Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling

Although patients with advanced refractory solid tumors have poor prognosis, the clinical development of targeted protein kinase inhibitors offers hope for the future treatment of many cancers. In vivo and in vitro studies have shown that the oral multikinase inhibitor, sorafenib, inhibits tumor growth and disrupts tumor microvasculature through antiproliferative, antiangiogenic, and/or proapoptotic effects. Sorafenib has shown antitumor activity in phase II/III trials involving patients with advanced renal cell carcinoma and hepatocellular carcinoma. The multiple molecular targets of sorafenib (the serine/threonine kinase Raf and receptor tyrosine kinases) may explain its broad preclinical and clinical activity. This review highlights the antitumor activity of sorafenib across a variety of tumor types, including renal cell, hepatocellular, breast, and colorectal carcinomas in the preclinical setting. In particular, preclinical evidence that supports the different mechanisms of action of sorafenib is discussed.     

Rindopepimut, a 14-mer injectable peptide vaccine against EGFRvIII for the potential treatment of glioblastoma multiforme

Celldex Therapeutics is developing rindopepimut (CDX-110), a 14-mer injectable peptide vaccine for the potential treatment of glioblastoma multiforme (GBM). Rindopepimut specifically targets a novel junctional epitope of the EGFR deletion mutant EGFRvIII, which is a constitutively active receptor that is expressed in approximately 60 to 70% of patients with GBM. EGFRvIII expression is correlated with worse prognosis and reduced overall survival. Importantly, EGFRvIII is not expressed in normal brain tissue, making it an excellent therapeutic target. Preclinical studies demonstrated lasting tumor regression and increased survival times, as well as efficient generation of EGFRvIII-specific humoral and cellular immune responses, in animals expressing EGFRvIII and vaccinated with rindopepimut. Phase I and II clinical trials in patients with GBM demonstrated significantly increased median time to progression and overall survival time in those vaccinated with rindopepimut compared with matched historical controls. Only limited side effects have been observed in patients. Given these results, rindopepimut is an extremely promising therapy for patients with GBM. Phase I and II clinical trials in patients with GBM were ongoing at the time of publication. In the future, it may be beneficial to combine rindopepimut with other treatment modalities to further prolong survival.     

RNA interference therapy for glioblastoma

Importance of the field: Despite numerous advances made during the last decade in brain tumor therapy, the prognosis of glioblastoma has not improved and these tumors inevitably recur with no effective treatment. Thus, any new therapeutic strategy to target this most malignant tumor will be of significant benefit. RNAi is a powful gene silencing method that might be used in combination with other agents to improve the efficacy of glioblastoma treatment.

Areas covered in this review: Recent progress and challenges of pre-clinical and clinical research of RNAi therapy for glioblastoma. The review covers literature from 2003 to 2009.

What the reader will gain: The principle of RNA interference therapy, three categories of RNAi triggers, different RNAi delivery system and pre-clinical and clinical studies that are currently underway to evaluate the validity of RNAi as a potential therapeutic strategy against glioblastoma are discussed.

Take home message: RNA inference therapy combined with other therapeutics may offer therapeutic potential for glioblastoma multiforme. Further studies are required to develop more efficient and specific delivery systems, select suitable gene targets, optimize treatment dose and administration schedule, evaluate the efficacy of combination treatment strategies, establish a validated clinical response measure system etc.     

microRNA regulation of cell viability and drug sensitivity in lung cancer

Introduction: microRNAs (miRNAs) are 19 - 23 nucleotide long RNAs found in multiple organisms that regulate gene expression and have been shown to play important roles in tumorigenesis. In the context of lung cancer, numerous studies have shown that tumor suppressor genes and oncogenes that play crucial roles in lung tumor development and progression are targets of miRNA regulation. Manipulation of miRNA levels that modulate lung cancer cell survival and drug sensitivity can therefore provide novel therapeutic targets and agents. Areas covered: Here, the authors review the published in vitro, in vivo and preclinical studies on the functional role of miRNAs in modulating lung cancer cell viability and drug response, and discuss the limitations and promise of translating current findings into miRNA-based therapeutic and diagnostic strategies. Expert opinion: Although many miRNAs have been identified as potent regulators of cell viability and drug sensitivity in lung cancer, most of them have not been characterized for potential clinical application. Further study is warranted to evaluate translation of the current findings to the clinic to improve the diagnosis and treatment of lung cancer. In addition, most studies have focused on non-small cell lung cancer (NSCLC). It is therefore important to raise interest in investigating miRNAs in small cell lung cancer (SCLC) as well as in comparative studies of miRNA expression and function in different histological subtypes of lung cancer.     

Barriers to carrier mediated drug and gene delivery to brain tumors.

Brain tumor patients face a poor prognosis despite significant advances in tumor imaging, neurosurgery and radiation therapy. Potent chemotherapeutic drugs fail when used to treat brain tumors because biochemical and physiological barriers limit drug delivery into the brain. In the past decade a number of strategies have been introduced to increase drug delivery into the brain parenchyma. In particular, direct drug administration into the brain tumor has shown promising results in both animal models and clinical trials. This technique is well suited for the delivery of liposome and polymer drug carriers, which have the potential to provide a sustained level of drug and to reach cellular targets with improved specificity. We will discuss the current approaches that have been used to increase drug delivery into the brain parenchyma in the context of fluid and solute transport into, through and from the brain, with a focus on liposome and polymer drug carriers.     

New Treatment Perspectives for Acute Relapses in Neuromyelitis Optica Spectrum Disorder

Neuromyelitis optica spectrum disorder (NMOSD) is a chronic autoimmune disease of the central nervous system, characterized by recurrent attacks of optic neuritis, transverse myelitis, brainstem, and/ or cerebral symptoms. Despite the current standard of care consisting of high-dose corticosteroids and therapeutic plasma exchange, many patients are left with a permanent neurological disability after each attack. With the recent advancements in understanding the pathogenic mechanisms involved in NMOSD relapses, possibilities to develop new targeted therapies are anticipated. To date, therapies targeted at inhibiting the complement cascade, inhibiting the vascular endothelial growth factor, inhibiting granulocyte migration and degranulation, and depleting B cells have been explored in phase I clinical trials, while other agents are being investigated in preclinical and early clinical trials. This review aims to discuss the potential targets for relapse treatment in NMOSD and provide the readers with a summary of the available data regarding some of the candidate agents for future application in clinical practice.     

Predictive biomarkers investigated in glioblastoma

Glioblastoma is the most aggressive primary brain tumor in adults. Consequently, new therapeutic strategies are needed. Tumor response to cytotoxic chemotherapy is heterogeneous across patients. Interestingly, predictive biomarkers of response to these classic chemotherapeutic agents have been identified in neuro-oncology (i.e., 1p/19q co-deletion, IDH mutation and O6-methylguanine DNA-methyltransferase promoter methylation). The most emblematic biomarker in glioblastoma is O6-methylguanine DNA-methyltransferase promoter methylation that predicts response to temozolomide. In parallel, innovative drugs are emerging. Some of these agents have shown some activity but in a limited number of glioblastoma patients. One of the major challenges is to identify molecular predictors of response to these smart drugs for an efficient personalized medicine. These novel agents have been tested in clinical trials enrolling glioblastoma patients. Although none of them has been validated prospectively in Phase III clinical trials, interesting molecular predictors of response to these drugs have been investigated and are presented in this review, which also reports more advanced biomarkers.     

microRNA regulation of cell viability and drug sensitivity in lung cancer

Introduction: microRNAs (miRNAs) are 19 – 23 nucleotide long RNAs found in multiple organisms that regulate gene expression and have been shown to play important roles in tumorigenesis. In the context of lung cancer, numerous studies have shown that tumor suppressor genes and oncogenes that play crucial roles in lung tumor development and progression are targets of miRNA regulation. Manipulation of miRNA levels that modulate lung cancer cell survival and drug sensitivity can therefore provide novel therapeutic targets and agents.

Areas covered: Here, the authors review the published in vitro, in vivo and preclinical studies on the functional role of miRNAs in modulating lung cancer cell viability and drug response, and discuss the limitations and promise of translating current findings into miRNA-based therapeutic and diagnostic strategies.

Expert opinion: Although many miRNAs have been identified as potent regulators of cell viability and drug sensitivity in lung cancer, most of them have not been characterized for potential clinical application. Further study is warranted to evaluate translation of the current findings to the clinic to improve the diagnosis and treatment of lung cancer. In addition, most studies have focused on non-small cell lung cancer (NSCLC). It is therefore important to raise interest in investigating miRNAs in small cell lung cancer (SCLC) as well as in comparative studies of miRNA expression and function in different histological subtypes of lung cancer.     

Novel angiogenesis inhibitors for molecular target therapy of cancer

Angiogenesis, neovascularization from pre-existing vasculature, is essential to allow growth of primary solid tumors and to enable metastasis. Recent biological studies in both tumor and endothelial cells have begun to present a wide variety of molecular targets for developing angiogenesis inhibitors. Therefore, angiogenesis inhibitors including anti-angiogenic agents as well as anti-vascular targeting agents have become promising drugs in cancer chemotherapy. However current unsolved problems in anti-angiogenic therapy are the lack of surrogate markers for therapeutic efficacy, as well as of establishment of effective combinations with other therapeutic approaches including conventional anticancer therapy, radiotherapy, and immunotherapy. This article focuses on the promising drugs with anti-angiogenic activity and their molecular targets under clinical trials, as well as the significance of clinical evaluation for anti-angiogenic therapies.     

The evolving landscape of therapeutic drug development for hepatocellular carcinoma

Currently, only one drug, sorafenib, is FDA approved for the treatment of advanced hepatocellular carcinoma (HCC), achieving modest objective response rates while still conferring an overall survival benefit. Unlike other solid tumors, no oncogenic addiction loops have been validated as clinically actionable targets in HCC. Outcomes of HCC could potentially be improved if critical molecular subclasses with distinct therapeutic vulnerabilities can be identified, biomarkers that predict recurrence or progression early can be determined and key epigenetic, genetic or microenvironment drivers that determine best response to a specific targeting treatment can be uncovered.Our group and others have examined the molecular heterogeneity of hepatocellular carcinoma. We have developed a panel of patient derived xenograft models to enable focused pre-clinical drug development of rationally designed therapies in specific molecular subgroups. We observed unique patterns, including synergies, of drug activity across our molecularly diverse HCC xenografts, pointing to specific therapeutic vulnerabilities for individual tumors. These efforts inform clinical trial designs and catalyze therapeutic development. It also argues for efficient strategic allocation of patients into appropriate enriched clinical trials. Here, we will discuss some of the recent important therapeutic studies in advanced HCC and also some of the potential strategies to optimize clinical therapeutic development moving forward.     

晚期胰腺导管腺癌药物治疗进展

由于特殊的免疫抑制微环境以及缺少可作为药物靶点的驱动基因突变,胰腺导管腺癌(pancreatic ductal adenocarcinoma, PDAC)患者的预后较其他恶性肿瘤患者差。目前化疗仍是多数晚期PDAC的主要治疗手段。近年来,随着抗肿瘤药物不断更新及二代测序技术进一步普及,基因检测可指导部分晚期PDAC患者化疗与分子靶向药物治疗方案的制订。国内外指南均推荐所有晚期PDAC患者接受体系及胚系基因检测,以确定最佳治疗策略。当前,针对PDAC主要驱动基因KRAS的分子靶向药物、肿瘤疫苗及抗肿瘤代谢药物等仍处于临床研究阶段。本文将对PDAC药物治疗现状及进展作一综述。     

非小细胞肺癌罕见靶点靶向治疗最新研究进展

靶向治疗的快速发展,使非小细胞肺癌(non-small cell lung cancer,NSCLC)的治疗取得革命性突破.相较于放化疗,靶向治疗可显著提高NSCLC患者的5年生存率,改善其预后.靶向治疗针对的靶点除常见的表皮生长因子受体(epidermal growth factor receptor,EGFR)突变...     

Heat-shock proteins-based immunotherapy for advanced melanoma in the era of target therapies and immunomodulating agents

Introduction: Heat-shock proteins (HSPs) are highly conserved, stress-induced proteins that function as chaperones, stabilizing proteins and delivering peptides. Tumor-derived HSP peptide complexes (HSPPCs) induced immunity against several malignancies in preclinical models, exhibiting activity across tumor types.

Areas covered: HSPPC-based vaccination showed clinical activity in subsets of patients with different malignancies (e.g., gastric, colorectal, pancreatic, ovarian cancer, and glioblastoma). In Phase III clinical trials for advanced melanoma and renal cell carcinoma patients, HSPPC-based vaccine demonstrated an excellent safety profile, thus emerging as a flexible tumor- and patient-specific therapeutic approach.

Expert opinion: Melanoma, renal clear cell carcinoma, and glioblastoma are among suitable targets for HSP-based treatment as demonstrated by immune responses and clinical activity observed in subsets of patients, mainly those with early stage of disease and limited tumor burden. In order to further improve clinical activity, combinations of HSPPC-based vaccines with mutation-driven therapies, antiangiogenic agents, or immunomodulating monoclonal antibodies should be tested in controlled clinical trials.     

Gene therapy for malignant glioma: current clinical status.

Glioblastoma is an aggressive brain tumor with a dismal prognosis. Gene therapy may offer a new option for the treatment of these patients. Several gene therapy approaches have shown anti-tumor efficiency in experimental studies, and the first clinical trials for the treatment of malignant glioma were conducted in the 1990s. HSV-tk gene therapy has been the pioneering and most commonly used approach, but oncolytic conditionally replicating adenoviruses and herpes simplex virus mutant vectors, p53, interleukins, interferons, and antisense oligonucleotides have also been used. During the past few years, adenoviruses have become the most popular gene transfer vectors, and some recent randomized, controlled trials have shown significant anti-tumor efficacy in clinical use. However, efficient gene delivery into the brain still presents a major problem, and there is a lack of definitive phase III trials, which would avoid potential problems associated with a small number of patients, inadvertent patient selection, and overinterpretation of results based on a few long-time survivors. For clinical efficacy, median survival is one of the most rigorous endpoints. It is used here to evaluate the usefulness of various treatment approaches and current clinical status of gene therapy for malignant glioma.     

Convection-enhanced delivery of 131I-chTNT-1/B mAB for treatment of high-grade adult gliomas

INTRODUCTION: Despite treatment advances for malignant gliomas in adults, prognosis remains poor, largely due to the infiltrative and heterogeneous biology of these tumors. Response to adjuvant therapy is not always uniform and the blood-brain barrier prevents the majority of chemotherapeutics from adequately reaching primary tumor sites. These obstacles necessitate development of novel delivery methods and agents. AREAS COVERED: (131)I-chTNT-1/B mAB (Cotara) is a genetically engineered chimeric monoclonal antibody that binds to the DNA-histone H1 complex. It carries (131)I, which delivers sufficient energy to kill adjacent tumor cells. Through convection-enhanced delivery (CED) it provides radioimmunotherapy directly to the resection cavity. We review the pharmacology and clinical experience with (131)I-chTNT-1/B mAB, detailing results of completed Phase I and II trials. EXPERT OPINION: Novel agents and therapeutic modalities, such as (131)I-chTNT-1/B mAB, are of interest for treatment of malignant glioma, for which the prognosis continues to be dismal. (131)I-chTNT-1/B mAB targets tumor cells and radioisotope labeling allows radiation delivery to the tumor with sharp fall-off. Data from Phase I and II trials of CED delivery of (131)I-chTNT-1/B mAB shows it is well tolerated. Phase II trial data suggests it could be promising therapeutically, though conclusions about efficacy require further trials and clinical experience. The compound is currently in a Phase II trial for dose confirmation in patients with malignant gliomas.     

Isolation of rare circulating tumor cells in cancer patients: technical aspects and clinical implications

Circulating tumor cells (CTCs) may be detected in the blood of patients with epithelial tumors using different analytical approaches. The relative number of CTCs is low and they include a heterogeneous population of cells with diverse biological and molecular characteristics, often different from those of the respective primary tumor. Until recently, they have been difficult to detect and, even though discordant results have been reported when different methods of detection were used, they may provide prognostic and predictive information. Several antibody- or molecular-based CTC detection methods have been developed, offering hope for individualized risk assessment by utilizing CTCs as biomarkers of disease progression and drug response. Pilot studies have also shown that by utilizing methods that permit, besides enumeration, a molecular characterization of CTCs, one could better identify high-risk patients, predict response to targeted therapies, analyze gene expression profiles (in order to identify new potential drug targets) and increase our knowledge of the metastatic process. In this article we review the techniques currently utilized for isolation and characterization of CTCs and we discuss their potential utility in clinical oncology focusing on the future perspectives in this field.     

Current and future disease‐modifying therapies in multiple sclerosis

The development of disease‐modifying therapies (DMT) in multiple sclerosis (MS) has rapidly evolved over the last few years and continues to do so. Prior to the United States Food and Drug Administration approval of the immunomodulatory agent, interferon‐β1b in 1993, no other drug had been shown to alter the course of the disease in a controlled study of MS. At present, there are five licenced disease‐modifying agents in MS – interferon‐β1b, interferon‐β1a, glatiramer acetate, natalizumab and mitoxantrone. All have shown significant therapeutic efficacy in large controlled trials. However, current therapies are only partially effective and are not free from adverse effects. Moreover, available DMTs are overwhelmingly biased in favour of those with relapsing‐remitting disease. Effective treatment for progressive MS is severely limited, with only interferon‐β1b and mitoxantrone having licenced use in secondary progressive, but not primary progressive disease. Monoclonal antibodies, such as natalizumab selectively target immune pathways involved in the pathogenic process of MS. Alemtuzumab, daclizumab and rituximab are other notable monoclonal antibodies currently undergoing phase II and III trials in MS. Alemtuzumab has so far shown promising therapeutic benefit in relapsing disease, although immunological adverse effects have been a problem. Oral therapies have the benefit of improved tolerability and patient compliance compared with current parenteral treatments. Cladribine and fingolimod (FTY720) have shown encouraging results in their phase III clinical trials. It is also worth noting the evidence for starting DMT in patients with clinically isolated syndrome, whereby early treatment has shown to delay the onset of clinically definite MS in separate phase III studies.     

Molecularly targeted therapies for colorectal cancer: Strategies for implementing translational research in clinical trials

Few breakthroughs in preclinical research have translated into meaningful benefits, either in clinical terms or quality of life, for patients with advanced colorectal cancer, despite important preclinical discoveries regarding aberrant biological pathways associated with disease development and progression. The many reasons for the slow progress are diverse, ranging from the failure to codevelop biomarkers and targeted therapies, the regulatory burdens imposed on academic investigators, and the failure to collect serial tumor biopsies during clinical trials. This review discusses promising translational research that could help reduce the disparity between preclinical discovery and patient benefit, and advocate the concentration of efforts and resources on the most promising therapeutic targets in colorectal cancer, such as EGFR, VEGF and Fcγ receptor.     

Volociximab in cancer

INTRODUCTION: Volociximab is a first-in-class chimeric monoclonal antibody that targets α5β1 integrin. Preclinical studies have shown the ability of volociximab to inhibit tumor neoangiogenesis by blocking the interaction between α5β1 and fibronectin. Volociximab's safety profile, pharmacokinetics and pharmacodynamics have been established. Ongoing clinical trials are evaluating its efficacy in the treatment of different types of solid tumors as a single agent or in combination with chemotherapy. In this review we focus on the biological effect of volociximab and results of completed clinical trials. AREAS COVERED: This review summarizes the structures and functions of integrin α5β1 and its ligand fibronectin, provides an overview of the early development of volociximab, a targeted monoclonal antibody that specifically binds and inhibits activation of integrin α5β1, and discusses the relevant data from pre-clinical and clinical studies. EXPERT OPINION: Volociximab has been well tolerated as monotherapy or in combination with chemotherapy. It has shown promising activity in different types of cancer. Randomized trials are required to validate those early results.