Assessment of a Radiomic Signature Developed in a General NSCLC Cohort for Predicting Overall Survival of ALK-Positive Patients With Different Treatment Types

Background: The purpose of the study was to investigate the potential of a radiomic signature developed in a general non–small-cell lung cancer (NSCLC) cohort for predicting the overall survival of anaplastic lymphoma kinase (ALK)-positive (ALK+) patients with different treatment types. Conclusion: This preliminary study suggests that the applicability of a general signature to ALK+ patients is limited. The general radiomic signature seems to be only applicable to ALK+ patients who had received nontargeted therapy, which indicates that developing special radiomics signatures for patients treated with tyrosine kinase inhibitors might be necessary. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2019.05.005

Authors: Lyu Huang, Jiayan Chen, Weigang Hu, Xinyan Xu, Di Liu, Junmiao Wen, Jiayu Lu, Jianzhao Cao, Junhua Zhang, Yu Gu, Jiazhou Wang, Min Fan

Management of CNS disease in ALK-positive non-small cell lung cancer: Is whole brain radiotherapy still needed?

Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (3 to 5% of all non-small cell lung cancers) carries a particularly high risk of central nervous system dissemination (60% to 90%). As the use of ALK inhibitors improves treatment outcomes over chemotherapy, the determent of central nervous system metastases has become an increasingly relevant therapeutic dilemma considering young age and possible extended overall survival. The goal of brain metastases management is to optimize both overall survival and quality of life, with the high priority of neurocognitive function preservation. Unfortunately in the first year on crizotinib, the pioneering ALK inhibitors, approximately one third of these patients fail in the central nervous system, which is explained by an inadequate central nervous system drug penetration through the blood-brain barrier. Central nervous system-directed radiotherapy represents the most important strategy to control intracranial disease burden and ..... READ ARTICLE

Cancer/Radiothérapie DOI:10.1016/j.canrad.2019.03.009

Authors: A. Wrona

An exploration of solvent-front region high affinity moiety leading to novel potent ALK & ROS1 dual inhibitors with mutant-combating effects

The pyrimidine-2,4-diamine analogs exerted excellent activities in down-regulation of ALK phosphorylation. However, the prevalent drug-resistant site-mutation has gradually prevented the agents from being widely used. Herein, we conducted an exploration of high affinity moiety that bound to the solvent-front region (G1202R located) within the ATP binding site of ALK leading to the synthesis of thirty-five pyrimidine-2,4-diamine derivatives. Among these compounds, urea group was extensively derivatized which finally resulted in the identification of the ‘semi-free urea’ compound 39. All compounds were assayed cytotoxicity and enzymatic activities and 39 turned out to be the most potent one with IC50 values of 2.1, 0.91, 4.3 and 0.73 nM towards ALKwt, ALKL1196M, ALKG1202R and ROS1, respectively. The performances of 39 on ALK- & ROS1-dependent cell lines were in good accordance with enzymatic activities with IC50 values below 0.06 µM. Besides, 39 induced cell apoptosis in a dose-dependent..... READ ARTICLE

Bioorganic & Medicinal Chemistry DOI:10.1016/j.bmc.2019.115051

Authors: Hongrui Lei, Fang Jia, Meng Cao, Jie Wang, Ming Guo, Minglin Zhu, Daiying Zuo, Xin Zhai

Malignant Pleural Effusion and Its Current Management: A Review

Malignant pleural effusion (MPE) is an exudative effusion with malignant cells. MPE is a common symptom and accompanying manifestation of metastatic disease. It affects up to 15% of all patients with cancer and is the most common in lung, breast cancer, lymphoma, gynecological malignancies and malignant mesothelioma. In the last year, many studies were performed focusing on the pathophysiological mechanisms of MPE. With the advancement in molecular techniques, the importance of tumor-host cell interactions is becoming more apparent. Additionally, the process of pathogenesis is greatly affected by activating mutations of EGFR, KRAS, PIK3CA, BRAF, MET, EML4/ALK and RET, which correlate with an increased incidence of MPE. Considering all these changes, the authors aim to present a literature review of the newest findings, review of the guidelines and pathophysiological novelties in this field. Review of the just recently, after seven years published, practice guidelines, as well as analys..... READ ARTICLE

Medicina (Kaunas) DOI:10.3390/medicina55080490

Authors: Kristijan Skok, Gaja Hladnik, Anja Grm, Anton Crnjac

Definition of Synchronous Oligometastatic Non–Small Cell Lung Cancer—A Consensus Report

Introduction: Improved outcome has been shown in patients with synchronous oligometastatic (sOM) NSCLC when treated with radical intent. As a uniform definition of sOM NSCLC is lacking, we developed a definition and diagnostic criteria by a consensus process. Conclusion: A multidisciplinary consensus statement on the definition and staging of sOM NSCLC has been formulated. This statement will help to standardize inclusion criteria in future clinical trials. READ ARTICLE

Journal of Thoracic Oncology. DOI: 10.1016/j.jtho.2019.07.025

Authors: Anne-Marie C. Dingemans, Lizza E.L. Hendriks, Thierry Berghmans, Antonin Levy, Baktiar Hasan, Corinne Faivre-Finn, Matteo Giaj-Levra, Niccolò Giaj-Levra, Nicolas Girard, Laurent Greillier, Sylvie Lantuéjoul, John Edwards, Mary O’Brien, Martin Reck, Egbert F. Smit, Paul Van Schil, Pieter E. Postmus, Sara Ramella, Yolande Lievens, Mina Gaga, Nir Peled, Giorgio V. Scagliotti, Suresh Senan, Luiz Paz-Ares, Matthias Guckenberger, Fiona McDonald, Simon Ekman, Tanja Cufer, Hester Gietema, Maurizio Infante, Rafal Dziadziuszko, Solange Peters, Ramon Rami Porta, Johan Vansteenkiste, Christophe Dooms, Dirk de Ruysscher, Benjamin Besse, Silvia Novello

When Should we Irradiate the Primary in Metastatic Lung Cancer?

Metastatic lung cancer encompasses a heterogenous group of patients in terms of burdens of disease, ranging from patients with extensive metastases to those with a limited number of metastatic lesions (oligometastatic disease). Histopathological heterogeneity also exists within two broad categories, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), portraying different patterns and evolution of disease. Local consolidative therapy to the primary tumour and metastatic sites, including surgery and/or radical dose radiotherapy, is increasingly being used to improve survival outcomes, particularly in the context of oligometastatic disease, with or without the use of molecular targeted therapy and immunotherapy. Recently, randomised studies in oligometastatic NSCLC have shown that local consolidative therapy may confer a survival advantage. This review explores whether treating just the primary tumour with radiotherapy may similarly produce improved clinical outcomes. Su..... READ ARTICLE

Clinical Oncology DOI:10.1016/j.clon.2019.07.012

Authors: A. M. Shiarli, F. McDonald, D. R. Gomez

Curcumin as tyrosine kinase inhibitor in cancer treatment

Curcumin is a natural substance known for ages, exhibiting a multidirectional effect in cancer prevention and adjuvant cancer therapies. The great advantage of using nutraceuticals of vegetable origin in comparison to popular cytostatic drugs is the minimized side effect and reduced toxicity. The targets in oncological therapy are, among others, tyrosine kinases, important mediators of signaling pathways whose impaired expression is observed in many types of cancer. Unfortunately, the hydrophobic nature of the curcumin molecule often limits its bioavailability, which is why many studies focus on the chemical modification of this compound. Current research is aimed at modifying structures that improve the pharmacokinetic parameters of curcumin, e.g. the formation of nanoparticles, complexes with metals or the synthesis of curcumin derivatives with functional substituents that allow tumor targeting. The article is a review and analysis of current literature on the properties of curcumin ..... READ ARTICLE

European Journal of Medicinal Chemistry DOI:10.1016/j.ejmech.2019.07.015

Authors: A. Golonko, H. Lewandowska, R. Świsłocka, U.T. Jasińska, W. Priebe, W. Lewandowski

New promising circulating RNA biomarkers for early diagnosis of lung adenocarcinoma

Clinical practice relies in the use of specific biological parameters which can be correlated with the onset, establishment, development and therapeutic response of diseases. Biomarkers have becoming even a more relevant research topic in clinics since the foundation of the precision medicine initiatives worldwide. The choice of specific biomarkers is dependent on their sensitivity and specificity for a particular disease, but also on technical aspects related with their collection protocol, stability and detection from biological samples. In clinical oncology, early diagnosis biomarkers are very important for the prevention of the incidence of cancers, but also for the establishment of proper therapeutic strategies... Despite of the lack of knowledge about the subjacent molecular mechanisms involved in the secretion of circRNAs by cancer cells, there is increased evidence about their use as molecular circulating biomarkers for the stratification and prognosis of tumors, as illustrate..... READ ARTICLE

Annals of Translational Medicine
DOI:10.21037/atm.2019.05.70

Authors: Francisco J. Enguita

Review PaperKirk SmithJuly 1, 2019Circulating RNA biomarkers, lung adenocarcinoma

Chapter 31 - Gene Fusion in NSCLC: ALK, ROS1, RET, and Related Treatments

Lung cancer is the leading cause of death from cancer. Some 80% of all lung cancers are lung adenocarcinomas, squamous cell carcinomas, and large cell carcinomas, which are grouped as non-small cell lung cancers (NSCLCs). The recent application of oncogenomics to NSCLCs has led to a radical change in the treatment of patients with advanced disease. Starting from the recognition of recurrent mutations in the tumor, new molecularly targeted therapies have been developed that have improved the outcomes of therapy for tailored subsets of patients with genetically homogeneous tumors. Roughly 45% of the mutations in NSCLC are point mutations involving the KRAS, EGFR, and BRAF genes; minor mutations giving rise to NSCLC consist of gene fusions that act as driver mutations in about 8% of cancers and involve the ALK, ROS1, and RET genes. While standard platinum-based chemotherapy remains the gold standard of treatment for NSCLCs without any targetable mutation, targeted tyrosine kinase inhibito..... READ ARTICLE

Oncogenomics DOI:10.1016/B978-0-12-811785-9.00031-4

Authors: Raffaele Palmirotta, Davide Quaresmini, Domenica Lovero, Francesco Mannavola, Franco Dammacco, Franco Silvestris

NK92-CD16 cells are cytotoxic to non-small cell lung cancer cell lines that have acquired resistance to tyrosine kinase inhibitors

Background: Treatment with tyrosine kinase inhibitors (TKIs) has improved the outcomes for patients with non-small cell lung cancer (NSCLC) harboring targetable driver mutations. However, acquired resistance to TKIs invariably develops within approximately 1 year of treatment by various mechanisms, including gatekeeper mutations, alternative pathway activation and histological transformations. Because immunotherapy is an option for patients with drug-resistant cancers, we generated several TKI-resistant NSCLC cell lines in vitro, and then evaluated the cytotoxicity of NK92-CD16 cells to these resistant cells. Conclusion: Treatment with tyrosine kinase inhibitors (TKIs) has improved the outcomes for patients with non-small cell lung cancer (NSCLC) harboring targetable driver mutations. However, acquired resistance to TKIs invariably develops within approximately 1 year of treatment by various mechanisms, including gatekeeper mutations, alternative pathway activation and histological transformations. READ ARTICLE

Cytotherapy DOI:10.1016/j.jcyt.2019.03.312

Authors: HA-RAM PARK, YONG-OON AHN, TAE MIN KIM, SOYEON KIM, SEULKI KIM, YU SOO LEE, MISO KIM, BHUMSUK KEAM, DONG-WAN KIM, DAE SEOG HEO

Meta-analysis comparing incidence of grade 3–4 neutropenia with ALK inhibitors and chemotherapy in patients with non-small-cell lung cancer

Aim: Using the available literature, this meta-analysis aimed to compare reports of the incidence of grade 3–4 neutropenia with ALK inhibitors and chemotherapy in patients with ALK-positive NSCLC. Conclusion: This meta-analysis of Phase III randomized clinical trials found no significant difference in the incidence of grade 3–4 neutropenia among patients with ALK-positive NSCLC treated with either an ALK inhibitor or chemotherapy, and this was not affected by adjusting for baseline tumor stage. READ ARTICLE

FUTURE ONCOLOGY
DOI:10.2217/fon-2018-0863

Authors: Bernardo Rapoport, Ramin B Arani, Nicola Mathieson, Andriy Krendyukov

Computed Tomography Imaging Characteristics of Non–Small-Cell Lung Cancer With Anaplastic Lymphoma Kinase Rearrangements: A Systematic Review and Meta-Analysis

Background: Young patients are rarely diagnosed with non-small cell lung cancer (NSCLC), and little is known about its predisposing genomic alterations and survival. Conclusions: Younger patients with NSCLC had a higher frequency of gene fusions than older patients and had a trend of worse OS. READ ARTICLE

Annals of Translational Medicine DOI:10.21037/atm.2019.03.39

Authors: Shifeng Yang, Zhengbo Song, Guoping Cheng

The safety and serious adverse events of approved ALK inhibitors in malignancies: a meta-analysis

Background: A total of 2%–7% of non-small cell lung cancer (NSCLC) patients have anaplastic lymphoma kinase (ALK) mutations. At present, three or more generations of ALK inhibitors have been used for ALK-positive NSCLC treatment, including crizotinib, alectinib, ceritinib, and brigatinib. Although most adverse events (AEs) of ALK inhibitors are grades 1 to 2 and generally can be well tolerated, serious adverse events (SAEs) of ALK inhibitors lack data analysis, and the lung toxicity of ALK inhibitors needs attention. Thus, we performed this meta-analysis to evaluate the safety of ALK inhibitors, especially in terms of drug-related SAEs. Conclusion: ALK-related SAEs should draw attention, especially in terms of lung toxicity. According to this meta-analysis, alectinib seems to be the safest ALK inhibitor. Physicians should focus on related SAEs when prescribing ALK inhibitors. Given that lung cancer patients have poor pulmonary function at baseline, the lung toxicity risk of ALK inhibi..... READ ARTICLE

Cancer Management and Research
DOI:10.2147/CMAR.S190098

Authors: Helei Hou, Dantong Sun, Kewei Liu, Man Jiang, Dong Liu, Jingjuan Zhu, Na Zhou, Jing Cong, Xiaochun Zhang

Crizotinib enhances anti-CD30-LDM induced antitumor efficacy in NPM-ALK positive anaplastic large cell lymphoma

Combining antibody-drug conjugates (ADCs) with targeted small-molecule inhibitors can enhance antitumor effects beyond those attainable with monotherapy. In this study, we investigated the therapeutic combination of a CD30-targeting ADC (anti-CD30-lidamycin [LDM]) with a small-molecule inhibitor (crizotinib) of nucleophosmin-anaplastic lymphoma kinase NPM-ALK in CD30+/ALK+ anaplastic large cell lymphoma (ALCL). In vitro, anti-CD30-LDM showed strong synergistic antiproliferative activity when combined with crizotinib. Furthermore, treatment with anti-CD30-LDM plus crizotinib resulted in a stronger induction of cell apoptosis than monotherapy with either treatment. Western blot analysis revealed that ERK1/2 phosphorylation was increased in response to anti-CD30-LDM-induced DNA damage. Interestingly, the addition of crizotinib inhibited the expression of phosphorylated ERK1/2 and further augmented anti-CD30-LDM-mediated apoptosis, providing a potential synergistic mechanism for DNA-damagi..... READ ARTICLE

Cancer Letters
DOI:10.1016/j.canlet.2019.02.002

Authors: Rong Wang, Liang Li, Aijun Duan, Yi Li, Xiujun Liu, Qingfang Miao, Jianhua Gong, Yongsu Zhen

Anaplastic lymphoma kinase inhibitors in non-small cell lung cancer patients with brain metastases: a meta-analysis

Background: Patients with anaplastic lymphoma kinase (ALK) rearrangements are particularly prone to development of brain metastases (BMs). Newer anti-ALK treatments have demonstrated far greater intracranial efficacy. Here we performed a meta-analysis with the aim of assessing the efficacy of ALK inhibitors on BMs. Conclusions: Despite the limitation from lack of published clinical data, our results showed that ALK inhibitors are effective at the brain site regardless of previous anti-ALK treatments, systemic therapy with ALK inhibitors should be considered as a preferred approach over for controlling BMs from ALK-positive NSCLC. READ ARTICLE

Journal of Thoracic Disease
DOI:10.21037/jtd.2019.03.76

Authors: Zhiguo Zhang, Hongwei Guo, Yuanli Lu, Wei Hao, Lei Han

Refining precision cancer therapy in ALK-positive NSCLC

The treatment approach to advanced anaplastic lymphoma kinase fusion-positive (ALK-positive) non-small cell lung cancer (NSCLC) serves as a paradigm for precision oncology. To date, five ALK-tyrosine kinase inhibitors (TKIs)—crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib—have been approved by the US Food and Drug Administration [1,2]. Although each TKI has significant efficacy in ALK-positive NSCLC, the duration of benefit is invariably limited by the development of acquired resistance... Finally, although not addressed in this study, ALK-independent mechanisms of resistance such as bypass signaling or lineage changes remain a major therapeutic hurdle in ALK-positive NSCLC. In an analysis of 20 lorlatinib-resistant tumour biopsies, 65% did not harbour compound ALK resistance mutations [8], implicating ALK-independent resistance. The prevalence of ALK-independent resistance mechanisms will likely rise as strategies to overcome ALK mutations continue to improve. Thus, eff..... READ ARTICLE

eBioMedicine
DOI:10.1016/j.ebiom.2019.01.059

Authors: Jessica J. Lin and Alice T. Shaw

Review PaperKirk SmithMarch 1, 2019precision cancer therapy, ALK-positive, NSCLC

ALK rearrangements: Biology, detection and opportunities of therapy in non-small cell lung cancer

The ALK receptor tyrosine kinase (ALK) gene encodes a transmembrane protein rearranged in 2–7% of non-small cell lung cancer (NSCLC) cases. This gene has become the second most studied therapeutic target after EGFR due to the implied therapeutic opportunities. While the diagnostic of ALK rearrangements is well established, small molecules targeting ALK are in constant evolution because tumor cells eventually will develop mechanisms of resistance. In this review we describe the biology of the ALK gene, alterations, epidemiology, diagnostic tests as well as strategies of treatment. READ ARTICLE

Critical Reviews in Oncology/Hematology DOI:10.1016/j.critrevonc.2019.02.006

Authors: Gina Rosas, Rossana Ruiz, Jhajaira M. Araujo, Joseph A. Pinto, Luis Mas

Concomitant radiotherapy and TKI in metastatic EGFR- or ALK-mutated non-small cell lung cancer: a multicentric analysis on behalf of AIRO lung cancer study group

Purpose: To investigate the role of radiotherapy (RT) in the management of EGFR- or ALK-mutated metastatic non-small cell lung cancer (NSCLC) treated with TKI. Conclusions: SRT seems to positively affect OS with limited toxicity in selected patients. READ ARTICLE

La radiologia medica
DOI:10.1007/s11547-019-00999-w

Authors: Paolo Borghetti,, Marco Lorenzo Bonù, Rachele Giubbolini, Niccolo’ Giaj Levra, Rosario Mazzola, Marco Perna, Luca Visani, Fiammetta Meacci, Maria Taraborrelli, Luca Triggiani, Davide Franceschini, Carlo Greco, Alessio Bruni, Stefano Maria Magrini, Vieri Scotti

Review PaperKirk SmithFebruary 15, 2019Stage IV NSCLC, EGFR, ALK, Stereotactic radiotherapy, Oligoprogression

Systematic review of sequencing of ALK inhibitors in ALK-positive non-small-cell lung cancer

The objective of this study was to understand outcomes of patients treated with ALK inhibitors, especially when ALK inhibitors are followed by other ALK inhibitors. A systematic literature review was conducted in PubMed, Embase, and Cochrane through July 17, 2017. Conference abstracts (three meetings in past 2 years) also were searched. Of 504 unique publications, 80 met inclusion criteria (47 clinical trials, 33 observational studies). Observational studies have the potential to provide information for ALK inhibitors used sequentially. Ten observational studies reported median overall survival of crizotinib-led sequences ranging from 30.3 to 63.75 months from initiation of crizotinib; 49.4-89.6 months from metastatic non-small-cell lung cancer diagnosis; and 15.5-22.0 months from initiation of the second-generation ALK inhibitor after initial crizotinib. Sequencing of ALK inhibitors may benefit patients progressing on initial ALK inhibitors. READ ARTICLE

Lung Cancer: Targets and Therapy DOI:10.2147/LCTT.S179349

Authors: Barrows SM, Wright K, Copley-Merriman C, Kaye JA, Chioda M, Wiltshire R, Torgersen KM, Masters ET.

Review PaperKirk SmithFebruary 8, 2019ALK, NSCLC, carcinoma, non-small-cell lung, non-small-cell lung cancer

An overview on Vadimezan (DMXAA): The vascular disrupting agent

Vascular disrupting agents (VDAs), a group of cancer remedies, can cause a specific and irreversible destruction of established tumor vessels, and the complete halt of blood flow in the tumor. DMXAA (ASA404) or Vadimezan, a flavone-acetic acid-based drug, is the most promising VDAs that induces a rapid shutdown of blood flow in tumors but not in normal tissue. The exact mechanism of vascular disruption is unknown; however, proposed direct and indirect mechanisms of action for DMXAA comprises (i) inducing apoptosis in endothelial cells; (ii) hemorrhagic necrosis and ischemia in tumor; (iii) release of serotonin (5-HT); (vi) stimulation of innate immune system; (v) production of inflammatory cytokines, for example TNF, IL-6, GCSF, KC, IP-10, and MCP-1; (vi) activation of NFκB and p38 (MAPK); (vii) production of nitric oxide; and (viii) reducing tumor energetics and membrane turnover. Despite the remarkable results from preclinical and phase I/II, DMXAA has failed in phase III clinical tr..... READ ARTICLE

Chemical Biology and Drug Design DOI:10.1111/cbdd.13166

Authors: Amir Daei Farshchi Adli, Rana Jahanban-Esfahlan, Khaled Seidi, Sonia Samandari-Rad and Nosratollah Zarghami