A novel model of controlling PD-L1 expression in ALK+ anaplastic large cell lymphoma revealed by CRISPR screening

The success of programmed cell death protein 1 (PD-1)/PD-L1-based immunotherapy highlights the critical role played by PD-L1 in cancer progression and reveals an urgent need to develop new approaches to attenuate PD-L1 function by gaining insight into how its expression is controlled. Anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALK+ ALCL) expresses a high level of PD-L1 as a result of the constitutive activation of multiple oncogenic signaling pathways downstream of ALK activity, making it an excellent model in which to define the signaling processes responsible for PD-L1 upregulation in tumor cells. Here, using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 library screening, we sought a comprehensive understanding of the molecular effectors required for PD-L1 regulation in ALK+ ALCL. Indeed, we determined that PD-L1 induction is dependent on the nucleophosmin-ALK oncoprotein activation of STAT3, as well as a signalosome containin..... READ ARTICLE

Blood DOI:10.1182/blood.2019001043

Authors: Jing-Ping Zhang, Zhihui Song, Hong-Bo Wang, Lang Lang, Yuan-Zhong Yang, Wenming Xiao, Daniel E. Webster, Wei Wei, Stefan K. Barta, Marshall E. Kadin, Louis M. Staudt, Masao Nakagawa,Yibin Yang

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

CRISPR genome editing of murine hematopoietic stem cells to create Npm1-Alk causes ALK+ lymphoma after transplantation

Introduction: ... Here, we successfully adapted these techniques to modeling hematologic malignancy for the first time by generating Npm1-Alk in the genome of transplantable hematopoietic stem cells (HSCs). Results and discussion: ... Early animal-modeling efforts with NPM1-ALK (discussed in “Introduction”) left the cell of origin for ALK+ ALCL unclear, and it still has not been definitively revealed. Recently, Malcolm et al shed key light on this question, showing that NPM1-ALK+ thymic precursors use the fusion oncogene to bypass the β-selection checkpoint before moving to the periphery to establish systemic lymphomas.31 By engineering the endogenous translocation into a subset of HSCs, our approach may have allowed recapitulation of this process, as opposed to earlier transgenic approaches placing NPM1-ALK expression under the control of specific T-lineage promoters. Additional evidence also exists for NPM1-ALK arising in early stem or progenitor cells. Trümper et al showed in 1998 ..... READ ARTICLE

Blood Advances DOI:10.1182/bloodadvances.2018025247

Authors: Soumya Sundara Rajan, Lingxiao Li, Mercedes F. Kweh, Kranthi Kunkalla, Amit Dipak Amin, Nitin K. Agarwal, Francisco Vega, Jonathan H. Schatz

Successful salvage surgery following multimodal therapy in a patient who harboured ALK-rearranged advanced lung adenocarcinoma with multiple organ metastases

The prognosis of stage IVb non-small cell lung cancer (NSCLC) patients with multiple distant metastases or involvement of different extra-thoracic sites is poor. The prognosis following salvage surgery for patients with more than five metastases has been reported as most unfavourable. The following case is of a 71-year-old man with a 9-year survival duration after being diagnosed with stage IVb ALK-rearranged lung adenocarcinoma, who was treated for 6 years with whole-brain radiotherapy, pemetrexed-based chemotherapy, ALK-tyrosine kinase inhibitors (TKIs) including ceritinib and alectinib, and salvage sublobar resection of the primary lung cancer and who obtained treatment-free remission (TFR) for more than 3 years following surgery. READ ARTICLE

Respirology Case Reports DOI:10.1002/rcr2.451

Authors: Yoshitsugu Horio, Tetsuya Mizuno, Yukinori Sakao, Yoshitaka Inaba, Yasushi Yatabe, Toyoaki Hida"

Case StudyKirk SmithJune 24, 2019Salvage surgery, multimodal therapy, ALK, lung adenocarcinoma, metastases

Effect of bevacizumab on brain radiation necrosis in anaplastic lymphoma kinase-positive lung cancer

Central nervous system (CNS) metastases from anaplastic lymphoma kinase (ALK)-positive lung cancer often results in failure of ALK-tyrosine kinase inhibitor (TKI) therapy. Patients with uncontrolled CNS metastases receive radiation therapy, which sometimes causes brain radiation necrosis. We added bevacizumab (15 mg/kg, every 3–4 weeks) to the regimen of four ALK-positive lung cancer patients with brain radiation necrosis who were receiving ALK-TKI therapy. A decrease in brain radiation necrosis was seen in all the patients, and an improvement in symptoms was seen in three patients. In one patient who was receiving corticosteroid therapy, we could taper the dose and subsequently discontinue it. While one patient discontinued bevacizumab because of adverse events, the other three continued with the treatment. Therefore, the combination of bevacizumab with ALK-TKI seems to be an effective, manageable, and tolerable treatment for brain radiation necrosis. READ ARTICLE

Respirology Case Reports DOI:10.1002/rcr2.454

Authors: Kengo Tanigawa, Keiko Mizuno, Yusuke Kamenohara, Taiji Unoki, Shunsuke Misono, Hiromasa Inoue

PCN129 PREVENTING BRAIN METASTASES WITH ALECTINIB IN ALK-POSITIVE NON-SMALL CELL LUNG CANCER: ECONOMIC IMPACT UNDER THE BRAZILIAN PRIVATE HEALTHCARE SYSTEM PERSPECTIVE

Objectives: Results of the ALEX trial demonstrated that alectinib decreased the risk of Central Nervous System (CNS) progression and prolonged progression-free survival of NSCLC ALK+ patients, compared with crizotinib. The objective of this study is to compare the economic burden of CNS progression with alectinib versus crizotinib, on the Brazilian private healthcare system. Conclusions: Alectinib can potentially decrease the economic burden of CNS metastasis of NSCLC ALK+ patients in the Brazilian private healthcare system, compared with the current standard of care. READ ARTICLE

Value in Health DOI:10.1016/j.jval.2019.04.253

Authors: D.Kashiura, M.Santos, L.Carmo, R.Leme-Souza

A phase 1, open-label, dose-escalation trial of oral TSR-011 in patients with advanced solid tumours and lymphomas

Background: Anaplastic lymphoma kinase (ALK) gene rearrangements are oncogenic drivers in non-small-cell lung cancer (NSCLC). TSR-011 is a dual ALK and tropomyosin-related kinase (TRK) inhibitor, active against ALK inhibitor resistant tumours in preclinical studies. Here, we report the safety, tolerability and recommended phase 2 dose (RP2D) of TSR-011 in patients with relapsed or refractory ALK- and TRK-positive advanced cancers. Conclusions: At the RP2D (40 mg Q8h), TSR-011 demonstrated a favourable safety profile with acceptable QTc changes. Limited clinical activity was observed. Based on the competitive ALK inhibitor landscape and benefit/risk considerations, further TSR-011 development was discontinued. READ ARTICLE

British Journal of Cancer DOI:10.1038/s41416-019-0503-9

Authors: Chia-Chi Lin, Hendrik-Tobias Arkenau, Sharon Lu, Jasgit Sachdev, Javier de Castro Carpeño, Monica Mita, Rafal Dziadziuszko, Wu-Chou Su, Dmitri Bobilev, Lorraine Hughes, Jian Chan, Zhi-Yi Zhang, Glen J. Weiss

Design, synthesis of orally bioavailable novel anaplastic lymphoma kinase (ALK) inhibitor diphenylaminopyrimidine analogs and efficacy study on NCI-H2228 xenografts mice model

Anaplastic lymphoma kinase (ALK) is an attractive therapeutic target for the treatment of non-small cell lung cancer (NSCLC). Within our ALK drug discovery program, we identified novel deuterated 2,4-diarylamino pyrimidine compounds as potent ALK inhibitors. The compound 11 showed better in vitro activity and in vivo efficacy with good pharmacokinetic profile. In vivo efficacy of compound 11 was better than standard drug ceritinib in NCI-H2228 xenograft mice model. READ ARTICLE

Bioorganic & Medicinal Chemistry Letters DOI:10.1016/j.bmcl.2019.04.012

Authors: Debasis Das, Jingbing Wang, Yong Li, Jingli Shi, Jian Hong

An antibody-drug conjugate directed to the ALK receptor demonstrates efficacy in preclinical models of neuroblastoma

Enthusiasm for the use of antibody-drug conjugates (ADCs) in cancer therapy has risen over the past few years. The success of this therapeutic approach relies on the identification of cell surface antigens that are widely and selectively expressed on tumor cells. Studies have shown that native ALK protein is expressed on the surface of most neuroblastoma cells, providing an opportunity for development of immune-targeting strategies. Clinically relevant antibodies for this target have not yet been developed. Here, we describe the development of an ALK-ADC, CDX-0125-TEI, which selectively targets both wild-type and mutated ALK-expressing neuroblastomas. CDX-0125-TEI exhibited efficient antigen binding and internalization, and cytotoxicity at picomolar concentrations in cells with different expression of ALK on the cell surface. In vivo studies showed that CDX-0125-TEI is effective against ALK wild-type and mutant patient-derived xenograft models. These data demonstrate that ALK is a bona fide immunotherapeutic target and provide a rationale for clinical development of an ALK-ADC approach for neuroblastomas and other ALK-expressing childhood cancers such as rhabdomyosarcomas. READ ARTICLE

Science Translational Medicine DOI: 10.1126/scitranslmed.aau9732

Authors: Renata Sano, Kateryna Krytska, Colleen E. Larmour, Pichai Raman, Daniel Martinez, Gwenda F. Ligonjay S. Lillquist, Ulisse Cucchi, Paolo Orsini, Simona Rizzi, Bruce R. Pawel, Diego Alvarado, Yael P. Mossé

Pre-ClinicalKirk SmithJune 6, 2019Neuroblastoma, ALK, ADC

Transformation to neuroendocrine carcinoma as a resistance mechanism to lorlatinib

Objectives: Small cell transformation is a well-recognized mechanism of resistance to EGFR-TKI therapy in EGFR-mutant NSCLC, yet it remains a poorly-described phenomenon in ALK-rearranged NSCLC. Conclusions: Given the inevitable development of resistance in ALK + NSCLC, if feasible, re-biopsy on progression should be standard over liquid biopsy. Neuroendocrine carcinoma transformation remains an important mechanism of acquired resistance to lorlatinib. READ ARTICLE

Lung Cancer: 10.1016/j.lungcan.2019.05.025

Authors: Niamh Coleman, Andrew Wotherspoon, Nadia Yousaf, Sanjay Popat

Impact of Tyrosine Kinase Inhibitor Starting Dose on Outcomes in Patients With Non-Small Cell Lung Cancer

Background: Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) can cause intolerable adverse events in patients with non-small cell lung cancer (NSCLC) and may be prescribed at a lower dose. Conclusion: Patients who initiated TKI therapy at a RD did not have different PFS and 15-month survival outcomes than patients who initiated TKI therapy at the FDA SD. READ ARTICLE

Journal of Pharmacy Practice DOI:10.1177/0897190019840596

Authors: Emily Miao, Nagashree Seetharamu, Kevin Sullivan, Stephen Eng, Chung-Shien Lee

Identification of a Novel EML4-ALK, BCL11A-ALK Double-Fusion Variant in Lung Adenocarcinoma Using Next-Generation Sequencing and Response to Crizotinib

ALK receptor tyrosine kinase gene (ALK) fusion is an important driving oncogene in NSCLC, and echinoderm microtubule associated protein like 4 gene (EML4)-ALK fusion is the most prevalent type. With the rapid development and popularity of tumor genomic sequencing, more and more uncommon ALK fusion partners have been discovered, including kinesin family member 5B gene (KIF5B), baculoviral IAP repeat containing 6 gene (BIRC6), and striatin gene (STRN). However, two ALK fusions detected simultaneously in one patient with NSCLC is still rare. Here we present a novel EML4-ALK, B-cell CLL/lymphoma 11A gene (BCL11A)-ALK double-fusion variant in a patient with lung adenocarcinoma who responded well to crizotinib and describe the dynamic change in these two ALK fusions after crizotinib treatment. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.01.032

Authors: Bao-Dong Qin, Xiao-Dong Jiao, Ke Liu, Ying Wu, Yuan-Sheng Zang

ALK-Positive Lung Adenocarcinoma Arising in an Adolescent Treated for Relapsed Neuroblastoma

Pediatric lung adenocarcinoma is rare, but has been reported in patients with nonpulmonary childhood cancers.1, 2, 3 We report a case of a 17-year-old male who developed pulmonary adenocarcinoma with ALK receptor tyrosine kinase (ALK) rearrangement following neuroblastoma therapy. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.02.010

Authors: Yazeed Alwelaie, Rebecca J. Deyell, Helen R. Nadel, Tracy Tucker, Janessa Laskin, S. Rod Rassekh, Chen Zhou, John C. English, Anna F. Lee

EditorialKirk SmithJune 1, 2019ALK-Positive, Lung Adenocarcinoma, Adolescent, Relapsed, Neuroblastoma

The repertoire of genetic alterations in salivary duct carcinoma including a novel HNRNPH3-ALK rearrangement

Salivary duct carcinoma (SDC) is a rare, aggressive malignancy with limited treatment options and poor outcome. Twenty-nine primary resected SDC, including 15 SDC de novo (SDCDN), and 14 SDC ex pleomorphic adenoma (SDCXPA) were subjected to the massive parallel sequencing assay (MSK-IMPACT) targeting 287 to 468 cancer-related genes. TP53 was the most frequently altered gene (69%). TP53 mutations and ERBB2 amplification were more frequent in SDCXPA than in SDCDN (P = .0007 and P = .01, respectively). Potentially targetable mutations were detected in 79% (23/29) of SDC involving ERBB2 (31%), PIK3CA (28%), HRAS (21%), ALK (7%) and BRAF (3%), and 22% (5/23) of those cases harbored possible primary resistance mutations involving CCNE1, NF1 and PTEN. A novel HNRNPH3-ALK rearrangement was found in one SDCDN. In another case, EML4-ALK fusion detected in the primary tumor was associated with ALK G1202R secondary resistance mutation in the post-treatment metastasis. A germline analysis of the DN..... READ ARTICLE

Human Pathology DOI:10.1016/j.humpath.2019.03.004

Authors: Snjezana Dogan, Charlotte K. Y. Ng, Bin Xu, Rahul Kumar, Lu Wang, Marcia Edelweiss, Sasinya N. Scott, Ahmet Zehir, Alexander Drilon, Luc, G. T. Morris, Nancy Y. Lee,Cristina R. Antonescu, Alan L. Ho, Nora Katabi, Michael F. Berger, Jorge S. Reis-Filho

Feasibility of liquid biopsy using plasma and platelets for detection of anaplastic lymphoma kinase rearrangements in non-small cell lung cancer

Purpose: Fluorescence in situ hybridization (FISH) using tumor tissue is the gold standard for detection of anaplastic lymphoma kinase (ALK) rearrangement in non-small cell lung cancer (NSCLC). However, this method often is not repeatable due to difficulties in the acquisition of tumor tissues. Blood-based liquid biopsy using reverse transcription polymerase chain reaction (RT-PCR) is expected to be useful to overcome this limitation. Here, we investigated the feasibility of liquid biopsy using plasma and platelets for detection of ALK rearrangement and prediction of ALK inhibitor treatment outcomes. Conclusion: Liquid biopsy could have applications in the diagnosis of ALK-positive NSCLC, even when using RT-PCR, and platelets can be useful for predicting treatment outcomes of ALK inhibitors. READ ARTICLE

Journal of Cancer Research and Clinical Oncology DOI:10.1007/s00432-019-02944-w

Authors: Cheol-Kyu Park, Ji-Eun Kim, Min-Seok Kim, Bo-Gun Kho, Ha-Young Park, Tae-Ok Kim, Hong-Joon Shin, Hyun-Joo Cho, Yoo-Duk Choi, In-Jae Oh, Young-Chul Kim

Targeting SLMAP-ALK—a novel gene fusion in lung adenocarcinoma

Assessment of ALK gene rearrangements is strongly recommended by the Molecular Testing Guideline for Selection of Lung Cancer Patients proposed by IASLC, AMP, and CAP at the time of diagnosis for patients with advanced stage disease. Non-small-cell lung cancer (NSCLC) with ALK gene rearrangements or the resulting fusion proteins have been, for the most part, successfully targeted with ALK tyrosine kinase inhibitors (TKIs). The most frequent rearrangement, the EML4-ALK oncogenic fusion, has more than 10 distinct variants, each with a discrete breakpoint in EML4. Recent studies have suggested that EML4-ALK variants may have differential responses to TKIs. Additionally, non-EML4-ALK fusions that result from ALK rearrangements with diverse 5′ partners could possibly have varied biologic and clinical implications in their therapeutic responses and outcomes of patients with NSCLC. Existing literature documents at least 20 non-EML4 fusion partners for ALK, and the clinical responsiveness to c..... READ ARTICLE

Cold Spring Harbor Molecular Case Studies DOI:10.1101/mcs.a003939

Authors: Carlos Pagan, Subit Barua, Susan J. Hsiao, Mahesh Mansukhani, Anjali Saqi, Vundavalli Murty, and Helen Fernandes

Case StudyKirk SmithJune 1, 2019Lung adenocarcinoma, SLMAP-ALK fusion

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

$Treatment of Refractory ALK Rearranged Anaplastic Large Cell Lymphoma With Alectinib$

Treatment of Refractory ALK Rearranged Anaplastic Large Cell Lymphoma With Alectinib

Discussion: ALK translocations, most commonly involving chromosome 2 translocations resulting in EML4-ALK fusion, occur in approximately 3% to 5% of lung adenocarcinomas. Therapies targeting the ALK tyrosine kinase have been well studied in patients with ALK-rearranged NSCLC. The first generation ALK-tyrosine kinase inhibitor, crizotinib, was approved for use in ALK-rearranged NSCLC in 2011 based on the PROFILE 1001 study and received full United States Food and Drug Administration approval after... Conclusion: In summary, to the authors' knowledge, this is the first published case of a patient with ALK-rearranged ALCL successfully treated with alectinib. Given the rapid progression and the significant neurologic toxicities related to the primary treatment with CHOEP, our patient had limited second-line treatment options. Within 2 months of therapy with alectinib, he experienced resolution of fever and had an impressive and sustained radiographic response on PET/CT imaging, which allowed him to... READ ARTICLE

Clinical Lymphoma Myeloma and Leukemia DOI:10.1016/j.clml.2019.03.001

Authors: Daniel R. Reed, Richard D. Hall, Ryan D. Gentzler, Leonid Volodin, Michael G. Douvas, Craig A. Portell

Tracing Oncogene Rearrangements in the Mutational History of Lung Adenocarcinoma

Mutational processes giving rise to lung adenocarcinomas (LADCs) in non-smokers remain elusive. We analyzed 138 LADC whole genomes, including 83 cases with minimal contribution of smoking-associated mutational signature. Genomic rearrangements were not correlated with smoking-associated mutations and frequently served as driver events of smoking-signature-low LADCs. Complex genomic rearrangements, including chromothripsis and chromoplexy, generated 74% of known fusion oncogenes, including EML4-ALK, CD74-ROS1, and KIF5B-RET. Unlike other collateral rearrangements, these fusion-oncogene-associated rearrangements were frequently copy-number-balanced, representing a genomic signature of early oncogenesis. Analysis of mutation timing revealed that fusions and point mutations of canonical oncogenes were often acquired in the early decades of life. During a long latency, cancer-related genes were disrupted or amplified by complex rearrangements. The genomic landscape was different between subgroups-EGFR-mutant LADCs had frequent whole-genome duplications with p53 mutations, whereas fusion-oncogene-driven LADCs had frequent SETD2 mutations. Our study highlights LADC oncogenesis driven by endogenous mutational processes READ ARTICLE

Cell DOI:10.1016/j.cell.2019.05.013

Authors: Jake June-Koo Lee, Seongyeol Park, Hansol Park, Sehui Kim, Jongkeun Lee, Junehawk Lee, Jeonghwan Youk, Kijong Yi, Yohan An, In Kyu Park, Chang Hyun Kang, Doo Hyun Chung, Tae Min Kim, Yoon Kyung Jeon, Dongwan Hong, Peter J Park, Young Seok Ju, Young Tae Kim

Synthesis and anti-tumor efficacy of novel 2, 4-diarylaminopyrimidine derivatives bearing N-(3-pyridinylmethyl) urea moiety as anaplastic lymphoma kinase inhibitors

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase responsible for development of various tumor types. In this study, we synthesized a series of novel 2,4-diarylaminopyrimidine derivatives possessing a unique N-(3-pyridinylmethyl)urea moiety as ALK inhibitors. The most promising analog 5m bearing a 3-methoxy-4-morpholinophenyl substituent significantly inhibited proliferation of ALK positive H3122 and Karpas-299 cells with IC50 values about 10 nM, which were comparable with positive control LDK378. Compound 5m suppressed phosphorylation of ALK and its downstream proteins, and showed low cytotoxicity on normal human primary fibroblast cells (BJ cells). The binding mode of 5m was proposed by docking simulation, which explains the important role of N-(3-pyridinylmethyl)urea moiety. Furthermore, compound 5m exhibited favorable liver microsomal stability and significant efficacy in H3122 xenograft mice model. Interestingly, compound 5m also showed broader anti-proliferative activity on other human tumor cell lines, which was different from other ALK inhibitors. READ ARTICLE

European Journal of Medicinal Chemistry DOI:10.1016/j.ejmech.2019.05.060

Authors: Hong Chen, Ridong Li, Xianling Ning, Xuyang Zhao, Yan Jin, Yuxin Yin

Pre-ClinicalKirk SmithMay 25, 2019