Cellular and molecular biology of small cell lung cancer: an overview.

Although the incidence of small cell lung cancer (SCLC) has declined during the past 30 years, it remains a frustrating disease to research and treat. Numerous attempts to enhance the anti-tumor effects of traditional chemotherapy for SCLC have not been successful. For any tumor to become cancerous, various genetic mutations and biologic alterations must occur in the cell that, when combined, render it a malignant neoplasm.

Tubulin inhibitors in non-small cell lung cancer: looking back and forward.

Introduction: Although the advent of target therapy for lung cancer has brought about outstanding results, this benefit is confined to a subgroup of molecularly selected patients, whereas for most non-small cell lung cancer (NSCLC) patients, chemotherapy still represents the milestone of treatment. Since their introduction into clinics, microtubule targeting agents (MTA), including vinca alkaloids and taxanes, have been extensively used for NSCLC in different settings and combinations.

Areas Covered: In this review, MTA are classified according to their mechanism of action, with a focus on the most common mechanisms of resistance.

Results of clinical trials with anti-programmed death 1/programmed death ligand 1 inhibitors in lung cancer.

One of the main hallmarks of cancer is the capability of evading immune destruction. In order to drive tumor progression, malignant cells are able to promote immunosuppressive mechanisms avoiding recognition and elimination. Increasing knowledge of the mechanisms of immune tolerance has led to the identification of several membrane receptors strongly implicated in this cancer feature: the immune checkpoints.

Immunotherapy meets targeted therapy: will this team end the war against cancer?

Cancer treatment as we know it today has dramatically changed over the last couple of decades. It has moved from non-specific treatment to personalized approaches. As oncologist, we now have further understanding of the processes leading to carcinogenesis; this has led to develop new therapeutic options.

Programmed cell death protein-1/programmed cell death ligand-1 pathway inhibition and predictive biomarkers: understanding transforming growth factor-beta role.

A deeper understanding of the key role of the immune system in regulating tumor growth and progression has led to the development of a number of immunotherapies, including cancer vaccines and immune checkpoint inhibitors. Immune checkpoint inhibitors target molecular pathways involved in immunosuppression, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway, with the goal to enhance the host's own immune anticancer response. In phase I-III trials, anti-PD-1/PD-L1 antibodies have demonstrated to be effective treatment strategies by inducing significant durable tumor responses, with manageable toxicities, in patients with various malignancies, including those traditionally considered non-immunogenic, such as non-small cell lung cancer (NSCLC).

Integrating the molecular background of targeted therapy and immunotherapy in lung cancer: a way to explore the impact of mutational landscape on tumor immunogenicity.

The results of randomized clinical trials employing immune checkpoint inhibitors for pre-treated advanced non-small-cell lung cancer (NSCLC) have recently revolutionised the standard available option for this disease setting. Nevertheless, the validation of reliable predictive biomarkers, able to define that proportion of patients most likely to benefit from immunotherapy, represents a crucial and still unsolved issue. This intensive research aimed at selecting potentially predictive biomarkers for immunotherapy is developed together with a wide range of analyses investigating the molecular profiling of lung cancer, leading to the spontaneous question of how these two parallel aspects of the same disease may coexist and influence one another.

Platelets and their role in cancer evolution and immune system.

Platelets are anucleate fragments formed from the cytoplasm of megakaryocytes and represent the smallest circulating hematopoietic cells. Thought for almost a century to possess solely hemostatic potentials, platelets actually play a much wider role in tissue regeneration and repair and interact intimately with tumor cells. On the one hand, tumor cells induce platelet aggregation, known to act as the trigger of cancer-associated thrombosis and on the other hand, platelets recruited to the tumor microenvironment interact directly with tumor cells favoring proliferation, and indirectly through the release of angiogenic and mitogenic proteins.

Moving towards a customized approach for drug development: lessons from clinical trials with immune checkpoint inhibitors in lung cancer.

Lung cancer has recently been discovered to be an immunological targetable disease, on the basis of the exciting results of the randomized trials with immune checkpoint inhibitors. Nevertheless, the survival benefit appears to not be entirely captured by the usual outcome measures, thus requiring a deep reflection about the appropriateness of the traditional statistical methodologies in this context. The intrinsic biological differences existing both in terms of mechanism of action and kinetic between immunotherapy and chemotherapy or targeted therapy, impact on patients' outcome, requiring a global revolution in the way to design clinical studies with the ideal aim to evolve towards trials carefully 'customized' on the basis of the investigational drug, the specific disease and the biological background.

Cancer stem cells and immunoresistance: clinical implications and solutions.

Tumor cells can be contained, but not eliminated, by traditional cancer therapies. A cell minor subpopulation is able to evade attack from therapies and may have cancer stem cell (CSC) characteristics, including self-renewal, multiple differentiation and tumor initiation (tumor initiating cells, or TICs). Thus, CSCs/TICs, aided by the microenvironment, produce more differentiated, metastatic cancer cells which the immune system detects and interacts with.

Circulating melanoma exosomes as diagnostic and prognosis biomarkers.

Background: Malignant melanoma is an aggressive cancer with an increasing incidence. Exosomes are actively secreted microvesicles, whose characteristics reflect those of the cell they are originated in. The aim of this study was to identify and evaluate the presence of the melanoma biomarkers MIA, S100B and tyrosinase-related protein 2 (TYRP2) in exosomes and their potential clinical utility.

cfDNA analysis from blood in melanoma.

Testing of tumor tissue remains the recommended method for detecting the presence of somatic mutations in human malignancies. V600E is the most frequent somatic point mutation in metastatic melanoma, providing a unique molecular marker for this malignancy. In addition, tumors carrying this mutation are primary candidates for BRAF-targeted therapy.

SMARCA4/BRG1 Is a Novel Prognostic Biomarker Predictive of Cisplatin-Based Chemotherapy Outcomes in Resected Non-Small Cell Lung Cancer.

Purpose: Identification of predictive biomarkers is critically needed to improve selection of patients who derive the most benefit from platinum-based chemotherapy. We hypothesized that decreased expression of SMARCA4/BRG1, a known regulator of transcription and DNA repair, is a novel predictive biomarker of increased sensitivity to adjuvant platinum-based therapies in non-small cell lung cancer (NSCLC).

Experimental Design: The prognostic value was tested using a gene-expression microarray from the Director's Challenge Lung Study (n = 440).

BIM and mTOR expression levels predict outcome to erlotinib in EGFR-mutant non-small-cell lung cancer.

BIM is a proapoptotic protein that initiates apoptosis triggered by EGFR tyrosine kinase inhibitors (TKI). mTOR negatively regulates apoptosis and may influence response to EGFR TKI. We examined mRNA expression of BIM and MTOR in 57 patients with EGFR-mutant NSCLC from the EURTAC trial.

Assessment of psychometric properties of the Postpartum Bonding Questionnaire (PBQ) in Spanish mothers.

The Postpartum Bonding Questionnaire (PBQ) was developed to assess mother-infant bonding disturbances in the postpartum period. The aim of this study was to examine the psychometric properties of the Spanish version of the PBQ in a sample of Spanish postpartum women. Eight hundred forty mothers were recruited in the postpartum visit (4-6 weeks after delivery): 513 from a gynecology unit (forming the general population sample) and 327 mothers from a perinatal psychiatry program (forming the clinical sample).

Immune checkpoint inhibitors: therapeutic advances in melanoma.

In recent years, new strategies for treating melanoma have been introduced, improving the outlook for this challenging disease. One of the most important advances has been the development of immunotherapy. The better understanding of the role of the immunological system in tumor control has paved the way for strategies to enhance the immune response against cancer cells.

Other targeted drugs in melanoma.

Targeted therapy drugs are developed against specific molecular alterations on cancer cells. Because they are "targeted" to the tumor, these therapies are more effective and better tolerated than conventional therapies such as chemotherapy. In the last decade, great advances have been made in understanding of melanoma biology and identification of molecular mechanisms involved in malignant transformation of cells.

Melanoma: oncogenic drivers and the immune system.

Advances and in-depth understanding of the biology of melanoma over the past 30 years have contributed to a change in the consideration of melanoma as one of the most therapy-resistant malignancies. The finding that oncogenic BRAF mutations drive tumor growth in up to 50% of melanomas led to a molecular therapy revolution for unresectable and metastatic disease. Moving beyond BRAF, inactivation of immune regulatory checkpoints that limit T cell responses to melanoma has provided targets for cancer immunotherapy.

Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study.

Purpose: Crizotinib confers improved progression-free survival compared with chemotherapy in anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC), but progression invariably occurs. We investigated the efficacy and safety of alectinib, a potent and selective ALK inhibitor with excellent CNS penetration, in patients with crizotinib-refractory ALK-positive NSCLC.

Patients And Methods: Alectinib 600 mg was administered orally twice daily.

Cerebrospinal fluid-derived circulating tumour DNA better represents the genomic alterations of brain tumours than plasma.

Cell-free circulating tumour DNA (ctDNA) in plasma has been shown to be informative of the genomic alterations present in tumours and has been used to monitor tumour progression and response to treatments. However, patients with brain tumours do not present with or present with low amounts of ctDNA in plasma precluding the genomic characterization of brain cancer through plasma ctDNA. Here we show that ctDNA derived from central nervous system tumours is more abundantly present in the cerebrospinal fluid (CSF) than in plasma.

Rearranged EML4-ALK fusion transcripts sequester in circulating blood platelets and enable blood-based crizotinib response monitoring in non-small-cell lung cancer.

Purpose: Non-small-cell lung cancers harboring EML4-ALK rearrangements are sensitive to crizotinib. However, despite initial response, most patients will eventually relapse, and monitoring EML4-ALK rearrangements over the course of treatment may help identify these patients. However, challenges associated with serial tumor biopsies have highlighted the need for blood-based assays for the monitoring of biomarkers.

Predictive factors for immunotherapy in melanoma.

Immunotherapy has emerged as an exciting strategy for cancer treatment. Therapeutic blockade of immune checkpoint regulators favors the ability of T cell responses to increase anti-tumor immunity. The cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death-1 (PD-1) are two T cell-inhibitory receptors with independent mechanisms of action.

Erratum to Assays for predicting and monitoring responses to lung cancer immunotherapy.

[This corrects the article on p. 87 in vol. 12, PMID: 26175924.

Advances in immunotherapy for treatment of lung cancer.

Different approaches for treating lung cancer have been developed over time, including chemotherapy, radiotherapy and targeted therapies against activating mutations. Lately, better understanding of the role of the immunological system in tumor control has opened multiple doors to implement different strategies to enhance immune response against cancer cells. It is known that tumor cells elude immune response by several mechanisms.

Pharmacogenomics in the treatment of lung cancer: an update.

Significant advances have been made in the analysis of the human genome in the first decades of the 21st century and understanding of tumor biology has matured greatly. The identification of tumor-associated mutations and the pathways involved has led to the development of targeted anticancer therapies. However, the challenge now in using chemotherapy to treat nonsmall-cell lung cancer is to identify more molecular markers predictive of drug sensitivity and determine the optimal drug sequences in order to tailor treatment to each patient.