poor. After the discovery of targeted therapies, research has focused on the new treatment options for AGC. In the last two decades, many targeted molecules were developed against AGC. Currently, two targeted therapy molecules have been approved for patients with AGC. In 2010, trastuzumab was the first molecule shown to improve survival in patients with HER2-positive AGC as part of a first-line combination regimen. In 2014, ramucirumab was the second targeted molecule to improve survival rates and was suggested as treatment for patients with AGC who had progressed after firstline platinum plus fluoropyrimidine with or without anthracycline chemotherapy. Ramucirumab was the first targeted therapy acting as a single agent in patients with advanced gastroesophageal cancers. Although these two molecules were introduced into clinical use, many other promising molecules have been tested in phase Ⅰ-Ⅱ trials. It is obvious that in the near future many different targeted therapies will be in use for treatment of AGC. In this review, the current status of targeted therapies in the treatment of AGC and gastroesophageal junction tumors, including HER(2-3) inhibitors, epidermal growth factor receptor inhibitors, tyrosine kinase inhibitors, antiangiogenic agents, c-MET inhibitors, mammalian target of rapamycin inhibitors, agents against other molecular pathways fibroblast growth factor, Claudins, insulin-like growth factor, heat shock proteins, and immunotherapy, will be discussed.     

Treatment for pancreatic cancer: current therapy and continued progress

In the last decade, continued efforts in pancreas cancer research have led to the development of new, more effective therapies. Additionally, progress in understanding the molecular processes underlying the development and progression of this disease provides hope for the development of more effective treatment strategies. Recent clinical trials have provided reason for hope that novel chemotherapy combinations and molecularly targeted agents will lead to improved clinical outcomes for patients with this disease. This article will summarize the data that has led to the current standards of therapy for patients with resectable and advanced pancreatic cancer and review new treatment strategies for this disease.     

Treatment options in patients with metastatic gastric cancer:Current status and future perspectives

Despite advances in the treatment of gastric cancer,it remains the world’s second highest cause of cancer death.As gastric cancer is often diagnosed at an advanced stage,systemic chemotherapy is the mainstay of treatment for these patients.However,no standard palliative chemotherapy regimen has been accepted for patients with metastatic gastric cancer.Palliative chemotherapy including fluoropyrimidine,platin compounds,docetaxel and epirubicin prolongs survival,and improves a high quality of life to a greater extent than best supportive care.The number of clinical investigations associated with targeted agents has recently increased.Agents targeting the epidermal growth factor receptor 1 and human epidermal growth factor receptor 2(HER2)have been widely tested.Trastuzumab was the first target drug developed,and pivotal phaseⅢtrials showed improved survival when trastuzumab was integrated into cisplatin/fluoropyrimidine-based chemotherapy in patients with metastatic gastric cancer.Trastuzumab in combination with chemotherapy was thus approved to be a new standard of care for patients with HER2-positive advanced esophagogastric adenocarcinoma.Thus,the evaluation of HER2 status in all patients with metastatic gastroesophageal adenocarcinoma should be considered.Other agents targeting vascular endothelial growth factor,mammalian target of rapamycin,and other biological pathways have also been investigated in clinical trials,but showed little impact on the survival of patients.In this review,systemic chemotherapy and targeted therapies for metastatic gastric cancer in the first-and second-line setting are summarized in the light of recent advances.     

Molecular mechanisms targeting drug-resistance and metastasis in colorectal cancer: Updates and beyond

Colorectal cancer(CRC) is the third most diagnosed malignancy and a major leading cause of cancer-related deaths worldwide.Despite advances in therapeutic regimens,the number of patients presenting with metastatic CRC(mCRC) is increasing due to resistance to therapy,conferred by a small population of cancer cells,known as cancer stem cells.Targeted therapies have been highly successful in prolonging the overall survival of patients with mCRC.Agents are being developed to target key molecules inv...     

Targeted therapeutic agents for colorectal cancer

The treatment of colorectal cancer (CRC) has evolved substantially during the past decade with the advent of molecular targeted therapies. Inhibitors to the vascular endothelial growth factor and epidermal growth factor receptor (EGFR) pathways have been shown to enhance the efficacy of cytotoxic chemotherapy in patients with advanced CRC, and anti-EGFR antibodies demonstrate modest activity as monotherapeutic agents. These biologic agents have improved patient outcomes and survival and have been incorporated into routine clinical practice establishing a new standard of care. Molecular markers have recently been adopted into clinical practice with the finding that the KRAS oncogene is a predictive biomarker for anti-EGFR therapy, whereby the therapeutic benefit of anti-EGFR treatment is restricted to tumors with wild-type KRAS. The use of molecular targeted agents has fewer yet more specific toxicities compared with conventional cytotoxic drugs and enables a more personalized approach to cancer therapy. In contrast to the results for advanced CRC, targeted therapies have not shown a benefit in the adjuvant setting for patients with resected colon cancer. The goal of this review is to provide an update on the medical management of CRC, with a focus on the use of targeted therapy.     

Advanced gastric cancer (GC) and cancer of the gastro-oesophageal junction (GEJ): focus on targeted therapies

Despite recent improvements in surgical techniques and chemotherapy treatments, locally advanced/metastatic gastroesophageal junction (GEJ) and gastric cancer (GC) are still associated with poor clinical outcome. However, increased understanding of molecular mechanisms underlying carcinogenesis and its implementation in the treatment of breast, colon, lung, and other cancers in recent years have spurred focus on the development and incorporation of targeted agents in current therapeutic options for this difficult-to-treat disease. Such agents have the ability to target a variety of cancer relevant targets, including epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) and its receptor. In this review, we describe the current status of targeted therapies in the treatment of advanced GC and GEJ cancer, focusing on pre-clinical and clinical data available on monoclonal antibodies and tyrosine kinase inhibitors acting in these pathways, including completed and ongoing phase III studies.     

Diffuse large B cell lymphoma: molecular targeted therapy

Diffuse large B cell lymphoma (DLBCL) is a biologically heterogeneous disease and the most common subtype of B cell non-Hodgkin??s lymphoma in the USA. Even though it is a curable lymphoma in advanced stages, up to 40?% of patients eventually relapse or fail to achieve remission. Improved understanding of the biologic complexity of DLBCL reveals a diverse range of oncogenic driver mutations and signaling pathways that are essential for growth and survival of malignant cells. Since many of these signaling pathways can be targeted by small-molecule inhibitors, the therapy for DLBCL is currently undergoing a paradigm shift away from conventional chemotherapy and toward targeted agents that capitalize on an improved biologic understanding of the subsets with the highest risk of treatment failure. Participation in well-conducted and rationally designed clinical trials will be essential to realize the potential of these targeted agents and realize the goal of improving overall outcomes in the most common B cell lymphoma in the world.     

Molecular target therapy for gastroenteropancreatic endocrine tumours: Biological rationale and clinical perspectives

Gastroenteropancreatic endocrine tumours (GEP ETs) represent a relatively rare and heterogeneous group of neoplasms whose therapy can be challenging. The poorly differentiated, fast-growing cases are treated with chemotherapy. In the slow-growing ones, biotherapy is usually performed. Several categories of targeted therapies have been studied for their treatment in vitro and in vivo. A critical review of molecular alterations suggests a rationale for targeting angiogenesis, and the phosphatidylinositol 3 kinase (PI₃K)/AKT/mammalian target of rapamycin (mTOR) pathway. Accordingly, antiangiogenic agents and mTOR inhibitors are presently the most tested agents in phase II and III studies. Bevacizumab, some multitarget inhibitors, and mTOR inhibitors showed promising results in patients with advanced GEP ETs. A limited activity has been reported for imatinib and epidermal growth factor receptor (EGFR) inhibitors. Combinations of molecular targeted therapies with different sites of action, and somatostatin analogues may be relevant to avoid molecular escape pathways. Future trials should include more homogeneous groups of patients and pay more attention to the subgroup with progressive disease.     

Milestones in the use of chemotherapy for the management of non-small cell lung cancer (NSCLC)

NSCLC, a tobacco-caused disease which is therefore highly preventable, is responsible for about 30% of all cancer deaths. Improvements in terms of survival have been overall disappointing. A major advance has been the demonstration of the value of platinum-based chemotherapy, not only for advanced disease, but also in the adjuvant and neoadjuvant settings. The favorable impact of second line therapy has been established as well.The most exciting recent development consists in the effective use of biological targeted therapies, namely the EGFR inhibitors. In selected groups of patients, these agents can be used successfully for first line or second line therapy.It is likely that other biologically targeted therapies will be developed in a near future. These progresses will lead hopefully to a more personalized and effective treatment of NSCLC.     

Molecular genetics and targeted therapeutics in biliary tract carcinoma

The primary malignancies of the biliary tract, cholangio-carcinoma and gallbladder cancer, often present at an advanced stage and are marginally sensitive to radiation and chemotherapy. Accumulating evidence indicates that molecularly targeted agents may provide new hope for improving treatment response in biliary tract carcinoma(BTC). In this article, we provide a critical review of the pathogenesis and genetic abnormalities of biliary tract neoplasms, in addition to discussing the current and emerging targeted therapeutics in BTC. Genetic studies of biliary tumors have identified the growth factors and receptors as well as their downstream signaling pathways that control the growth and survival of biliary epithelia. Target-specific monoclonal antibodies and small molecules inhibitors directed against the signaling pathways that drive BTC growth and invasion have been developed. Numerous clinical trials designed to test these agents as either monotherapy or in combination with conventional chemotherapy have been completed or are currently underway. Research focusing on understanding the molecular basis of biliary tumorigenesis will continue to identify for targeted therapy the key mutations that drive growth and invasion of biliary neoplasms. Additional strategies that have emerged for treating this malignant disease include targeting the epigenetic alterations of BTC and immunotherapy. By integrating targeted therapy with molecular profiles of biliary tumor, we hope to provide precision treatment for patients with malignant diseases of the biliary tract.     

Targeted therapy in esophageal cancer

An increasing number of patients are diagnosed with esophageal cancer at an advanced stages, and only a small group of them can benefit from the traditional chemotherapy and radiotherapy. So far, multiple monoclonal antibodies and tyrosine kinase inhibitors have been developed, alone or in combination with traditional therapy, to improve the prognosis of patients with advanced esophageal cancer. This review summarizes the recent advances of targeted therapies against EGFR, HER2, VEGFR and c-MET in esophageal cancer. More clinical trials should be performed to evaluate the efficacy and safety of various targeted therapy regimens. Future basic research should focus on investigating the molecular mechanisms of therapeutic targets in esophageal cancer.     

Targeted therapy in advanced non-small-cell lung cancer

Molecularly targeted therapies have recently expanded the options available for patients with advanced non-small-cell lung cancer (NSCLC). Two cancer cell pathways in particular have been exploited, the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) pathway. The former has emerged as a key regulator of cancer cell proliferation and invasion, and several EGFR inhibitors have been developed. Erlotinib, a small-molecule inhibitor of the EGFR intracellular tyrosine kinase, has been found to improve survival compared with placebo in previously treated patients with advanced NSCLC and is Food and Drug Administration (FDA)-approved in this setting. Clinical and molecular predictors of response to erlotinib, such as a history of never smoking and EGFR gene mutation or amplification, are presently being evaluated to select patients for earlier therapy with erlotinib. Additional EGFR inhibitors are also being examined in randomized trials. The VEGF pathway, a key mediator of angiogenesis, has become an attractive target in multiple malignancies, including lung cancer. Bevacizumab, a monoclonal antibody to VEGF, received FDA approval for use in advanced non-squamous-cell NSCLC in 2006 after a phase III trial reported a significant survival advantage when bevacizumab was added to standard first-line chemotherapy. Small-molecule inhibitors of the VEGF receptor tyrosine kinase, such as sunitinib and sorafenib, have also shown promise in phase II trials and are being further investigated in phase III studies. Because preclinical data suggest a synergistic effect when VEGF and EGFR inhibitors are combined, the concurrent use of erlotinib and bevacizumab has additionally been evaluated in a phase II trial, with encouraging early results suggesting at least equivalent activity to standard salvage chemotherapy, with less toxicity. Several other novel agents are being examined, including inhibitors of histone deacteylases and the 26S proteosome. Research efforts are currently focusing on tailoring such therapies according to predictive clinical and molecular markers.     

Targeted therapy for the treatment of advanced non-small cell lung cancer: a review of the epidermal growth factor receptor antagonists

Lung cancer is the most common cause of cancer death. The vast majority of patients present with non-small cell lung cancer (NSCLC) in advanced inoperable stages. The current first-line treatment for patients with advanced NSCLC includes chemotherapy and palliative radiotherapy, but most patients relapse and eventually succumb to the disease. Advances in our knowledge of cancer cell biology have led to the development of specific molecular-targeted therapeutic agents. Mutations in the epidermal growth factor receptor (EGFR) have been identified in NSCLC cells, and overexpression of the EGFR and its ligands is a common feature of many cancers; therefore, EGFR has become an attractive target for various antitumor strategies. Aberrant signaling from the EGFR is known to be important in the development and progression of NSCLC. Two oral EGFR inhibitors, gefitinib and erlotinib, are small-molecule agents that selectively inhibit the intracellular tyrosine kinase activity of the EGFR. Both have demonstrated antitumor activity in patients with advanced NSCLC who have failed all prior treatment regimens. In addition, the anti-EGFR monoclonal antibody cetuximab has shown promising activity in both first-line and second-line settings in patients with advanced NSCLC. Furthermore, patients with severe comorbidities who would not be eligible for systemic chemotherapy are candidates for these targeted therapies. Finally, these agents have also been shown to be effective for relieving symptoms, maintaining stable disease, and improving quality of life without the adverse events that may be associated with cytotoxic cancer therapies. This report will review the mechanism of action, indications, contraindications, patient selection, and efficacy and side effects of this new class of compounds. It is important for pulmonologists to be aware of this class of compounds, as they can provide benefit to patients with NSCLC who may not have been previously considered for antitumor therapy.     

Growth factor receptors and related signalling pathways as targets for novel treatment strategies of hepatocellular cancer

Growth factors and their corresponding receptors are commonly overexpressed and/or dysregulated in many cancers including hepatocellular cancer （HCC）. Clinical trials indicate that growth factor receptors and their related signalling pathways play important roles in HCC cancer etiology and progression, thus providing rational targets for innovative cancer therapies. A number of strategies including monoclonal antibodies, tyrosine kinase inhibitors （＂small molecule inhibitors＂） and antisense oligonucleotides have already been evaluated for their potency to inhibit the activity and downstream signalling cascades of these receptors in HCC. First clinical trials have also shown that multi-kinase inhibition is an effective novel treatment strategy in HCC. In this respect sorafenib, an inhibitor of Raf-, VEGF- and PDGF-signalling, is the first multi-kinase inhibitor that has been approved by the FDA for the treatment of advanced HCC. Moreover, the serine-threonine kinase of mammalian target of rapamycin （mTOR） upon which the signalling of several growth factor receptors converge plays a central role in cancer cell proliferation, roTOR inhibition of HCC is currently also being studied in preclinical trials. As HCCs represent hypervascularized neoplasms, inhibition of tumour vessel formation via interfering with the VEGF/VEGFR system is another promising approach in HCC treatment. This review will summarize the current status of the various growth factor receptor-based treatment strategies and in view of the multitude of novel targeted approaches, the rationale for combination therapies for advanced HCC treatment will also be taken into account.     

Targeting epidermal growth factor receptor--are we missing the mark?

CONTEXT: Aberrant signalling through the epidermal growth factor receptor (EGFR) is associated with neoplastic cell proliferation, migration, stromal invasion, resistance to apoptosis, and angiogenesis. The high frequency of abnormalities in EGFR signalling in human carcinomas and gliomas and laboratory studies showing that inhibition of EGFRcan impair tumour growth means that EGFR is an attractive target for the development of cancer therapeutics. Among the classes of agents targeting EGFR in clinical development are monoclonal antibodies against the extracellular ligand-binding domain of the receptor, and small molecules that inhibit activation of the receptor tyrosine kinase. Although there are pharmacological and mechanistic differences between the two classes of inhibitor, preclinical studies suggest they both inhibit cell proliferation and have additive or synergistic cytotoxicity with standard therapies. Results from early clinical trials indicate that these agents are well tolerated and have anti-tumour activity. STARTING POINT: In May, 2003, the Australian Therapeutic Goods Administration and the US Food and Drug Administration approved the EGFR inhibitor gefitinib (ZD1839, Iressa) for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) previously treated with chemotherapy. The US approval was based on results of a phase 2 study of 216 patients with NSCLC, including 142 patients with refractory disease. In this subgroup, the response rate was about 10%. The approval of the drug was granted despite negative results from two randomised controlled trials in over 2000 previously untreated patients with NSCLC, which showed no benefit in survival, objective tumour response, or time to progression when gefitinib was added to chemotherapy. WHERE NEXT? Research is needed to identify and validate predictive factors that can be used to select patients with disease likely to respond to EGFR inhibitors, and to elucidate the mechanism of interaction of these agents with standard therapies and other molecularly targeted agents. Appropriately designed clinical trials are required to define the optimum dose, schedule, and sequence for these agents in combination with conventional therapies and other targeted agents.     

Epidermal growth factor receptor inhibition strategies in oncology

Molecular targeting strategies for cancer therapy are distinct from conventional chemotherapy and radiotherapy in their potential to provide increased tumor specificity. One particular molecular target of high promise in oncology is the epidermal growth factor receptor (EGFR). The EGFR is overexpressed, dysregulated or mutated in many epithelial malignancies, and EGFR activation appears important in tumor growth and progression. Advances in signal transduction biology continue to sharpen our understanding regarding specific contributions of EGFR signaling networks to cancer behavior. Two predominant classes of EGFR inhibitors have been developed including monoclonal antibodies (mAbs) that target the extracellular domain of EGFR, such as cetuximab (Erbitux), and small molecule tyrosine kinase inhibitors (TKIs) that target the receptor catalytic domain of EGFR, such as gefitinib (Iressa) and erlotinib (Tarceva). Mechanisms of action for EGFR inhibitors have been investigated in preclinical model systems. Safety, activity, pharmacokinetics and pharmacodynamics have been assessed in clinical trials. The anti-EGFR mAbs and TKIs have partially overlapping toxicity profiles, but distinct routes of administration, serum half-lives and therefore dosing schedules. Both classes of agents show clear antitumor activity, and cetuximab and gefitinib have been recently FDA approved for colorectal and lung cancer indications respectively. However, the absence of survival benefit for EGFR TKIs in combination with chemotherapy in large-scale phase III lung cancer trials in 2003 underscores a major challenge in anti-EGFR oncology therapeutics; namely to identify those tumors and patients that will respond predictably to EGFR inhibitor approaches. Newly identified mutations in the EGFR catalytic domain that appear to confer sensitivity to EGFR TKIs promise to open new doors of investigation regarding response prediction. Advances will also require enhanced molecular understanding of the overall EGFR signaling network, and improved methods to gauge the dependence of individual tumors on EGFR signaling pathways for growth advantage. Results from newly reported phase III trials in 2004 now confirm a survival advantage for the use of EGFR inhibitors in combination with high-dose radiation in head and neck cancer, and in refractory lung cancer respectively. It appears likely that EGFR inhibitors (and other rationally designed molecular growth inhibitors) will play a meaningful role in cancer therapy in the years to come.     

肺癌化疗的研究进展

本文综述和分析了近年来肺癌化疗的临床应用现状和研究新进展。包括新的细胞毒性抗肿瘤药、铂类化合物及针对关键靶点的新型抗肿瘤药,如肿瘤新生血管（TA）抑制剂、拓扑异构酶I抑制剂、微管蛋白活性抑制剂等。大量的临床实验及临床应用结果显示,这一系列新型抗肿瘤药物的研制成功,为人类最终战胜肿瘤开辟了新的途径,标志着人类对肿瘤治疗的研究已进入了一个新的阶段。     

New approaches in angiogenic targeting for colorectal cancer

Colorectal carcinoma （CRC） is one of the leading causes of cancer death worldwide. In the last decade, the addition of irinotecan and oxaliplatin to standard fluorouracil-based chemotherapy regimens have set the new benchmark of survival for patients with metastatic CRC at approximately 20 too. Despite these advances in the management of CRC, there is a strong medical need for more effective and well-tolerated therapies. The dependence of tumor growth and metastasis on blood vessels makes angiogenesis a rational target for therapy. One of the major pathways involved in this process is the vascular endothelial growth factor （VEGF） and its receptors （VEGFR）. In 2004, the first agent targeting angiogenesis, bevacizumab （BV）, was approved as an adjunct to first-line cytotoxic treatment of metastatic CRC. The role of BV as part of adjuvant treatment and in combination with other targeted therapies is the subject of ongoing trials. However, BV is associated with an increase in the risk of arterial thromboembolic events, hypertension and gastrointestinal perforations and its use must be cautious. Novel VEGFR TK inhibitors with different ranges of nanomolar potencies, selectivities, and pharmacokinetic properties are entering phase 111 trials for the treatment of cancer. Conversely, one of these novel agents, vatalanib, has been shown not to confer survival benefit in first and second-line treatment of advanced CRC. The basis of these findings is being extensively evaluated. Ongoing and new well-designed trials will define the optimal clinical application of the actual antiangiogenic agents, and, on the other hand, intensive efforts in basic research will identify new agents with different antiangiogenic approaches for the treatment of CRC. In this review we discuss and highlight current and future approaches in angiogenic targeting for CRC.     

New molecular targeted therapies for advanced non-small-cell lung cancer

Non-small-cell lung cancer (NSCLC) is a uniformly fatal disease and most patients will present with advanced stage. Treatment outcomes remain unsatisfactory, with low long-term survival rates. Standard treatment, such as palliative chemotherapy and radiotherapy, offers a median survival not exceeding 1 year. Hence, considerable efforts have started to be made in order to identify new biological agents which may safely and effectively be administered to advanced NSCLC patients. Two cancer cell pathways in particular have been exploited, the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR) pathways. However, novel targeted therapies that interfere with other dysregulated pathways in lung cancer are already in the clinic. This review outlines the most promising research approaches to the treatment of NSCLC, discussed according to the specific molecular pathway targeted.