2020年
No.2
Medical Abstracts ( IF > 20 )
1. N Engl J Med. 2020 Jul 23;383(4):359-368. doi: 10.1056/NEJMoa1915176.
Vitamin D Supplements for Prevention of Tuberculosis Infection and Disease.
Ganmaa D(1), Uyanga B(1), Zhou X(1), Gantsetseg G(1), Delgerekh B(1), Enkhmaa
D(1), Khulan D(1), Ariunzaya S(1), Sumiya E(1), Bolortuya B(1), Yanjmaa J(1),
Enkhtsetseg T(1), Munkhzaya A(1), Tunsag M(1), Khudyakov P(1), Seddon JA(1),
Marais BJ(1), Batbayar O(1), Erdenetuya G(1), Amarsaikhan B(1), Spiegelman D(1),
Tsolmon J(1), Martineau AR(1).
Author information:
(1)From the Harvard T.H. Chan School of Public Health (D.G., P.K., D.S.) and the
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard
Medical School (D.G.) - all in Boston; the Mongolian Health Initiative (D.G., …
BACKGROUND: Vitamin D metabolites support innate immune responses to
Mycobacterium tuberculosis. Data from phase 3, randomized, controlled trials of
vitamin D supplementation to prevent tuberculosis infection are lacking.
METHODS: We randomly assigned children who had negative results for M.
tuberculosis infection according to the QuantiFERON-TB Gold In-Tube assay (QFT)
to receive a weekly oral dose of either 14,000 IU of vitamin D3 or placebo for 3
years. The primary outcome was a positive QFT result at the 3-year follow-up,
expressed as a proportion of children. Secondary outcomes included the serum
25-hydroxyvitamin D (25[OH]D) level at the end of the trial and the incidence of
tuberculosis disease, acute respiratory infection, and adverse events.
RESULTS: A total of 8851 children underwent randomization: 4418 were assigned to
the vitamin D group, and 4433 to the placebo group; 95.6% of children had a
baseline serum 25(OH)D level of less than 20 ng per milliliter. Among children
with a valid QFT result at the end of the trial, the percentage with a positive
result was 3.6% (147 of 4074 children) in the vitamin D group and 3.3% (134 of
4043) in the placebo group (adjusted risk ratio, 1.10; 95% confidence interval
[CI], 0.87 to 1.38; P = 0.42). The mean 25(OH)D level at the end of the trial
was 31.0 ng per milliliter in the vitamin D group and 10.7 ng per milliliter in
the placebo group (mean between-group difference, 20.3 ng per milliliter; 95%
CI, 19.9 to 20.6). Tuberculosis disease was diagnosed in 21 children in the
vitamin D group and in 25 children in the placebo group (adjusted risk ratio,
0.87; 95% CI, 0.49 to 1.55). A total of 29 children in the vitamin D group and
34 in the placebo group were hospitalized for treatment of acute respiratory
infection (adjusted risk ratio, 0.86; 95% CI, 0.52 to 1.40). The incidence of
adverse events did not differ significantly between the two groups.
CONCLUSIONS: Vitamin D supplementation did not result in a lower risk of
tuberculosis infection, tuberculosis disease, or acute respiratory infection
than placebo among vitamin D-deficient schoolchildren in Mongolia. (Funded by
the National Institutes of Health; ClinicalTrials.gov number, NCT02276755.).
Copyright © 2020 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa1915176
PMID: 32706534 [Indexed for MEDLINE]
2. Science. 2020 Jun 12;368(6496):1211-1219. doi: 10.1126/science.aba9102. Epub
2020 Apr 23.
Structures of cell wall arabinosyltransferases with the anti-tuberculosis drug
ethambutol.
Zhang L(#)(1)(2), Zhao Y(#)(1)(3)(4), Gao Y(5), Wu L(1), Gao R(4)(6),…
Author information:
(1)Shanghai Institute for Advanced Immunochemical Studies, iHuman Institute,
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210,
China.
(2)State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center
for Cell Response, College of Life Sciences, College of Pharmacy, Nankai
University, Tianjin 300353, China.
(3)CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of
Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031,
China.
…
The arabinosyltransferases EmbA, EmbB, and EmbC are involved in Mycobacterium
tuberculosis cell wall synthesis and are recognized as targets for the
anti-tuberculosis drug ethambutol. In this study, we determined cryo-electron
microscopy and x-ray crystal structures of mycobacterial EmbA-EmbB and EmbC-EmbC
complexes in the presence of their glycosyl donor and acceptor substrates and
with ethambutol. These structures show how the donor and acceptor substrates
bind in the active site and how ethambutol inhibits arabinosyltransferases by
binding to the same site as both substrates in EmbB and EmbC. Most
drug-resistant mutations are located near the ethambutol binding site.
Collectively, our work provides a structural basis for understanding the
biochemical function and inhibition of arabinosyltransferases and the
development of new anti-tuberculosis agents.
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American
Association for the Advancement of Science. No claim to original U.S. Government
Works.
DOI: 10.1126/science.aba9102
PMID: 32327601 [Indexed for MEDLINE]
3. Nature. 2020 Jul;583(7818):807-812. doi: 10.1038/s41586-020-2481-8. Epub 2020
Jul 15.
The National Lung Matrix Trial of personalized therapy in lung cancer.
Middleton G(1)(2), Fletcher P(3), Popat S(4), Savage J(3), Summers Y(5),
Greystoke A(6), Gilligan D(7), Cave J(8), O'Rourke N(9), Brewster A(10), Toy
E(11), Spicer J(12), Jain P(13), Dangoor A(14), Mackean M(15), Forster M(16),
Farley A(17), Wherton D(3), Mehmi M(3), Sharpe R(3), Mills TC(18), Cerone
MA(18), Yap TA(19), Watkins TBK(20), Lim E(20), Swanton C(20)(21), Billingham
L(3).
Author information:
(1)Institute of Immunology & Immunotherapy, University of Birmingham,
Birmingham, UK. g.middleton@bham.ac.uk.
(2)University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
g.middleton@bham.ac.uk.
(3)Cancer Research UK Clinical Trials Unit, University of Birmingham,
Birmingham, UK.
…
The majority of targeted therapies for non-small-cell lung cancer (NSCLC) are
directed against oncogenic drivers that are more prevalent in patients with
light exposure to tobacco smoke1-3. As this group represents around 20% of all
patients with lung cancer, the discovery of stratified medicine options for
tobacco-associated NSCLC is a high priority. Umbrella trials seek to streamline
the investigation of genotype-based treatments by screening tumours for multiple
genomic alterations and triaging patients to one of several genotype-matched
therapeutic agents. Here we report the current outcomes of 19 drug-biomarker
cohorts from the ongoing National Lung Matrix Trial, the largest umbrella trial
in NSCLC. We use next-generation sequencing to match patients to appropriate
targeted therapies on the basis of their tumour genotype. The Bayesian trial
design enables outcome data from open cohorts that are still recruiting to be
reported alongside data from closed cohorts. Of the 5,467 patients that were
screened, 2,007 were molecularly eligible for entry into the trial, and 302
entered the trial to receive genotype-matched therapy-including 14 that
re-registered to the trial for a sequential trial drug. Despite pre-clinical
data supporting the drug-biomarker combinations, current evidence shows that a
limited number of combinations demonstrate clinically relevant benefits, which
remain concentrated in patients with lung cancers that are associated with
minimal exposure to tobacco smoke.
DOI: 10.1038/s41586-020-2481-8
PMID: 32669708
4. N Engl J Med. 2020 Feb 6;382(6):503-513. doi: 10.1056/NEJMoa1911793. Epub 2020
Jan 29.
Reduced Lung-Cancer Mortality with Volume CT Screening in a Randomized Trial.
de Koning HJ(1), van der Aalst CM(1), de Jong PA(1), Scholten ET(1), Nackaerts
K(1), Heuvelmans MA(1), Lammers JJ(1), Weenink C(1), Yousaf-Khan U(1), Horeweg
N(1),…
Author information:
(1)From the Departments of Public Health (H.J.K., C.M.A., U.Y.-K., K.H.) and
Pulmonology (J.G.J.V.A.), Erasmus MC-University Medical Center Rotterdam, and
the Departments of Pulmonology (S.W.) and Pathology (M.A.B.), Maasstad Hospital,
Rotterdam, the Departments of Radiology (P.A.J., W.P.M., F.A.A.M.H.) and …
Comment in
N Engl J Med. 2020 Feb 6;382(6):572-573.
Nat Rev Clin Oncol. 2020 Apr;17(4):197.
N Engl J Med. 2020 May 28;382(22):2164.
N Engl J Med. 2020 May 28;382(22):2164-2165.
N Engl J Med. 2020 May 28;382(22):2165.
BACKGROUND: There are limited data from randomized trials regarding whether
volume-based, low-dose computed tomographic (CT) screening can reduce
lung-cancer mortality among male former and current smokers.
METHODS: A total of 13,195 men (primary analysis) and 2594 women (subgroup
analyses) between the ages of 50 and 74 were randomly assigned to undergo CT
screening at T0 (baseline), year 1, year 3, and year 5.5 or no screening. We
obtained data on cancer diagnosis and the date and cause of death through
linkages with national registries in the Netherlands and Belgium, and a review
committee confirmed lung cancer as the cause of death when possible. A minimum
follow-up of 10 years until December 31, 2015, was completed for all
participants.
RESULTS: Among men, the average adherence to CT screening was 90.0%. On average,
9.2% of the screened participants underwent at least one additional CT scan
(initially indeterminate). The overall referral rate for suspicious nodules was
2.1%. At 10 years of follow-up, the incidence of lung cancer was 5.58 cases per
1000 person-years in the screening group and 4.91 cases per 1000 person-years in
the control group; lung-cancer mortality was 2.50 deaths per 1000 person-years
and 3.30 deaths per 1000 person-years, respectively. The cumulative rate ratio
for death from lung cancer at 10 years was 0.76 (95% confidence interval [CI],
0.61 to 0.94; P = 0.01) in the screening group as compared with the control
group, similar to the values at years 8 and 9. Among women, the rate ratio was
0.67 (95% CI, 0.38 to 1.14) at 10 years of follow-up, with values of 0.41 to
0.52 in years 7 through 9.
CONCLUSIONS: In this trial involving high-risk persons, lung-cancer mortality
was significantly lower among those who underwent volume CT screening than among
those who underwent no screening. There were low rates of follow-up procedures
for results suggestive of lung cancer. (Funded by the Netherlands Organization
of Health Research and Development and others; NELSON Netherlands Trial Register
number, NL580.).
Copyright © 2020 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa1911793
PMID: 31995683 [Indexed for MEDLINE]
5. Annu Rev Pharmacol Toxicol. 2020 Aug 17. doi:
10.1146/annurev-pharmtox-030920-011143. Online ahead of print.
Development of New Tuberculosis Drugs: Translation to Regimen Composition for
Drug-Sensitive and Multidrug-Resistant Tuberculosis.
Ernest JP(1), Strydom N(1), Wang Q(1), Zhang N(1), Nuermberger E(2), Dartois
V(3), Savic RM(1).
Author information:
(1)Department of Bioengineering and Therapeutic Sciences, University of
California, San Francisco, California 94158, USA; email: rada.savic@ucsf.edu.
(2)Center for Tuberculosis Research, Johns Hopkins University School of
Medicine, Baltimore, Maryland 21231, USA.
(3)Center for Discovery and Innovation, Hackensack Meridian School of Medicine
at Seton Hall University, Nutley, New Jersey 07110, USA.
Tuberculosis (TB) kills more people than any other infectious disease.
Challenges for developing better treatments include the complex pathology due to
within-host immune dynamics, interpatient variability in disease severity and
drug pharmacokinetics-pharmacodynamics (PK-PD), and the growing emergence of
resistance. Model-informed drug development using quantitative and translational
pharmacology has become increasingly recognized as a method capable of drug
prioritization and regimen optimization to efficiently progress compounds
through TB drug development phases. In this review, we examine translational
models and tools, including plasma PK scaling, site-of-disease lesion PK,
host-immune and bacteria interplay, combination PK-PD models of multidrug
regimens, resistance formation, and integration of data across nonclinical and
clinical phases. We propose a workflow that integrates these tools with
computational platforms to identify drug combinations that have the potential to
accelerate sterilization, reduce relapse rates, and limit the emergence of
resistance. Expected final online publication date for the Annual Review of
Pharmacology and Toxicology, Volume 61 is January 8, 2021. Please see
http://www.annualreviews.org/page/journal/pubdates for revised estimates.
DOI: 10.1146/annurev-pharmtox-030920-011143
PMID: 32806997
6. Nat Med. 2020 Jun 29. doi: 10.1038/s41591-020-0940-2. Online ahead of print.
Bacterial and host determinants of cough aerosol culture positivity in patients
with drug-resistant versus drug-susceptible tuberculosis.
Theron G(1)(2), Limberis J(1), Venter R(2), Smith L(1)(2), Pietersen E(1),
Esmail A(1), Calligaro G(1), Te Riele J(3), de Kock M(2), van Helden P(2), Gumbo
T(4), Clark TG(5)(6), Fennelly K(7), Warren R(2), Dheda K(8)(9).
Author information:
(1)Centre for Lung Infection and Immunity, Division of Pulmonology, Department
of Medicine and UCT Lung Institute & South African MRC/UCT Centre for the Study
of Antimicrobial Resistance, University of Cape Town, Cape Town, South Africa.
(2)DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research and South
African Medical Research Centre for Tuberculosis Research, Division of Molecular
Biology and Human Genetics, Faculty of Medicine and Health Sciences,
Stellenbosch University, Cape Town, South Africa.
(3)Brooklyn Chest Hospital, Cape Town, South Africa.
…
A burgeoning epidemic of drug-resistant tuberculosis (TB) threatens to derail
global control efforts. Although the mechanisms remain poorly clarified,
drug-resistant strains are widely believed to be less infectious than
drug-susceptible strains. Consequently, we hypothesized that lower proportions
of patients with drug-resistant TB would have culturable Mycobacterium
tuberculosis from respirable, cough-generated aerosols compared to patients with
drug-susceptible TB, and that multiple factors, including mycobacterial genomic
variation, would predict culturable cough aerosol production. We enumerated the
colony forming units in aerosols (≤10 µm) from 452 patients with TB (227 with
drug resistance), compared clinical characteristics, and performed mycobacterial
whole-genome sequencing, dormancy phenotyping and drug-susceptibility analyses
on M. tuberculosis from sputum. After considering treatment duration, we found
that almost half of the patients with drug-resistant TB were cough aerosol
culture-positive. Surprisingly, neither mycobacterial genomic variants, lineage,
nor dormancy status predicted cough aerosol culture positivity. However,
mycobacterial sputum bacillary load and clinical characteristics, including a
lower symptom score and stronger cough, were strongly predictive, thereby
supporting targeted transmission-limiting interventions. Effective treatment
largely abrogated cough aerosol culture positivity; however, this was not always
rapid. These data question current paradigms, inform public health strategies
and suggest the need to redirect TB transmission-associated research efforts
toward host-pathogen interactions.
DOI: 10.1038/s41591-020-0940-2
PMID: 32601338
7. Nat Immunol. 2020 Apr;21(4):464-476. doi: 10.1038/s41590-020-0610-z. Epub 2020
Mar 16.
Mouse transcriptome reveals potential signatures of protection and pathogenesis
in human tuberculosis.
Moreira-Teixeira L(1), Tabone O(1), Graham CM(1), Singhania A(1), Stavropoulos
E(1), Redford PS(1)(2), Chakravarty P(3), Priestnall SL(4)(5), Suarez-Bonnet
A(4)(5), Herbert E(4)(5), Mayer-Barber KD(6), Sher A(7), Fonseca
KL(8)(9)(10)(11), Sousa J(8)(9)(10), Cá B(8)(9)(10)(11), Verma R(12), Haldar
P(12), Saraiva M(8)(9), O'Garra A(13)(14).
Author information:
(1)Laboratory of Immunoregulation and Infection, The Francis Crick Institute,
London, UK.
(2)GSK R&D, Medicines Research Centre, Stevenage, UK.
(3)Bioinformatics Core, The Francis Crick Institute, London, UK.
…
Although mouse infection models have been extensively used to study the host
response to Mycobacterium tuberculosis, their validity in revealing determinants
of human tuberculosis (TB) resistance and disease progression has been heavily
debated. Here, we show that the modular transcriptional signature in the blood
of susceptible mice infected with a clinical isolate of M. tuberculosis
resembles that of active human TB disease, with dominance of a type I interferon
response and neutrophil activation and recruitment, together with a loss in B
lymphocyte, natural killer and T cell effector responses. In addition, resistant
but not susceptible strains of mice show increased lung B cell, natural killer
and T cell effector responses in the lung upon infection. Notably, the blood
signature of active disease shared by mice and humans is also evident in latent
TB progressors before diagnosis, suggesting that these responses both predict
and contribute to the pathogenesis of progressive M. tuberculosis infection.
DOI: 10.1038/s41590-020-0610-z
PMID: 32205882 [Indexed for MEDLINE]
8. Nat Med. 2020 Apr;26(4):529-534. doi: 10.1038/s41591-020-0770-2. Epub 2020 Feb
17.
Dynamic imaging in patients with tuberculosis reveals heterogeneous drug
exposures in pulmonary lesions.
Ordonez AA(1)(2)(3), Wang H(4), Magombedze G(5), Ruiz-Bedoya CA(1)(2)(3),
Srivastava S(5), Chen A(1)(6), Tucker EW(1)(2)(7), Urbanowski ME(2)(8), Pieterse
L(1)(2)(7), Fabian Cardozo E(9), Lodge MA(6), Shah MR(2)(8), Holt DP(6), Mathews
WB(6), Dannals RF(6), Gobburu JVS(4), Peloquin CA(10), Rowe SP(6), Gumbo T(5),
Ivaturi VD(4), Jain SK(11)(12)(13)(14).
Author information:
(1)Center for Infection and Inflammation Imaging Research, Johns Hopkins
University School of Medicine, Baltimore, MD, USA.
(2)Center for Tuberculosis Research, Johns Hopkins University School of
Medicine, Baltimore, MD, USA.
(3)Department of Pediatrics, Johns Hopkins University School of Medicine,
Baltimore, MD, USA.
…
Tuberculosis (TB) is the leading cause of death from a single infectious agent,
requiring at least 6 months of multidrug treatment to achieve cure1. However,
the lack of reliable data on antimicrobial pharmacokinetics (PK) at infection
sites hinders efforts to optimize antimicrobial dosing and shorten TB
treatments2. In this study, we applied a new tool to perform unbiased,
noninvasive and multicompartment measurements of antimicrobial
concentration-time profiles in humans3. Newly identified patients with
rifampin-susceptible pulmonary TB were enrolled in a first-in-human study4 using
dynamic [11C]rifampin (administered as a microdose) positron emission tomography
(PET) and computed tomography (CT). [11C]rifampin PET-CT was safe and
demonstrated spatially compartmentalized rifampin exposures in pathologically
distinct TB lesions within the same patients, with low cavity wall rifampin
exposures. Repeat PET-CT measurements demonstrated independent temporal
evolution of rifampin exposure trajectories in different lesions within the same
patients. Similar findings were recapitulated by PET-CT in experimentally
infected rabbits with cavitary TB and confirmed using postmortem mass
spectrometry. Integrated modeling of the PET-captured concentration-time
profiles in hollow-fiber bacterial kill curve experiments provided estimates on
the rifampin dosing required to achieve cure in 4 months. These data, capturing
the spatial and temporal heterogeneity of intralesional drug PK, have major
implications for antimicrobial drug development.
DOI: 10.1038/s41591-020-0770-2
PMCID: PMC7160048
PMID: 32066976 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests The authors declare no
competing interests.
9. Cancer Cell. 2020 Aug 10;38(2):229-246.e13. doi: 10.1016/j.ccell.2020.06.012.
Epub 2020 Jul 23.
Emergence of a High-Plasticity Cell State during Lung Cancer Evolution.
Marjanovic ND(1), Hofree M(2), Chan JE(3), Canner D(4), Wu K(5), Trakala M(4),
…
Author information:
(1)Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA
02142, USA; David H. Koch Institute for Integrative Cancer Research,
Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Computational
and Systems Biology PhD Program, Massachusetts Institute of Technology,
Cambridge, MA 02139, USA.
(2)Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA
02142, USA.
(3)Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial
Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine,
Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
…
Tumor evolution from a single cell into a malignant, heterogeneous tissue
remains poorly understood. Here, we profile single-cell transcriptomes of
genetically engineered mouse lung tumors at seven stages, from pre-neoplastic
hyperplasia to adenocarcinoma. The diversity of transcriptional states increases
over time and is reproducible across tumors and mice. Cancer cells progressively
adopt alternate lineage identities, computationally predicted to be mediated
through a common transitional, high-plasticity cell state (HPCS). Accordingly,
HPCS cells prospectively isolated from mouse tumors and human patient-derived
xenografts display high capacity for differentiation and proliferation. The HPCS
program is associated with poor survival across human cancers and demonstrates
chemoresistance in mice. Our study reveals a central principle underpinning
intra-tumoral heterogeneity and motivates therapeutic targeting of the HPCS.
Copyright © 2020 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ccell.2020.06.012
PMID: 32707077
10. Cancer Cell. 2020 Jul 13;38(1):129-143.e7. doi: 10.1016/j.ccell.2020.05.003.
Epub 2020 Jun 11.
Unbiased Proteomic Profiling Uncovers a Targetable GNAS/PKA/PP2A Axis in Small
Cell Lung Cancer Stem Cells.
Coles GL(1), Cristea S(1), Webber JT(2), Levin RS(3), Moss SM(4), He A(1),
Sangodkar J(5), Hwang YC(6), Arand J(1), Drainas AP(1), Mooney NA(7), Demeter
J(7), Spradlin JN(8), Mauch B(1), Le V(1), Shue YT(1), Ko JH(1), Lee MC(1), Kong
C(9), Nomura DK(10), Ohlmeyer M(11), Swaney DL(12), Krogan NJ(12), Jackson
PK(13), Narla G(5), Gordan JD(14), Shokat KM(3), Sage J(15).
Author information:
(1)Department of Pediatrics, Stanford University, 265 Campus Drive, Stanford, CA
94305-5457, USA; Department of Genetics, Stanford University, Stanford, CA
94305, USA.
(2)Department of Bioengineering and Therapeutic Sciences, University of
California San Francisco, San Francisco, CA 94158, USA.
(3)Howard Hughes Medical Institute, University of California San Francisco, San
Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology,
University of California San Francisco, San Francisco, CA 94158, USA.
…
Using unbiased kinase profiling, we identified protein kinase A (PKA) as an
active kinase in small cell lung cancer (SCLC). Inhibition of PKA activity
genetically, or pharmacologically by activation of the PP2A phosphatase,
suppresses SCLC expansion in culture and in vivo. Conversely, GNAS (G-protein α
subunit), a PKA activator that is genetically activated in a small subset of
human SCLC, promotes SCLC development. Phosphoproteomic analyses identified many
PKA substrates and mechanisms of action. In particular, PKA activity is required
for the propagation of SCLC stem cells in transplantation studies. Broad
proteomic analysis of recalcitrant cancers has the potential to uncover
targetable signaling networks, such as the GNAS/PKA/PP2A axis in SCLC.
Copyright © 2020 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ccell.2020.05.003
PMCID: PMC7363571
PMID: 32531271
11. Cancer Cell. 2020 Jul 13;38(1):60-78.e12. doi: 10.1016/j.ccell.2020.05.001. Epub 2020 May 30.
MYC Drives Temporal Evolution of Small Cell Lung Cancer Subtypes by
Reprogramming Neuroendocrine Fate.
Ireland AS(1), Micinski AM(1), Kastner DW(1), Guo B(1), Wait SJ(1), Spainhower
KB(1), Conley CC(2), Chen OS(3), Guthrie MR(1), Soltero D(1), Qiao Y(4), Huang
X(4), Tarapcsák S(4), Devarakonda S(5), Chalishazar MD(1), Gertz J(1), Moser
JC(6), Marth G(4), Puri S(7), Witt BL(8), Spike BT(1), Oliver TG(9).
Author information:
(1)Department of Oncological Sciences, Huntsman Cancer Institute, University of
Utah, Salt Lake City, UT 84112, USA.
(2)Huntsman Cancer Institute Bioinformatic Analysis Shared Resource, Huntsman
Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
(3)Huntsman Cancer Institute High-Throughput Genomics Shared Resource, Huntsman
Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
…
Small cell lung cancer (SCLC) is a neuroendocrine tumor treated clinically as a
single disease with poor outcomes. Distinct SCLC molecular subtypes have been
defined based on expression of ASCL1, NEUROD1, POU2F3, or YAP1. Here, we use
mouse and human models with a time-series single-cell transcriptome analysis to
reveal that MYC drives dynamic evolution of SCLC subtypes. In neuroendocrine
cells, MYC activates Notch to dedifferentiate tumor cells, promoting a temporal
shift in SCLC from ASCL1+ to NEUROD1+ to YAP1+ states. MYC alternatively
promotes POU2F3+ tumors from a distinct cell type. Human SCLC exhibits
intratumoral subtype heterogeneity, suggesting that this dynamic evolution
occurs in patient tumors. These findings suggest that genetics, cell of origin,
and tumor cell plasticity determine SCLC subtype.
Copyright © 2020 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ccell.2020.05.001
PMCID: PMC7393942
PMID: 32473656
12. Cancer Cell. 2020 Jul 13;38(1):97-114.e7. doi: 10.1016/j.ccell.2020.04.016. Epub 2020 May 28.
MAX Functions as a Tumor Suppressor and Rewires Metabolism in Small Cell Lung
Cancer.
Augert A(1), Mathsyaraja H(2), Ibrahim AH(1), Freie B(2), Geuenich MJ(3), Cheng
PF(2), Alibeckoff SP(4), Wu N(1), Hiatt JB(1), Basom R(5), Gazdar A(6), Sullivan
LB(4), Eisenman RN(7), MacPherson D(8).
Author information:
(1)Division of Human Biology, Fred Hutchinson Cancer Research Center, 1100
Fairview Avenue N, Seattle, WA 98109, USA.
(2)Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
98109, USA.
(3)Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
98109, USA; Quest University Canada, 3200 University Boulevard, Squamish, BC V8B
0N8, Canada.
…
Small cell lung cancer (SCLC) is a highly aggressive and lethal neoplasm. To
identify candidate tumor suppressors we applied CRISPR/Cas9 gene inactivation
screens to a cellular model of early-stage SCLC. Among the top hits was MAX, the
obligate heterodimerization partner for MYC family proteins that is mutated in
human SCLC. Max deletion increases growth and transformation in cells and
dramatically accelerates SCLC progression in an Rb1/Trp53-deleted mouse model.
In contrast, deletion of Max abrogates tumorigenesis in MYCL-overexpressing
SCLC. Max deletion in SCLC resulted in derepression of metabolic genes involved
in serine and one-carbon metabolism. By increasing serine biosynthesis,
Max-deleted cells exhibit resistance to serine depletion. Thus, Max loss results
in metabolic rewiring and context-specific tumor suppression.
Copyright © 2020. Published by Elsevier Inc.
DOI: 10.1016/j.ccell.2020.04.016
PMCID: PMC7363581
PMID: 32470392
13. Nat Med. 2020 May;26(5):732-740. doi: 10.1038/s41591-020-0840-5. Epub 2020 Apr
27.
Safety and feasibility of CRISPR-edited T cells in patients with refractory
non-small-cell lung cancer.
Lu Y(1), Xue J(2), Deng T(3), Zhou X(2), Yu K(3), Deng L(4), Huang M(2), Yi
X(5), Liang M(6), Wang Y(7), Shen H(7), Tong R(2), Wang W(8), Li L(2), Song
J(5), Li J(5), Su X(9), Ding Z(2), Gong Y(2), Zhu J(2), Wang Y(2)(6), Zou B(2),
Zhang Y(2), Li Y(2), Zhou L(2), Liu Y(2), Yu M(2), Wang Y(5), Zhang X(2), Yin
L(2), Xia X(5), Zeng Y(3), Zhou Q(10), Ying B(11), Chen C(12), Wei Y(12), Li
W(13), Mok T(14).
Author information:
(1)Department of Thoracic Oncology, Cancer Center and State Key Laboratory of
Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
radyoulu@hotmail.com.
(2)Department of Thoracic Oncology, Cancer Center and State Key Laboratory of
Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
(3)Chengdu MedGenCell, Co., Ltd, Chengdu, China.
…
Erratum in
Nat Med. 2020 Jul;26(7):1149.
Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 editing
of immune checkpoint genes could improve the efficacy of T cell therapy, but the
first necessary undertaking is to understand the safety and feasibility. Here,
we report results from a first-in-human phase I clinical trial of CRISPR-Cas9
PD-1-edited T cells in patients with advanced non-small-cell lung cancer
(ClinicalTrials.gov NCT02793856). Primary endpoints were safety and feasibility,
and the secondary endpoint was efficacy. The exploratory objectives included
tracking of edited T cells. All prespecified endpoints were met. PD-1-edited T
cells were manufactured ex vivo by cotransfection using electroporation of Cas9
and single guide RNA plasmids. A total of 22 patients were enrolled; 17 had
sufficient edited T cells for infusion, and 12 were able to receive treatment.
All treatment-related adverse events were grade 1/2. Edited T cells were
detectable in peripheral blood after infusion. The median progression-free
survival was 7.7 weeks (95% confidence interval, 6.9 to 8.5 weeks) and median
overall survival was 42.6 weeks (95% confidence interval, 10.3-74.9 weeks). The
median mutation frequency of off-target events was 0.05% (range, 0-0.25%) at 18
candidate sites by next generation sequencing. We conclude that clinical
application of CRISPR-Cas9 gene-edited T cells is generally safe and feasible.
Future trials should use superior gene editing approaches to improve therapeutic
efficacy.
DOI: 10.1038/s41591-020-0840-5
PMID: 32341578
