Molecular mechanisms of drug resistance

Resistance to chemotherapy limits the effectiveness of anti-cancer drug treatment. Tumours may be intrinsically drug-resistant or develop resistance to chemotherapy during treatment. Acquired resistance is a particular problem, as tumours not only become resistant to the drugs originally used to treat them, but may also become cross-resistant to other drugs with different mechanisms of action. Resistance to chemotherapy is believed to cause treatment failure in over 90% of patients with metastatic cancer, and resistant micrometastic tumour cells may also reduce the effectiveness of chemotherapy in the adjuvant setting. Clearly, if drug resistance could be overcome, the impact on survival would be highly significant. This review focuses on molecular mechanisms of drug resistance that operate to reduce drug sensitivity in cancer cells. Drug resistance can occur at many levels, including increased drug efflux, drug inactivation, alterations in drug target, processing of drug-induced damage, and evasion of apoptosis. Advances in DNA microarray and proteomic technology, and the ongoing development of new targeted therapies have opened up new opportunities to combat drug resistance. We are now able to characterize the signalling pathways involved in regulating tumour cell response to chemotherapy more completely than ever before. This will facilitate the future development of rational combined chemotherapy regimens, in which the newer targeted therapies are used in combination with cytotoxic drugs to enhance chemotherapy activity. The ability to predict response to chemotherapy and to modulate this response with targeted therapies will permit selection of the best treatment for individual patients.     

Targeted Therapies for Solid Tumors

The therapeutic benefits of targeted clinical interventions with increased selectivity and fewer adverse effects hold great promise in the treatment of solid malignancies, both in monotherapy and in combination. Molecular targeted therapies offer increasingly customized solutions based on the targeting of multiple specific pathways essential for cancer development and metastasis, allowing the maintenance of quality of life while efficiently attacking the tumor. To date, several monoclonal antibodies (mAbs) and small-molecule inhibitors have been approved for the treatment of colorectal, breast, head and neck, non-small cell lung and renal cell cancer. A number of additional targeted therapies are currently being investigated in ongoing clinical trials in various tumor types such as lung, gastric, cervical, uterine melanoma, and brain tumors. This article describes current and newly developed targeted therapies in solid tumors, with a special focus on tyrosine kinase inhibitors. These include mAbs and small-molecule inhibitors that aim to specifically disrupt receptor signaling pathways, which are essential for proliferation, survival and migration of tumor cells.     

Cytopathology of lung cancer: moving from morphology to molecular

The recent discovery and availability of new targeted therapies for lung cancer has presented new challenges to pathologists. Since many lung cancers are diagnosed by aspiration or exfoliative cytology specimens in the primary or metastatic setting, these new therapies have had an impact on the practice of respiratory cytopathology. In particular, accurate subclassification of non-small cell carcinomas and acquisition of sufficient material for molecular studies is crucial. Balancing the need of adequate material for accurate diagnosis with the demands of clinicians to do more with less tissue has been a challenge and continues to impact the way lung cancers are approached in cytopathology. This review focuses on the changes and impact of the molecular era on the diagnosis of lung cancer in cytopathology.     

Immune consequences of kinase inhibitors in development,undergoing clinical trials and in current use in melanoma treatment

Metastatic malignant melanoma is a frequently fatal cancer. In recent years substantial therapeutic progress has occurred with the development of targeted kinase inhibitors and immunotherapeutics. Targeted therapies often result in rapid clinical benefit however responses are seldom durable. Immune therapies can result in durable disease control but responses may not be immediate. Optimal cancer therapy requires both rapid and durable cancer control and this can likely best be achieved by combining targeted therapies with immunotherapeutics. To achieve this, a detailed understanding of the immune consequences of the various kinase inhibitors, in development, clinical trial and currently used to treat melanoma is required.     

The challenge of classifying poorly differentiated tumours in the lung

The lung is a common site for primary carcinomas as well as a wide range of metastatic carcinomas and other rarer primary and secondary tumours that clinically and radiologically may mimic lung cancer. The World Health Organization classification of lung tumours is based on the morphological appearances in resected specimens. This provides a widely applicable system for classification, which, although complex, can be applied universally. The vast majority of patients with lung cancer, however, do not have their tumours resected, and the application of the same classification system to small biopsy specimens is problematic due in large part to sampling. Recognition of this has led to the widespread use of the term 'non-small cell carcinoma'. Future developments in our understanding of lung cancer and the development of novel targeted therapies may mean that in the future classification will become based more on the molecular features of tumours that predict response to therapies and prognosis rather than simple morphology. The predictive validity of such an approach using small biopsy or cytology specimens, however, still requires to be established. The problem of tumour heterogeneity, which is problematic for morphological classification, may also pose similar challenges for molecular approaches.     

Brain cancer stem cells display preferential sensitivity to Akt inhibition

Malignant brain tumors are among the most lethal cancers, and conventional therapies are largely limited to palliation. Novel therapies targeted against specific molecular pathways may offer superior efficacy and less toxicity than conventional therapies, but initial clinical trials of molecular targeted agents in brain cancer therapy have been frequently disappointing. In brain tumors and other cancers, subpopulations of tumor cells have recently been characterized by their ability to self-renew and initiate tumors. Although these cancer stem cells, or tumor initiating cells, are often only present in small numbers in human tumors, mounting evidence suggests that cancer stem cells contribute to tumor maintenance and therapeutic resistance. Thus, the development of therapies that target cancer stem cell signal transduction and biology may improve brain tumor patient survival. We now demonstrate that populations enriched for cancer stem cells are preferentially sensitive to an inhibitor of Akt, a prominent cell survival and invasion signaling node. Treatment with an Akt inhibitor more potently reduced the numbers of viable brain cancer stem cells relative to matched nonstem cancer cells associated with a preferential induction of apoptosis and a suppression of neurosphere formation. Akt inhibition also reduced the motility and invasiveness of all tumor cells but had a greater impact on cancer stem cell behaviors. Furthermore, inhibition of Akt activity in cancer stem cells increased the survival of immunocompromised mice bearing human glioma xenografts in vivo. Together, these results suggest that Akt inhibitors may function as effective anticancer stem cell therapies.     

EGFR靶向药物治疗非小细胞肺癌的研究进展

在世界范围内,肺癌是死亡率最高的恶性肿瘤,其中以非小细胞肺癌(non-small cell lung cancer,NSCLC)为主.近年来,随着人表皮生长因子受体(epidermal growth factor receptor,EGFR)突变体的发现,以吉非替尼(gefitinib)和厄洛替尼(erlotinib)为代表的EGFR酪氨酸激酶抑制剂(EGFR-TKIs)对于携带有EGFR敏感突变的NSCLC具有良好的疗效.然而,耐药问题的出现增加了临床治疗的难度,针对非小细胞肺癌的EGFR靶向治疗,目前仍有很多问题亟待解决.本文现就EGFR靶向治疗的现状与发展进行综述.     

Targeted therapy in prostate cancer

The therapeutic approach to advanced prostate cancer has seen greater changes in the last 7 years than it did in the preceding 70. Although only one of the newly approved agents that improve overall survival is a targeted agent, it is a validation of the method of pathway analysis and drug design in delivering novel, clinically usable agents. As our knowledge of the molecular circuitry of tumour invasion, metastases and treatment resistance has become more refined, the number of new, potentially useful, targets has grown exponentially. This is reflected in the vast array of diverse targeted agents that are currently being evaluated in human trials. In this review, we briefly describe some of the key pathways that are involved in the evolution of the prostate cancer 'lethal phenotype', and review the clinical activity of some of the newly approved targeted therapies or those in advanced phases of clinical development.     

Combining targeted therapy with immunotherapy. Can 1 + 1 equal more than 2?

Targeted therapies have induced high response rates and improved survival in patients with cancer. However, the long-term effectiveness of targeted therapies has been limited by the development of acquired resistance in the majority of patients. On the other hand, the modern immunotherapy strategies have been associated with durable responses but in limited number of patients. Accordingly, research efforts have been focused on examining the effects of combinations of targeted therapy and immunotherapy in several different histological subtypes of cancer. There has been accumulated evidence to suggest that targeted therapy can induce immune effects in the tumor cells, the host immune system, and the tumor microenvironment. Subsequently, clinical trials have been designed to examine the efficacy of combining immune checkpoint blockade or adoptive cell transfer with tyrosine kinase inhibitors, HER family blockade, anti-angiogenic agents, histone deacetylase inhibitors, and cancer stem cell inhibitors. To date, the combination of immunotherapy with targeted therapy has demonstrated potential as a cancer treatment strategy, but further optimizations are required and caution must be taken to avoid toxicity. The current review summarizes existing evidence and provides rationale supporting the use of combined targeted and immune-therapy approaches in patients with different types of cancer.     

Genetically informed lung cancer medicine

Knowledge of tumour mutation status has become increasingly important for the prioritization of targeted therapies for cancer. We review here the major known 'driver' mutations with therapeutic relevance in non-small cell lung cancer. We also discuss a variety of methods now being employed in molecular diagnostic laboratories to detect genetic alterations in lung tumours. A genetically-informed approach to lung cancer medicine is rapidly becoming the standard of care worldwide and should lead to improved outcomes for patients.     

Overview and update on molecular testing in non-small cell lung carcinoma utilizing endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) samples

Lung carcinoma remains one of the most frequent and aggressive human neoplasms. Fortunately, in the last decades, the increasing knowledge of the molecular mechanisms leading to cancer development has allowed the use of targeted therapies with improvement of prognosis in many patients. Clinical management has also changed after the introduction of endobronchialultrasonographic bronchoscopy that allows a conservative staging of lung tumors, avoiding the need of mediastinoscopy for lymph node staging. Lung pathologists and cytopathologists are facing the challenge of giving the more comprehensive prognostic and predictive information with ever smaller tissue or cytological samples. The aim of this review is to summarize the molecular testing for non-small cell lung carcinoma and how pathologists can contribute to the patient's outcome with a conscious management of biological samples.     

Biologic and clinical significance of HER-2/neu (cerbB-2) in breast cancer

HER-2/neu (also known as c-erbB-2) oncogene is a member of the epidermal growth factor receptor family and its amplification is one of the most common genetic alterations associated with human breast cancer. Preclinical studies have suggested that HER-2/neu overexpression enhances metastatic potential of breast cancer cells. Although some discrepancies exist in clinical studies, in general, HER-2/neu amplification is found to be associated with more aggressive clinicopathologic features. HER-2/neu amplification is also associated with drug resistance or sensitivity to specific chemotherapy and hormonal therapy regimens. Advances in breast cancer therapies in recent years have moved towards the development of tumor-specific targeted therapies. Monoclonal antibodies directed against HER-2/neu have been developed and used in clinical practice. These developments necessitate a reliable assay for assessment of HER-2/neu. This article is a review of biologic and clinical significance of HER-2/neu and summarizes HER-2/neu detection methods.     

Matrix metalloproteinase induction of Rac1b, a key effector of lung cancer progression

Lung cancer is more deadly than colon, breast, and prostate cancers combined, and treatment improvements have failed to improve prognosis significantly. Here, we identify a critical mediator of lung cancer progression, Rac1b, a tumor-associated protein with cell-transforming properties that are linked to the matrix metalloproteinase (MMP)-induced epithelial-mesenchymal transition (EMT) in lung epithelial cells. We show that expression of mouse Rac1b in lung epithelial cells of transgenic mice stimulated EMT and spontaneous tumor development and that activation of EMT by MMP-induced expression of Rac1b gave rise to lung adenocarcinoma in the transgenic mice through bypassing oncogene-induced senescence. Rac1b is expressed abundantly in stages 1 and 2 of human lung adenocarcinomas and, hence, is an attractive molecular target for the development of new therapies that prevent progression to later-stage lung cancers.     

Growth factor transduction pathways: paradigm of anti-neoplastic targeted therapy

Molecularly targeted cancer treatment has become an achievable goal thanks to systematic analysis of cancer genome as well as development of highly selective tumor targeted drugs. In many human cancers, deregulation of the RTK/RAS/MAPK pathway is the driving force of the disease. Indeed, cancer cells become addicted to such signaling, rendering them susceptible to drugs that can intercept growth factor signaling cascade at different levels. Discovery of mutations or aberrant expression of components of this cascade in radio- and chemotherapy refractory human melanoma acted as an enormous stimulus for scientist to try to identify and clinically test new therapeutic approaches blocking the RTK/RAS/MAPK cascade. These efforts not only resulted in the identification of new drugs for melanoma treatment but also in a better understanding of molecular basis of primary and secondary resistance to targeted therapies.     

Molecular pathology of lung cancer: key to personalized medicine

The majority of lung adenocarcinoma patients with epidermal growth factor receptor- (EGFR) mutated or EML4-ALK rearrangement-positive tumors are sensitive to tyrosine kinase inhibitors. Both primary and acquired resistance in a significant number of those patients to these therapies remains a major clinical problem. The specific molecular mechanisms associated with tyrosine kinase inhibitor resistance are not fully understood. Clinicopathological observations suggest that molecular alterations involving so-called 'driver mutations' could be used as markers that aid in the selection of patients most likely to benefit from targeted therapies. In this review, we summarize recent developments involving the specific molecular mechanisms and markers that have been associated with primary and acquired resistance to EGFR-targeted therapy in lung adenocarcinomas. Understanding these mechanisms may provide new treatment avenues and improve current treatment algorithms.     

Pulmonary small cell carcinoma: Review,common and uncommon differentials,genomics and management

Lung cancer is the leading cause of cancer‐related death worldwide. It is divided into sub‐categories based upon morphology, immunostaining pattern, biology, molecular profile, and/or treatment options. Up until the early 2000s when driver mutations with targeted therapies were identified in a subset of adenocarcinomas, the most critical distinction of lung carcinomas was driven by differences in treatment between small cell carcinoma (SCC) and nonsmall cell lung carcinoma (NSCLC). The distinction between SCC and NSCLC remains critical in the 21st century for management, especially for advanced stage cancer. In the vast majority of cases, morphological features are sufficient to separate SCC from other types of lung cancers. In some instances, however, cytomorphological features and immunohistochemical overlap with other tumors, limited sample availability, and/or crush artifact pose diagnostic challenges. The aim of this review is to highlight salient features of SCC and ancillary studies to distinguish it from common and uncommon potential mimickers, as well as provide updates in genomics and management.     

Karzinome der Lunge

The diagnostics of pulmonary neoplasms has considerably changed in recent years. Based on large-scale molecular characterization studies and the development of targeted therapies, precise morphological, immunohistochemical and molecular pathological tumor subtyping is now of utmost importance for evidence-based treatment decisions. This review highlights recent developments in morphological and immunohistochemical subtyping of pulmonary neoplasms, concepts of tumor progression and provides a preview of relevant changes of the forthcoming new WHO classification, which is expected to be published in 2015. It becomes apparent that a 3-step diagnostic procedure based on morphology, immunohistochemistry and molecular pathology is important to meet the requirements of an increasingly more complex, interdisciplinary care of lung cancer patients and to allow reliable, clinically meaningful tumor diagnosis.     

Targeted therapies for cancer 2004

The regulatory agency approvals in the United States and Europe of imatinib mesylate (Gleevec) for patients with bcr/abl-positive chronic myelogenous leukemia, cetuximab (Erbitux) for patients with epidermal growth factor receptor overexpressing metastatic colorectal cancer, the antiangiogenesis agent bevacizumab (Avastin), and the proteasome inhibitor bortezomib (Velcade)--and the considerable public interest in new anticancer drugs that take advantage of specific genetic defects that render the malignant cells more likely to respond to specific treatment--are driving a new era of integrated diagnostics and therapeutics. The recent discovery of a drug response predicting activating mutation in the epidermal growth factor receptor gene for patients with non-small cell lung cancer treated with gefitinib (Iressa) has intensified this interest. In this review, the history of targeted anticancer therapies is highlighted, with focus on the development of molecular diagnostics for hematologic malignancies and the emergence of trastuzumab (Herceptin), an antibody-based targeted therapy for HER-2/neu overexpressing metastatic breast cancer: The potential of pharmacogenomic strategies and the use of high-density genomic microarrays to classify and select therapy for cancer are briefly considered. This review also considers the widely held view that, in the next 5 to 10 years, the clinical application of molecular diagnostics will further revolutionize the drug discovery and development process; customize the selection, dosing, route of administration of existing and new therapeutic agents; and truly personalize medical care for cancer patients.     

Internal high linear energy transfer (LET) targeted radiotherapy for cancer

High linear energy transfer (LET) radiation for internal targeted therapy has been a long time coming on to the medical therapy scene. While fundamental principles were established many decades ago, the clinical implementation has been slow. Localized neutron capture therapy, and more recently systemic targeted alpha therapy, are at the clinical trial stage. What are the attributes of these therapies that have led a band of scientists and clinicians to dedicate so much of their careers? High LET means high energy density, causing double strand breaks in DNA, and short-range radiation, sparing adjacent normal tissues. This targeted approach complements conventional radiotherapy and chemotherapy. Such therapies fail on several fronts. Foremost is the complete lack of progress for the control of primary GBM, the holy grail for cancer therapies. Next is the inability to regress metastatic cancer on a systemic basis. This has been the task of chemotherapy, but palliation is the major application. Finally, there is the inability to inhibit the development of lethal metastatic cancer after successful treatment of the primary cancer. This review charts, from an Australian perspective, the developing role of local and systemic high LET, internal radiation therapy.     

Lung transplantation: infection, inflammation, and the microbiome

Lung transplantation is the only therapeutic option for patients with end-stage pulmonary disorders. Despite the improvements in surgical techniques and immunosuppressive therapy, allograft function and long-term survival are limited by the development of chronic lung transplant rejection. In this review, we focus on bronchiolitis obliterans syndrome (BOS) which is the major manifestation of chronic lung allograft rejection. We specifically review the effect of infection, a risk factor for BOS, cytokines/chemokines in the pathogenesis of BOS, and the potential link between the allograft microbiome and immune responses that may mediate the development of BOS. Understanding the allograft microbiome and how it relates to the pathologic mechanisms of BOS may suggest targeted therapies to improve long-term survival post-lung transplantation.