Resistance is futile: overcoming resistance to targeted therapies in lung adenocarcinoma.

The advent of genomics has led to the identification of specific "driver" mutations in oncogenic kinases, and the development of targeted small molecule inhibitors to block their tumor-driving functions. These specific inhibitors have been a clinical success, and often significantly prolong the lives of individuals with cancer. Inevitably, however, the treated tumors recur as resistance to these targeted therapies develops. Here, we review the major mechanisms by which a cancer cell can evade targeted therapy, focusing on mechanisms of resistance to kinase inhibitors in lung cancer. We discuss the promising concept of rational upfront polytherapy in lung cancer, which involves concurrently targeting multiple proteins in critical signaling pathways in a cancer cell to prevent or delay resistance

Targeting Oncogenic BRAF: Past, Present, and Future.

Identifying recurrent somatic genetic alterations of, and dependency on, the kinase BRAF has enabled a "precision medicine" paradigm to diagnose and treat BRAF-driven tumors. Although targeted kinase inhibitors against BRAF are effective in a subset of mutant BRAF tumors, resistance to the therapy inevitably emerges. In this review, we discuss BRAF biology, both in wild-type and mutant settings. We discuss the predominant BRAF mutations and we outline therapeutic strategies to block mutant BRAF and cancer growth. We highlight common mechanistic themes that underpin different classes of resistance mechanisms against BRAF-targeted therapies and discuss tumor heterogeneity and co-occurring molecular alterations as a potential source of therapy resistance. We outline promising therapy approaches to overcome these barriers to the long-term control of BRAF-driven tumors and emphasize how an extensive understanding of these themes can offer more pre-emptive, improved therapeutic strategies

Non-Canonical Thinking for Targeting ALK-Fusion Onco-Proteins in Lung Cancer.

Anaplastic lymphoma kinase (ALK) gene rearrangements have been identified in lung cancer at 3-7% frequency, thus representing an important subset of genetic lesions that drive oncogenesis in this disease. Despite the availability of multiple FDA-approved small molecule inhibitors targeting ALK fusion proteins, drug resistance to ALK kinase inhibitors is a common problem in clinic. Thus, there is an unmet need to deepen the current understanding of genomic characteristics of ALK rearrangements and to develop novel therapeutic strategies that can overcome ALK inhibitor resistance. In this review, we present the genomic landscape of ALK fusions in the context of co-occurring mutations with other cancer-related genes, pointing to the central role of genetic epistasis (gene-gene interactions) in ALK-driven advanced-stage lung cancer. We discuss the possibility of targeting druggable domains within ALK fusion partners in addition to available strategies inhibiting the ALK kinase domain directly. Finally, we examine the potential of targeting ALK fusion-specific neoantigens in combination with other treatments, a strategy that could open a new avenue for the improved treatment of ALK positive lung cancer patients

Polarization and angular distribution of the radiation emitted in laser-assisted recombination

The effect of an intense external linear polarized radiation field on the angular distributions and polarization states of the photons emitted during the radiative recombination is investigated. It is predicted, on symmetry grounds, and corroborated by numerical calculations of approximate recombination rates, that emission of elliptically polarized photons occurs when the momentum of the electron beam is not aligned to the direction of the oscillating field. Moreover, strong modifications to the angular distributions of the emitted photons are induced by the external radiation field.Comment: 5 pages, 3 figure

Two-color ionization of hydrogen by short intense pulses

Photoelectron energy spectra resulting by the interaction of hydrogen with two short pulses having carrier frequencies, respectively, in the range of the infrared and XUV regions have been calculated. The effects of the pulse duration and timing of the X-ray pulse on the photoelectron energy spectra are discussed. Analysis of the spectra obtained for very long pulses show that certain features may be explained in terms of quantum interferences in the time domain. It is found that, depending on the duration of the X-ray pulse, ripples in the energy spectra separated by the infrared photon energy may appear. Moreover, the temporal shape of the low frequency radiation field may be inferred by the breadth of the photoelectron energy spectra.Comment: 12 pages, 8 figure

RADIATIVE RECOMBINATION IN THE PRESENCE OF A FEW CYCLE LASER PULSE

We have investigated the laser-assisted radiative recombination in the presence of a few-cycle pulse with the aim of demonstrating means of controlling such process. Within the Coulomb-Volkov approach already employed to describe the radiative recombination assisted by a monochromatic laser field, we have found that the emitted photon spectrum is affected by both the cycle number n(c) and the carrier-envelope relative phase.. In particular, it has been shown that the minimum and the maximum values of the emitted photon energy may be controlled by varying nc and.. Finally, it has been found that the enhancement of radiative recombination occurring in the presence of a monochromatic field, takes place also by using a few-cycle laser pulse

Overcoming the challenges of cancer drug resistance through bacterial-mediated therapy.

Despite tremendous efforts to fight cancer, it remains a major public health problem and a leading cause of death worldwide. With increased knowledge of cancer pathways and improved technological platforms, precision therapeutics that specifically target aberrant cancer pathways have improved patient outcomes. Nevertheless, a primary cause of unsuccessful cancer therapy remains cancer drug resistance. In this review, we summarize the broad classes of resistance to cancer therapy, particularly pharmacokinetics, the tumor microenvironment, and drug resistance mechanisms. Furthermore, we describe how bacterial-mediated cancer therapy, a bygone mode of treatment, has been revitalized by synthetic biology and is uniquely suited to address the primary resistance mechanisms that confound traditional therapies. Through genetic engineering, we discuss how bacteria can be potent anticancer agents given their tumor targeting potential, anti-tumor activity, safety, and coordinated delivery of anti-cancer drugs

A Case of Metastatic Atypical Neuroendocrine Tumor with ALK Translocation and Diffuse Brain Metastases.

A challenge in precision medicine requires identification of actionable driver mutations. Critical to such effort is the deployment of sensitive and well-validated assays for mutation detection. Although identification of such alterations within the tumor tissue remains the gold standard, many advanced non-small cell lung cancer cases have only limited tissue samples, derived from small biopsies or fine-needle aspirates, available for testing. More recently, noninvasive methods using either circulating tumor cells or tumor DNA (ctDNA) have become an alternative method for identifying molecular biomarkers and screening patients eligible for targeted therapies. In this article, we present a case of a 52-year-old never-smoking male who presented with widely metastatic atypical neuroendocrine tumor to the bones and the brain. Molecular genotyping using DNA harvested from a bone metastasis was unsuccessful due to limited material. Subsequent ctDNA analysis revealed an ALK translocation. The clinical significance of the mutation in this particular cancer type and therapeutic strategies are discussed.Key pointsTo our knowledge, this index case represents the first reported ALK translocation identified in an atypical carcinoid tumor.Liquid biopsy such as circulating tumor DNA is a feasible alternative platform for identifying sensitizing genomic alterations.Second-generation ALK inhibitors represent a new paradigm for treating ALK-positive patients with brain metastases

Detecting significant features in modeling microRNA-target interactions

MicroRNAs (miRNAs) are small non-coding RNA molecules mediating the translational repression and degradation of target mRNAs in the cell. Mature miRNAs are used as a template by the RNA-induced silencing complex (RISC) to recognize the complementary mRNAs to be regulated. Up to 60% of human genes are putative targets of one or more miRNAs. Several prediction tools are available to suggest putative miRNA targets, however, only a small part of the interaction pairs has been validated by experimental approaches. The analysis of the expression profile of the RNA fraction immunoprecipitated (IP) with the RISC proteins is an established method to detect which genes are actually regulated by the RISC machinery. In fact, genes that result over-expressed in the IP sample with respect to the whole cell lysate RNA, are considered as involved in the RISC complex, then miRNA targets. Here, we aim to find the features useful to predict which genes are overexpressed in IP, i.e. miRNA targets, without actually performing the IP experiments. To this purpose, we compiled and analyzed a novel high throughput data set suitable to unravel the features involved in the miRNA regulatory activities. We analyzed IP samples obtained by the immunoprecipitation of two RISC proteins, AGO2 and GW182. The two proteins shows different behaviors, in terms of enriched genes and features characterizing the immunoprecipitated RNA fractio. Further analysis is needed to unravel the reason of such different behavior

Procalcitonin and community-acquired pneumonia (CAP) in children

The role of procalcitonin (PCT) as a biomarker for sepsis in adults is well documented, while its role in infections affecting neonatal children remains controversial. Among these infections, Community-Acquired pneumonia (CAP) has been studied extensively, because it's the second cause of death in children in developing countries, and one of the most frequent causes of hospitalization in industrialized countries. The PubMed database and the Cochrane Library were used to search for the following keywords: CAP, procalcitonin, children. Thirteen articles were studied to determine the role of PCT in CAP management, specifically its usefulness for distinguishing pneumococcal infections from viral and unknown infections, for predicting severity and the correct antibiotic treatment. This paper focuses on the studies performed to identify the best inflammatory biomarker for CAP management. Although there is an increase in studies confirming the usefulness of PCT in CAP management in children, further studies are needed to have better understanding of its role for pediatric CAP management