Medical Abstracts

Keyword: lung cancer

1. Nature. 2019 Mar;567(7749):479-485. doi: 10.1038/s41586-019-1032-7. Epub 2019 Mar 20.

Neoantigen-directed immune escape in lung cancer evolution.

Rosenthal R(1)(2)(3), Cadieux EL(4), Salgado R(5)(6), Bakir MA(3), Moore DA(7),

Hiley CT(1)(3), Lund T(8)(9), Tani? M(10), Reading JL(8)(9), Joshi K(8)(9), Henry

JY(8)(9), Ghorani E(8)(9), Wilson GA(1)(3), Birkbak NJ(1)(3), Jamal-Hanjani M(1),

Veeriah S(1), Szallasi Z(11)(12), Loi S(6), Hellmann MD(13)(14), Feber A(15),

Chain B(16)(17), Herrero J(2), Quezada SA(1)(8)(9), Demeulemeester J(4)(18), Van

Loo P(4)(18), Beck S(10), McGranahan N(19)(20), Swanton C(21)(22); TRACERx

consortium.

Author information:

(1)Cancer Research UK Lung Cancer Centre of Excellence, University College London

Cancer Institute, University College London, London, UK.

(2)Bill Lyons Informatics Centre, University College London Cancer Institute,

University College London, London, UK.

(3)Cancer Evolution and Genome Instability Laboratory, The Francis Crick

Institute, London, UK.

…

The interplay between an evolving cancer and a dynamic immune microenvironment

remains unclear. Here we analyse 258 regions from 88 early-stage, untreated

non-small-cell lung cancers using RNA sequencing and histopathology-assessed

tumour-infiltrating lymphocyte estimates. Immune infiltration varied both between

and within tumours, with different mechanisms of neoantigen presentation

dysfunction enriched in distinct immune microenvironments. Sparsely infiltrated

tumours exhibited a waning of neoantigen editing during tumour evolution,

indicative of historical immune editing, or copy-number loss of previously clonal

neoantigens. Immune-infiltrated tumour regions exhibited ongoing immunoediting,

with either loss of heterozygosity in human leukocyte antigens or depletion of

expressed neoantigens. We identified promoter hypermethylation of genes that

contain neoantigenic mutations as an epigenetic mechanism of immunoediting. Our

results suggest that the immune microenvironment exerts a strong selection

pressure in early-stage, untreated non-small-cell lung cancers that produces

multiple routes to immune evasion, which are clinically relevant and forecast

poor disease-free survival.

DOI: 10.1038/s41586-019-1032-7

PMID: 30894752

2. Nat Med. 2019 Mar;25(3):517-525. doi: 10.1038/s41591-018-0323-0. Epub 2019 Jan

21.

Deciphering the genomic, epigenomic, and transcriptomic landscapes of

pre-invasive lung cancer lesions.

Teixeira VH(1), Pipinikas CP(1)(2), Pennycuick A(1), Lee-Six H(3),

Chandrasekharan D(1), Beane J(4), Morris TJ(2), Karpathakis A(2), Feber A(2),

Breeze CE(2), Ntolios P(1), Hynds RE(1)(5)(6), Falzon M(7), Capitanio A(7),

Carroll B(8), Durrenberger PF(9), Hardavella G(8), Brown JM(1), Lynch AG(10)(11),

Farmery H(10), Paul DS(2), Chambers RC(9), McGranahan N(5), Navani N(1)(8),

Thakrar RM(1)(8), Swanton C(5)(6), Beck S(2), George PJ(8), Spira A(4)(12),

Campbell PJ(3), Thirlwell C(2), Janes SM(13)(14).

Author information:

(1)Lungs for Living Research Centre, UCL Respiratory, University College London,

London, UK.

(2)Research Department of Cancer Biology and Medical Genomics Laboratory, UCL

Cancer Institute, University College London, London, UK.

(3)The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK.

…

The molecular alterations that occur in cells before cancer is manifest are

largely uncharted. Lung carcinoma in situ (CIS) lesions are the pre-invasive

precursor to squamous cell carcinoma. Although microscopically identical, their

future is in equipoise, with half progressing to invasive cancer and half

regressing or remaining static. The cellular basis of this clinical observation

is unknown. Here, we profile the genomic, transcriptomic, and epigenomic

landscape of CIS in a unique patient cohort with longitudinally monitored

pre-invasive disease. Predictive modeling identifies which lesions will progress

with remarkable accuracy. We identify progression-specific methylation changes on

a background of widespread heterogeneity, alongside a strong chromosomal

instability signature. We observed mutations and copy number changes

characteristic of cancer and chart their emergence, offering a window into early

carcinogenesis. We anticipate that this new understanding of cancer precursor

biology will improve early detection, reduce overtreatment, and foster

preventative therapies targeting early clonal events in lung cancer.

DOI: 10.1038/s41591-018-0323-0

PMID: 30664780

3. Nat Commun. 2019 Mar 27;10(1):1382. doi: 10.1038/s41467-019-09289-5.

FBXW2 suppresses migration and invasion of lung cancer cells via promoting

β-catenin ubiquitylation and degradation.

Yang F(1)(2), Xu J(2), Li H(2), Tan M(2), Xiong X(1), Sun Y(3)(4).

Author information:

(1)Cancer Institute of the Second Affiliated Hospital, and Institute of

Translational Medicine, Zhejiang University School of Medicine, 310029, Hangzhou,

China.

(2)Division of Radiation and Cancer Biology, Departments of Radiation Oncology,

University of Michigan, 4424B MS-1, 1301 Catherine Street, Ann Arbor, MI,

MI48109, USA.

(3)Cancer Institute of the Second Affiliated Hospital, and Institute of

Translational Medicine, Zhejiang University School of Medicine, 310029, Hangzhou,

China. sunyi@umich.edu.

(4)Division of Radiation and Cancer Biology, Departments of Radiation Oncology,

University of Michigan, 4424B MS-1, 1301 Catherine Street, Ann Arbor, MI,

MI48109, USA. sunyi@umich.edu.

FBXW2 inhibits proliferation of lung cancer cells by targeting SKP2 for

degradation. Whether and how FBXW2 regulates tumor invasion and metastasis is

previously unknown. Here, we report that FBXW2 is an E3 ligase for β-catenin.

FBXW2 binds to β-catenin upon EGF-AKT1-mediated phosphorylation on Ser552, and

promotes its ubiquitylation and degradation. FBXW2 overexpression reduces

β-catenin levels and protein half-life, whereas FBXW2 knockdown increases

β-catenin levels, protein half-life and transcriptional activity. Functionally,

FBXW2 overexpression inhibits migration and invasion by blocking transactivation

of MMPs driven by β-catenin, whereas FXBW2 knockdown promotes migration, invasion

and metastasis both in vitro and in vivo lung cancer models. In human lung cancer

specimens, while FBXW2 levels are inversely correlated with β-catenin levels and

lymph-node metastasis, lower FBXW2 coupled with higher β-catenin, predict a worse

patient survival. Collectively, our study demonstrates that FBXW2 inhibits tumor

migration, invasion and metastasis in lung cancer cells by targeting β-catenin

for degradation.

DOI: 10.1038/s41467-019-09289-5

PMCID: PMC6437151

PMID: 30918250 [Indexed for MEDLINE]

4. Am J Respir Crit Care Med. 2019 Mar 21. doi: 10.1164/rccm.201806-1178OC. [Epub

ahead of print]

Driver Mutations in Normal Airway Epithelium Elucidate Spatiotemporal Resolution

of Lung Cancer.

Kadara H(1), Sivakumar S(2)(3), Jakubek Y(2), San Lucas FA(2), Lang W(4),

McDowell T(4), Weber Z(5), Behrens C(6), Davies GE(5), Kalhor N(7), Moran C(8),

El-Zein R(9), Mehran R(10), Swisher SG(10), Wang J(11), Zhang J(12), Fujimoto

J(4), Fowler J(13), Heymach JV(14), Dubinett S(15), Spira AE(16), Ehli EA(5),

Wistuba II(17), Scheet P(2).

Author information:

(1)University of Texas MD Anderson Cancer Center, 4002, Translational Molecular

Pathology, Houston, Texas, United States ; hkadara@mdanderson.org.

(2)University of Texas MD Anderson Cancer Center, Epidemiology, Houston, Texas,

United States.

(3)MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences,

Houston, Texas, United States.

…

RATIONALE: Uninvolved normal-appearing airway epithelium has been shown to

exhibit specific mutations characteristic of nearby non-small cell lung cancers

(NSCLCs). Yet, its somatic mutational landscape in early-stage NSCLC patients is

unknown.

OBJECTIVES: To comprehensively survey the somatic mutational architecture of the

normal airway epithelium in early-stage NSCLC patients.

METHODS: Multi-region normal airways, comprising tumor-adjacent small airways,

tumor-distant large airways, nasal epithelium and uninvolved normal lung

(collectively airway field), matched NSCLCs as well as blood cells (n = 498) from

48 patients were interrogated for somatic single nucleotide variants (SNVs) by

deep targeted DNA sequencing and for chromosomal allelic imbalance (AI) events by

genome-wide genotype array profiling. Spatiotemporal relationships between the

airway field and NSCLCs were assessed by phylogenetic analysis.

MEASUREMENTS AND MAIN RESULTS: Genomic airway field carcinogenesis was observed

in 25 cases (52%). The airway field epithelium exhibited a total of 269 somatic

mutations in a large majority of patients (n = 36) including key drivers which

were shared with the NSCLCs. Allele frequencies of these acquired variants were

overall higher in NSCLCs. Integrative analysis of SNVs and AI events revealed

driver genes with shared "two-hit" alterations in the airway field (e.g., TP53,

KRAS, KEAP1, STK11, CDKN2A) as well as those with single hits progressing to two

in the NSCLCs (e.g., PIK3CA, NOTCH1).

CONCLUSIONS: Tumor-adjacent and -distant normal-appearing airway epithelia

exhibit somatic driver alterations that undergo selection-driven clonal expansion

in the NSCLC. These events offer spatiotemporal insights into the development of

NSCLC and, thus, potential targets for early treatment.

DOI: 10.1164/rccm.201806-1178OC

PMID: 30896962

5. J Clin Oncol. 2019 Mar 20:JCO1802236. doi: 10.1200/JCO.18.02236. [Epub ahead of

print]

ALK Resistance Mutations and Efficacy of Lorlatinib in Advanced Anaplastic

Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer.

Shaw AT(1), Solomon BJ(2), Besse B(3), Bauer TM(4), Lin CC(5), Soo RA(6), Riely

GJ(7), Ou SI(8), Clancy JS(9), Li S(10), Abbattista A(11), Thurm H(10), Satouchi

M(12), Camidge DR(13), Kao S(14), Chiari R(15), Gadgeel SM(16), Felip E(17),

Martini JF(10).

Author information:

(1)1 Massachusetts General Hospital, Boston, MA.

(2)2 Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

(3)3 Gustave Roussy Cancer Campus, Villejuif, France.

(4)4 Sarah Cannon Cancer Research Institute/Tennessee Oncology PLLC, Nashville,

TN.

…

PURPOSE: Lorlatinib is a potent, brain-penetrant, third-generation anaplastic

lymphoma kinase (ALK)/ROS1 tyrosine kinase inhibitor (TKI) with robust clinical

activity in advanced ALK-positive non-small-cell lung cancer, including in

patients who have failed prior ALK TKIs. Molecular determinants of response to

lorlatinib have not been established, but preclinical data suggest that ALK

resistance mutations may represent a biomarker of response in previously treated

patients.

PATIENTS AND METHODS: Baseline plasma and tumor tissue samples were collected

from 198 patients with ALK-positive non-small-cell lung cancer from the

registrational phase II study of lorlatinib. We analyzed plasma DNA for ALK

mutations using Guardant360. Tumor tissue DNA was analyzed using an ALK

mutation-focused next-generation sequencing assay. Objective response rate,

duration of response, and progression-free survival were evaluated according to

ALK mutation status.

RESULTS: Approximately one quarter of patients had ALK mutations detected by

plasma or tissue genotyping. In patients with crizotinib-resistant disease, the

efficacy of lorlatinib was comparable among patients with and without ALK

mutations using plasma or tissue genotyping. In contrast, in patients who had

failed 1 or more second-generation ALK TKIs, objective response rate was higher

among patients with ALK mutations (62% v 32% [plasma]; 69% v 27% [tissue]).

Progression-free survival was similar in patients with and without ALK mutations

on the basis of plasma genotyping (median, 7.3 months v 5.5 months; hazard ratio,

0.81) but significantly longer in patients with ALK mutations identified by

tissue genotyping (median, 11.0 months v 5.4 months; hazard ratio, 0.47).

CONCLUSION: In patients who have failed 1 or more second-generation ALK TKIs,

lorlatinib shows greater efficacy in patients with ALK mutations compared with

patients without ALK mutations. Tumor genotyping for ALK mutations after failure

of a second-generation TKI may identify patients who are more likely to derive

clinical benefit from lorlatinib.

DOI: 10.1200/JCO.18.02236

PMID: 30892989

6. Nano Lett. 2019 Apr 10;19(4):2231-2242. doi: 10.1021/acs.nanolett.8b04309. Epub

2019 Mar 21.

Optimized Bexarotene Aerosol Formulation Inhibits Major Subtypes of Lung Cancer

in Mice.

Zhang Q, Lee SB, Chen X, Stevenson ME(1), Pan J, Xiong D, Zhou Y, Miller MS(2),

Lubet RA(2), Wang Y, Mirza SP(3), You M.

Author information:

(1)Department of Psychology , University of Wisconsin , Milwaukee , Wisconsin

53211 , United States.

(2)Division of Cancer Prevention , National Cancer Institute , Rockville ,

Maryland 20850 , United States.

(3)Department of Chemistry and Biochemistry , University of Wisconsin , Milwaukee

, Wisconsin 53211 , United States.

Bexarotene has shown inhibition of lung and mammary gland tumorigenesis in

preclinical models and in clinical trials. The main side effects of orally

administered bexarotene are hypertriglyceridemia and hypercholesterolemia. We

previously demonstrated that aerosolized bexarotene administered by nasal

inhalation has potent chemopreventive activity in a lung adenoma preclinical

model without causing hypertriglyceridemia. To facilitate its future clinical

translation, we modified the formula of the aerosolized bexarotene with a

clinically relevant solvent system. This optimized aerosolized bexarotene

formulation was tested against lung squamous cell carcinoma mouse model and lung

adenocarcinoma mouse model and showed significant chemopreventive effect. This

new formula did not cause visible signs of toxicity and did not increase plasma

triglycerides or cholesterol. This aerosolized bexarotene was evenly distributed

to the mouse lung parenchyma, and it modulated the microenvironment in vivo by

increasing the tumor-infiltrating T cell population. RNA sequencing of the lung

cancer cell lines demonstrated that multiple pathways are altered by bexarotene.

For the first time, these studies demonstrate a new, clinically relevant

aerosolized bexarotene formulation that exhibits preventive efficacy against the

major subtypes of lung cancer. This approach could be a major advancement in lung

cancer prevention for high risk populations, including former and present

smokers.

DOI: 10.1021/acs.nanolett.8b04309

PMID: 30873838

7. J Exp Med. 2019 Apr 1;216(4):982-1000. doi: 10.1084/jem.20180870. Epub 2019 Mar

14.

Secreted PD-L1 variants mediate resistance to PD-L1 blockade therapy in non-small

cell lung cancer.

Gong B(1)(2), Kiyotani K(3), Sakata S(4), Nagano S(5)(6), Kumehara S(5)(6), Baba

S(4), Besse B(7)(8), Yanagitani N(9), Friboulet L(7), Nishio M(9), Takeuchi

K(4)(10), Kawamoto H(5), Fujita N(1)(2), Katayama R(11).

Author information:

(1)Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo,

Japan.

(2)Department of Computational Biology and Medical Sciences, Graduate School of

Frontier Sciences, The University of Tokyo, Chiba, Japan.

(3)Immunopharmacogenomics Group, Cancer Precision Medicine Center, Japanese

Foundation for Cancer Research, Tokyo, Japan.

…

Immune checkpoint blockade against programmed cell death 1 (PD-1) and its ligand

PD-L1 often induces durable tumor responses in various cancers, including

non-small cell lung cancer (NSCLC). However, therapeutic resistance is

increasingly observed, and the mechanisms underlying anti-PD-L1 (aPD-L1) antibody

treatment have not been clarified yet. Here, we identified two unique secreted

PD-L1 splicing variants, which lacked the transmembrane domain, from

aPD-L1-resistant NSCLC patients. These secreted PD-L1 variants worked as "decoys"

of aPD-L1 antibody in the HLA-matched coculture system of iPSC-derived CD8 T

cells and cancer cells. Importantly, mixing only 1% MC38 cells with secreted

PD-L1 variants and 99% of cells that expressed wild-type PD-L1 induced resistance

to PD-L1 blockade in the MC38 syngeneic xenograft model. Moreover, anti-PD-1

(aPD-1) antibody treatment overcame the resistance mediated by the secreted PD-L1

variants. Collectively, our results elucidated a novel resistant mechanism of

PD-L1 blockade antibody mediated by secreted PD-L1 variants.

© 2019 Gong et al.

DOI: 10.1084/jem.20180870

PMCID: PMC6446862

PMID: 30872362

8. J Clin Oncol. 2019 Mar 1;37(7):537-546. doi: 10.1200/JCO.18.00149. Epub 2019 Jan

8.

Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy

for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50%

or Greater.

Reck M(1), Rodríguez-Abreu D(2), Robinson AG(3), Hui R(4), Cs?szi T(5), Fülöp

A(6), Gottfried M(7), Peled N(8), Tafreshi A(9), Cuffe S(10), O'Brien M(11), Rao

S(12), Hotta K(13), Vandormael K(14), Riccio A(15), Yang J(15), Pietanza MC(15),

Brahmer JR(16).

Author information:

(1)Lung Clinic Grosshansdorf, Airway Research Center North, Grosshansdorf,

Germany.

(2)Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria,

Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.

(3)Cancer Centre of Southeastern Ontario at Kingston General Hospital, Kingston,

Ontario, Canada.

…

PURPOSE: In the randomized, open-label, phase III KEYNOTE-024 study,

pembrolizumab significantly improved progression-free survival and overall

survival (OS) compared with platinum-based chemotherapy in patients with

previously untreated advanced non-small-cell lung cancer (NSCLC) with a

programmed death ligand 1 tumor proportion score of 50% or greater and without

EGFR/ALK aberrations. We report an updated OS and tolerability analysis,

including analyses adjusting for potential bias introduced by crossover from

chemotherapy to pembrolizumab.

PATIENTS AND METHODS: Patients were randomly assigned to pembrolizumab 200 mg

every 3 weeks (for up to 2 years) or investigator's choice of platinum-based

chemotherapy (four to six cycles). Patients assigned to chemotherapy could cross

over to pembrolizumab upon meeting eligibility criteria. The primary end point

was progression-free survival; OS was an important key secondary end point.

Crossover adjustment analysis was done using the following three methods:

simplified two-stage method, rank-preserving structural failure time, and inverse

probability of censoring weighting.

RESULTS: Three hundred five patients were randomly assigned (pembrolizumab, n =

154; chemotherapy, n = 151). At data cutoff (July 10, 2017; median follow-up,

25.2 months), 73 patients in the pembrolizumab arm and 96 in the chemotherapy arm

had died. Median OS was 30.0 months (95% CI, 18.3 months to not reached) with

pembrolizumab and 14.2 months (95% CI, 9.8 to 19.0 months) with chemotherapy

(hazard ratio, 0.63; 95% CI, 0.47 to 0.86). Eighty-two patients assigned to

chemotherapy crossed over on study to receive pembrolizumab. When adjusted for

crossover using the two-stage method, the hazard ratio for OS for pembrolizumab

versus chemotherapy was 0.49 (95% CI, 0.34 to 0.69); results using

rank-preserving structural failure time and inverse probability of censoring

weighting were similar. Treatment-related grade 3 to 5 adverse events were less

frequent with pembrolizumab compared with chemotherapy (31.2% v 53.3%,

respectively).

CONCLUSION: With prolonged follow-up, first-line pembrolizumab monotherapy

continues to demonstrate an OS benefit over chemotherapy in patients with

previously untreated, advanced NSCLC without EGFR/ALK aberrations, despite

crossover from the control arm to pembrolizumab as subsequent therapy.

DOI: 10.1200/JCO.18.00149

PMID: 30620668

9. J Clin Invest. 2019 Mar 1;129(3):1211-1228. doi: 10.1172/JCI123319. Epub 2019 Feb 11.

PARP inhibition enhances tumor cell-intrinsic immunity in ERCC1-deficient

non-small cell lung cancer.

Chabanon RM(1)(2)(3)(4), Muirhead G(3), Krastev DB(3)(4), Adam J(2), Morel

D(1)(2), Garrido M(2), Lamb A(5), Hénon C(1)(2), Dorvault N(2), Rouanne M(1)(6),

Marlow R(7), Bajrami I(3)(4), Cardeñosa ML(3)(4)(8), Konde A(3)(4), Besse

B(1)(9), Ashworth A(10), Pettitt SJ(3)(4), Haider S(3), Marabelle A(6)(11), Tutt

AN(3)(7), Soria JC(1), Lord CJ(3)(4), Postel-Vinay S(1)(2)(11).

Author information:

(1)Université Paris Saclay, Université Paris-Sud, Faculté de médicine, Le Kremlin

Bicêtre, Paris, France.

(2)ATIP-Avenir group, Inserm U981, Gustave Roussy, Villejuif, France.

(3)The Breast Cancer Now Toby Robins Breast Cancer Research Centre and.

(4)CRUK Gene Function Laboratory, The Institute of Cancer Research, London,

United Kingdom.

…

The cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway detects

cytosolic DNA to activate innate immune responses. Poly(ADP-ribose) polymerase

inhibitors (PARPi) selectively target cancer cells with DNA repair deficiencies

such as those caused by BRCA1 mutations or ERCC1 defects. Using isogenic cell

lines and patient-derived samples, we showed that ERCC1-defective non-small cell

lung cancer (NSCLC) cells exhibit an enhanced type I IFN transcriptomic signature

and that low ERCC1 expression correlates with increased lymphocytic infiltration.

We demonstrated that clinical PARPi, including olaparib and rucaparib, have

cell-autonomous immunomodulatory properties in ERCC1-defective NSCLC and

BRCA1-defective triple-negative breast cancer (TNBC) cells. Mechanistically,

PARPi generated cytoplasmic chromatin fragments with characteristics of

micronuclei; these were found to activate cGAS/STING, downstream type I IFN

signaling, and CCL5 secretion. Importantly, these effects were suppressed in

PARP1-null TNBC cells, suggesting that this phenotype resulted from an on-target

effect of PARPi on PARP1. PARPi also potentiated IFN-γ-induced PD-L1 expression

in NSCLC cell lines and in fresh patient tumor cells; this effect was enhanced in

ERCC1-deficient contexts. Our data provide a preclinical rationale for using

PARPi as immunomodulatory agents in appropriately molecularly selected

populations.

DOI: 10.1172/JCI123319

PMCID: PMC6391116 [Available on 2019-06-01]

PMID: 30589644

10. Autophagy. 2019 Mar;15(3):391-406. doi: 10.1080/15548627.2018.1511503. Epub 2018 Sep 6.

Identification of compound CA-5f as a novel late-stage autophagy inhibitor with

potent anti-tumor effect against non-small cell lung cancer.

Zhang L(1), Qiang P(1), Yu J(1), Miao Y(1), Chen Z(1), Qu J(1), Zhao Q(1), Chen

Z(1), Liu Y(1), Yao X(1), Liu B(1), Cui L(1), Jing H(1), Sun G(2).

Author information:

(1)a College of Bioengineering , Henan University of Technology , Zhengzhou ,

China.

(2)b College of Chemistry and Chemical Engineering , Henan University of

Technology , Zhengzhou , China.

Currently, particular focus is placed on the implication of autophagy in a

variety of human diseases, including cancer. Discovery of small-molecule

modulators of autophagy as well as their potential use as anti-cancer therapeutic

agents would be of great significance. To this end, a series of curcumin analogs

previously synthesized in our laboratory were screened. Among these compounds,

(3E,5E)-3-(3,4-dimethoxybenzylidene)-5-[(1H-indol-3-yl)methylene]-1-methylpiperid in-4-one (CA-5f) was identified as a potent late-stage macroautophagy/autophagy

inhibitor via inhibiting autophagosome-lysosome fusion. We found that CA-5f

neither impaired the hydrolytic function nor the quantity of lysosomes. Use of an

isobaric tag for relative and absolute quantitation (iTRAQ)-based proteomic

screen in combination with bioinformatics analysis suggested that treatment of

human umbilical vein endothelial cells (HUVECs) with CA-5f for 1 h suppressed the

levels of cytoskeletal proteins and membrane traffic proteins. Subsequent studies

showed that CA-5f exhibited strong cytotoxicity against A549 non-small cell lung

cancer (NSCLC) cells, but low cytotoxicity to normal human umbilical vein

endothelial cells (HUVECs), by increasing mitochondrial-derived reactive oxygen

species (ROS) production. Moreover, CA-5f effectively suppressed the growth of

A549 lung cancer xenograft as a single agent with an excellent tolerance in vivo.

Results from western blot, immunofluorescence, and TdT-mediated dUTP nick end

labeling (TUNEL) assays showed that CA-5f inhibited autophagic flux, induced

apoptosis, and did not affect the level of CTSB (cathepsin B) and CTSD (cathepsin

D) in vivo, which were consistent with the in vitro data. Collectively, these

results demonstrated that CA-5f is a novel late-stage autophagy inhibitor with

potential clinical application for NSCLC therapy. Abbreviations: 3-MA,

3-methyladenine; ANXA5, annexin A5; ATG, autophagy related; CA-5f,

(3E,5E)-3-(3,4-dimethoxybenzylidene)-5-[(1H-indol-3-yl)methylene]-1-methylpiperid in-4-one; CQ, chloroquine; CTSB, cathepsin B; CTSD, cathepsin D; DMSO, dimethyl

sulfoxide; DNM2, dynamin 2; EBSS, Earle's balanced salt solution; GFP, green

fluorescent protein; HCQ, hydroxyl CQ; HEK293, human embryonic kidney 293; HUVEC,

human umbilical vein endothelial cells; LAMP1, lysosomal associated membrane

protein 1; LC-MS/MS, liquid chromatography coupled to tandem mass spectrometry;

LDH, lactic acid dehydrogenase; LMO7, LIM domain 7; MAP1LC3B/LC3B, microtubule

associated protein 1 light chain 3 beta; NAC, N-acetyl cysteine; MYO1E, myosin

IE; NSCLC, non-small cell lung cancer; PARP1, poly(ADP-ribose) polymerase 1; PI,

propidium iodide; RFP, red fluorescent protein; ROS, reactive oxygen species;

SQSTM1, sequestosome 1; TUNEL, terminal deoxynucleotidyl transferase-mediated

dUTP nick-end labeling.

DOI: 10.1080/15548627.2018.1511503

PMCID: PMC6351124 [Available on 2019-09-06]

PMID: 30145925

11. Ann Surg. 2019 Mar 26. doi: 10.1097/SLA.0000000000003231. [Epub ahead of print]

A National Analysis of Short-term Outcomes and Long-term Survival Following

Thoracoscopic Versus Open Lobectomy for Clinical Stage II Non-Small-Cell Lung

Cancer.

Yang CJ(1), Kumar A(2), Deng JZ(1), Raman V(2), Lui NS(1), D'Amico TA(2), Berry

MF(1)(3).

Author information:

(1)Department of Cardiothoracic Surgery, Stanford University Medical Center,

Stanford, CA.

(2)Division of Thoracic Surgery, Department of Surgery, Duke University Medical

Center, Durham, NC.

(3)VA Palo Alto Health Care System, Palo Alto, CA.

MINI: In this national analysis, thoracoscopic lobectomy was associated with

shorter hospital stay and no significant difference in long-term survival when

compared to open lobectomy for cT1-2N1M0 non-small-cell lung cancer (NSCLC).

These results suggest that thoracoscopic techniques are feasible in the treatment

of stage II (cN1) NSCLC.OBJECTIVE: To compare outcomes after open versus

thoracoscopic (VATS) lobectomy for clinical stage II (cN1) non-small-cell lung

cancer (NSCLC).

BACKGROUND: There have been no published studies evaluating the impact of a VATS

approach to lobectomy for N1 NSCLC on short-term outcomes and survival.

METHODS: Outcomes of patients with clinical T1-2, N1, M0 NSCLC who underwent

lobectomy without induction therapy in the National Cancer Data Base (2010-2012)

were evaluated using multivariable Cox proportional hazards modeling and

propensity score-matched analysis.

RESULTS: Median follow-up of 1559 lobectomies (1204 open and 355 VATS) was 43.2

months. The VATS approach was associated with a shorter median hospitalization (5

vs 6 d, P < 0.001) than the open approach. There were no significant differences

between the VATS and open approach with regard to nodal upstaging (12.0% vs

10.5%, P = 0.41), 30-day mortality (2.3% vs 3.1%, P = 0.31), and overall survival

(5-yr survival: 48.6% vs 48.7%, P = 0.76; multivariable-adjusted HR for VATS

approach: 1.08, 95% CI: 0.90-1.30, P = 0.39). A propensity score-matched analysis

of 334 open and 334 VATS patients who were well matched by 14 common prognostic

covariates, including tumor size, and comorbidities, continued to show no

significant differences in nodal upstaging, 30-day mortality, and 5-year survival

between the VATS and open groups.

CONCLUSION: In this national analysis, VATS lobectomy was used in the minority of

N1 NSCLC cases but was associated with shorter hospitalization and similar nodal

upstaging rates, 30-day mortality, and long-term survival when compared to open

lobectomy. These findings suggest thoracoscopic techniques are feasible for the

treatment of stage II (cN1) NSCLC.

DOI: 10.1097/SLA.0000000000003231

PMID: 30946089

12. Cancer Res. 2019 Mar 22. pii: canres.2156.2018. doi:

10.1158/0008-5472.CAN-18-2156. [Epub ahead of print]

Elevated heme synthesis and uptake underpin intensified oxidative metabolism and

tumorigenic functions in non-small cell lung cancer cells.

Sohoni S(1), Ghosh P(1), Wang T(2), Kalainayakan SP(1), Vidal C(2), Dey S(1),

Konduri PC(1), Zhang L(3).

Author information:

(1)Biological Sciences, The University of Texas at Dallas.

(2)Department of Biological Sciences, University of Texas at Dallas.

(3)Biological Sciences, The University of Texas at Dallas li.zhang@utdallas.edu.

Tumors of human non-small cell lung cancer (NSCLC) are heterogeneous but exhibit

elevated glycolysis and glucose oxidation relative to benign lung. Heme is a

central molecule for oxidative metabolism and ATP generation via mitochondrial

oxidative phosphorylation (OXPHOS). Here we showed that levels of heme synthesis

and uptake, mitochondrial heme, oxygen-utilizing hemoproteins, oxygen

consumption, ATP generation, and key mitochondrial biogenesis regulators were

enhanced in NSCLC cells relative to non-tumorigenic cells. Likewise, proteins and

enzymes relating to heme and mitochondrial functions were upregulated in human

NSCLC tissues relative to normal tissues. Engineered heme-sequestering peptides

(HSP) reduced heme uptake, intracellular heme levels, and tumorigenic functions

of NSCLC cells. Addition of heme largely reversed the effect of HSP on

tumorigenic functions. Furthermore, HSP2 significantly suppressed the growth of

human NSCLC xenograft tumors in mice. HSP2-treated tumors exhibited reduced

oxygen consumption rates and ATP levels. To further verify the importance of heme

in promoting tumorigenicity, we generated NSCLC cell lines with increased heme

synthesis or uptake by overexpressing either the rate-limiting heme synthesis

enzyme ALAS1 or uptake protein SLC48A1, respectively. These cells exhibited

enhanced migration and invasion and accelerated tumor growth in mice. Notably,

tumors formed by cells with increased heme synthesis or uptake also displayed

elevated oxygen consumption rates and ATP levels. These data show that elevated

heme flux and function underlie enhanced OXPHOS and tumorigenicity of NSCLC

cells. Targeting heme flux and function offers a potential strategy for

developing therapies for lung cancer.

Copyright 2019, American Association for Cancer Research.

DOI: 10.1158/0008-5472.CAN-18-2156

PMID: 30902795

13. Br J Pharmacol. 2019 Mar 1. doi: 10.1111/bph.14652. [Epub ahead of print]

Diosmetin induces apoptosis and enhances the chemotherapeutic efficacy of

paclitaxel in non-small cell lung cancer cells via Nrf2 inhibition.

Chen X(1)(2)(3), Wu Q(1)(2)(3), Chen Y(1)(2)(3), Zhang J(1)(2)(3), Li H(1)(2)(3),

Yang Z(1)(2)(3), Yang Y(1)(2)(3), Deng Y(1)(2)(3), Zhang L(2)(3)(4), Liu

B(1)(2)(3).

Author information:

(1)Department of Clinical pharmacy, School of Pharmacy, Guangdong Pharmaceutical

University, Guangzhou, 510006, China.

(2)Guangzhou key laboratory of construction and application of new drug screening

model systems, Guangdong Pharmaceutical University, Guangzhou, 510006, China.

(3)Key Laboratory of New Drug Discovery and Evaluation of ordinary universities

of Guangdong province, Guangdong Pharmaceutical University, Guangzhou, 510006,

China.

(4)The Center for Drug Research and Development, Guangdong Pharmaceutical

University, Guangzhou, 510006, China.

BACKGROUND AND PURPOSE: Non-small cell lung cancer (NSCLC) accounts for up to

80-85% of all lung cancers with a disappointing prognosis. Flavonoids exert

anti-cancer properties, mostly involving stimulation of ROS production without

significant toxicity to normal cells. This study was aimed to delineate the

effect of diosmetin, a natural flavonoid, on NSCLC cells and the ability to

enhance the anti-tumour activity of paclitaxel.

EXPERIMENTAL APPROACH: NSCLC cells, normal cell lines HLF-1 and BEAS-2B, as well

as immunodeficient mice were chosen as a model to study the treatment effects.

Changes in cell viability, apoptosis and ROS were analyzed by MTT assay, flow

cytometry assay and fluorescent probe DCFH-DA. Molecule expression was determined

by western blotting and real-time RT-PCR. Xenografted tumors, spleens and other

vital organs were harvested and subjected to growth inhibition measurement,

histological and immunohistochemical analyses.

KEY RESULTS: Diosmetin induced selective apoptotic death in NSCLC cells, but

spared normal cells, via ROS accumulation. Diosmetin induced ROS production in

NSCLC cells probably via reducing Nrf2 stability through disruption of

PI3K/Akt/GSK-3 pathway. The in vitro and in vivo xenograft studies showed that

combined treatment of diosmetin and paclitaxel synergistically suppressed NSCLC

cells. Histological analysis of vital organs showed no obvious toxicity of

diosmetin, which matched our in vitro findings.

CONCLUSIONS AND IMPLICATIONS: Diosmetin selectively induces apoptosis and

enhances the paclitaxel efficacy in NSCLC cells via ROS accumulation through

disruption of PI3K/Akt/GSK-3尾/Nrf2 pathway. Therefore, diosmetin may be a

promising candidate for NSCLC adjuvant treatment.

This article is protected by copyright. All rights reserved.

DOI: 10.1111/bph.14652

PMID: 30825187

14. Cancer Res. 2019 Mar 15;79(6):1204-1213. doi: 10.1158/0008-5472.CAN-18-1082. Epub 2018 Dec 20.

Early Noninvasive Detection of Response to Targeted Therapy in Non-Small Cell

Lung Cancer.

Phallen J(1), Leal A(1), Woodward BD(2), Forde PM(1), Naidoo J(1), Marrone KA(1),

Brahmer JR(1), Fiksel J(1), Medina JE(1), Cristiano S(1), Palsgrove DN(1), Gocke

CD(1), Bruhm DC(1), Keshavarzian P(2), Adleff V(1), Weihe E(2), Anagnostou V(1),

Scharpf RB(1), Velculescu VE(3), Husain H(4).

Author information:

(1)The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School

of Medicine, Baltimore, Maryland.

(2)Division of Hematology and Oncology, Moores Cancer Center, University of

California, San Diego, La Jolla, California.

(3)The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School

of Medicine, Baltimore, Maryland. velculescu@jhmi.edu hhusain@ucsd.edu.

(4)Division of Hematology and Oncology, Moores Cancer Center, University of

California, San Diego, La Jolla, California. velculescu@jhmi.edu

hhusain@ucsd.edu.

With the advent of precision oncology, there is an urgent need to develop

improved methods for rapidly detecting responses to targeted therapies. Here, we

have developed an ultrasensitive measure of cell-free tumor load using targeted

and whole-genome sequencing approaches to assess responses to tyrosine kinase

inhibitors in patients with advanced lung cancer. Analyses of 28 patients treated

with anti-EGFR or HER2 therapies revealed a bimodal distribution of cell-free

circulating tumor DNA (ctDNA) after therapy initiation, with molecular responders

having nearly complete elimination of ctDNA (>98%). Molecular nonresponders

displayed limited changes in ctDNA levels posttreatment and experienced

significantly shorter progression-free survival (median 1.6 vs. 13.7 months, P <

0.0001; HR = 66.6; 95% confidence interval, 13.0-341.7), which was detected on

average 4 weeks earlier than CT imaging. ctDNA analyses of patients with

radiographic stable or nonmeasurable disease improved prediction of clinical

outcome compared with CT imaging. These analyses provide a rapid approach for

evaluating therapeutic response to targeted therapies and have important

implications for the management of patients with cancer and the development of

new therapeutics.Significance: Cell-free tumor load provides a novel approach for

evaluating longitudinal changes in ctDNA during systemic treatment with tyrosine

kinase inhibitors and serves an unmet clinical need for real-time, noninvasive

detection of tumor response to targeted therapies before radiographic

assessment.See related commentary by Zou and Meyerson, p. 1038.

2018 American Association for Cancer Research.

DOI: 10.1158/0008-5472.CAN-18-1082

PMCID: PMC6481620

PMID: 30573519

15. Cancer Res. 2019 Mar 15;79(6):1214-1225. doi: 10.1158/0008-5472.CAN-18-1127. Epub 2018 Dec 12.

Dynamics of Tumor and Immune Responses during Immune Checkpoint Blockade in

Non-Small Cell Lung Cancer.

Anagnostou V(#)(1)(2), Forde PM(#)(3)(2), White JR(3), Niknafs N(3), Hruban C(3),

Naidoo J(3)(2), Marrone K(3)(2), Sivakumar IKA(3)(4)(5), Bruhm DC(3), Rosner

S(6), Phallen J(3), Leal A(3), Adleff V(3), Smith KN(3)(2), Cottrell TR(3)(7),

Rhymee L(3), Palsgrove DN(3), Hann CL(3), Levy B(3), Feliciano J(3), Georgiades

C(8), Verde F(8), Illei P(3)(2)(7), Li QK(3)(7), Gabrielson E(3)(7), Brock MV(9),

Isbell JM(10), Sauter JL(11), Taube J(3)(2)(7), Scharpf RB(3), Karchin R(3)(4),

Pardoll DM(3)(2), Chaft JE(12), Hellmann MD(12), Brahmer JR(3)(2), Velculescu

VE(1)(2)(4).

Author information:

(1)The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School

of Medicine, Baltimore, Maryland. vanagno1@jhmi.edu velculescu@jhmi.edu.

(2)The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins

University School of Medicine, Baltimore, Maryland.

(3)The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School

of Medicine, Baltimore, Maryland.

(4)Institute for Computational Medicine, Johns Hopkins University, Baltimore,

Maryland.

…

Despite the initial successes of immunotherapy, there is an urgent clinical need

for molecular assays that identify patients more likely to respond. Here, we

report that ultrasensitive measures of circulating tumor DNA (ctDNA) and T-cell

expansion can be used to assess responses to immune checkpoint blockade in

metastatic lung cancer patients (N = 24). Patients with clinical response to

therapy had a complete reduction in ctDNA levels after initiation of therapy,

whereas nonresponders had no significant changes or an increase in ctDNA levels.

Patients with initial response followed by acquired resistance to therapy had an

initial drop followed by recrudescence in ctDNA levels. Patients without a

molecular response had shorter progression-free and overall survival compared

with molecular responders [5.2 vs. 14.5 and 8.4 vs. 18.7 months; HR 5.36; 95%

confidence interval (CI), 1.57-18.35; P = 0.007 and HR 6.91; 95% CI, 1.37-34.97;

P = 0.02, respectively], which was detected on average 8.7 weeks earlier and was

more predictive of clinical benefit than CT imaging. Expansion of T cells,

measured through increases of T-cell receptor productive frequencies, mirrored

ctDNA reduction in response to therapy. We validated this approach in an

independent cohort of patients with early-stage non-small cell lung cancer (N =

14), where the therapeutic effect was measured by pathologic assessment of

residual tumor after anti-PD1 therapy. Consistent with our initial findings,

early ctDNA dynamics predicted pathologic response to immune checkpoint blockade.

These analyses provide an approach for rapid determination of therapeutic

outcomes for patients treated with immune checkpoint inhibitors and have

important implications for the development of personalized immune targeted

strategies.Significance: Rapid and sensitive detection of circulating tumor DNA

dynamic changes and T-cell expansion can be used to guide immune targeted therapy

for patients with lung cancer.See related commentary by Zou and Meyerson, p.

1038.

2018 American Association for Cancer Research.

DOI: 10.1158/0008-5472.CAN-18-1127

PMCID: PMC6432636

PMID: 30541742