Research Highlight |
Featured
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Review Article |
Targeting cuproplasia and cuproptosis in cancer
Copper is an essential trace element with inherent redox properties and fundamental roles in a diverse range of biological processes; therefore, maintaining copper homeostasis is crucial. In this Review, the authors discuss new insights into the mechanisms by which disrupted copper homeostasis contributes to tumour initiation and development, including the recently defined concepts of cuproplasia (copper-dependent cell growth and proliferation) and cuproptosis (a mitochondrial pathway of cell death triggered by excessive copper exposure). They also discuss potential strategies to exploit cuproplasia and cuproptosis for the treatment of cancer.
- Daolin Tang
- , Guido Kroemer
- & Rui Kang
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Review Article |
Dendritic cells as orchestrators of anticancer immunity and immunotherapy
Dendritic cells (DCs) are antigen-presenting cells that function at the interface between innate and adaptive immunity, thereby acting as key mediators of antitumour immune responses and immunotherapy efficacy. In this Review, the authors outline the emerging complexity of intratumoural DC states that is being revealed through single-cell analyses as well as the contributions of different DC subsets to anticancer immunity and the activity of immune-checkpoint inhibitors. The authors also discuss advances in the development of DC-based cancer therapies and considerations for their potential combination with other anticancer therapies.
- Ignacio Heras-Murillo
- , Irene Adán-Barrientos
- & David Sancho
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Review Article |
TAM family kinases as therapeutic targets at the interface of cancer and immunity
The TAM (TYRO3, AXL and MERTK) family receptor tyrosine kinases (RTKs) have diverse cancer-promoting functions in malignant cells as well as immune cells and other cell types in the tumour microenvironment, presenting an attractive opportunity for both direct and immune-mediated therapeutic activity manifest through inhibition of a single target. Accordingly, a variety of agents designed to selectively target TAM RTKs are entering clinical testing. This Review provides an essential guide to the TAM RTKs for clinicians. The authors comprehensively review the various roles of TAM RTKs in cancer, the evidence supporting their potential as therapeutic targets, and the translational development of TAM-targeted agents as cancer treatments.
- Deborah DeRyckere
- , Justus M. Huelse
- & Douglas K. Graham
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Review Article |
The roles and implications of RNA m6A modification in cancer
Dysregulation of N6-methyladenosine (m6A), the most prevalent internal modification in eukaryotic mRNA, is common in various cancer types. The authors of this Review provide an overview of the mechanisms of m6A-dependent RNA regulation, summarize current knowledge of their pathological effects and potential utility as biomarkers in cancer, and describe ongoing efforts to develop small-molecule inhibitors of oncogenic m6A modifiers.
- Xiaolan Deng
- , Ying Qing
- & Jianjun Chen
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Review Article |
Criteria for the translation of radiomics into clinically useful tests
Despite a considerable increase in research output over the past decades, the translation of radiomic research into clinically useful tests has been limited. In this Review, the authors provide 16 key criteria to guide the clinical translation of radiomics with the hope of accelerating the use of this technology to improve patient outcomes.
- Erich P. Huang
- , James P. B. O’Connor
- & Lalitha K. Shankar
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Review Article |
Advancing therapy for neuroblastoma
Neuroblastomas are tumours of sympathetic origins typically seen in infants (≤5 years of age). In this Review, the authors describe progress in the treatment of patients with neuroblastoma, which has resulted in considerable improvements in survival outcomes over the past several decades. The authors then summarize ongoing attempts to personalize therapy in patients with high-risk disease, and to safely de-escalate therapy in those with low-risk disease.
- Bo Qiu
- & Katherine K. Matthay
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Review Article |
Mechanisms regulating PD-L1 expression in cancers and associated opportunities for novel small-molecule therapeutics
Antibodies targeting PD-1 or its ligand PD-L1 have revolutionized cancer therapy. Increased understanding of the mechanisms regulating PD-L1 has revealed links with several important oncogenic signalling pathways. Herein, the authors review the transcriptional, post-transcriptional and translational regulation of PD-L1 expression in cancers as well as the diverse post-translational modifications, including phosphorylation, palmitoylation, glycosylation, acetylation and ubiquitination, that affect PD-L1 stability and activity. They also discuss the possibility to simultaneously target key oncogenic pathways and modulate PD-L1 expression using small-molecule agents, which have potential advantages over or might synergize with anti-PD-1/PD-L1 antibodies.
- Hirohito Yamaguchi
- , Jung-Mao Hsu
- & Mien-Chie Hung
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News & Views |
Tumour antigen-induced T cell exhaustion — the archenemy of immune-hot malignancies
Two recent studies addressed the functional properties and clinical significance of tumour antigen-specific effector T cells in human melanomas and lung carcinomas using single-cell strategies. Herein, we discuss their findings, which expand our understanding of T cell alterations in the tumour microenvironment and demonstrate that CD8+ T cell exhaustion is mediated by exposure to tumour cell-specific antigens and is associated with a tissue-resident memory phenotype.
- Miguel Lopez de Rodas
- & Kurt A. Schalper
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Review Article |
A comparison of chimeric antigen receptors containing CD28 versus 4-1BB costimulatory domains
Chimeric antigen receptor (CAR) T cell therapies are generating substantial excitement and have been approved for the treatment of various haematological malignancies. All approved CARs consist of an extracellular antigen-binding domain linked to an intracellular region containing a costimulatory domain and a T cell activation domain. A key question is whether the CD28-derived and 4-1BB-derived costimulatory domains used in current commercial CAR T cell products are associated with different cellular and clinical effects. Herein, Cappell and Kochenderfer provide an overview of CD28 and 4-1BB costimulatory pathways and compare the outcomes observed in preclinical and clinical studies with CARs incorporating either costimulatory domain.
- Kathryn M. Cappell
- & James N. Kochenderfer
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News & Views |
First clinical proof-of-concept that FMT can overcome resistance to ICIs
An unfavourable gut bacterial composition has been shown to reduce the likelihood of clinical benefit from immune-checkpoint inhibitors (ICIs). The results of two first-in-human studies of faecal microbiota transplantation in patients with melanoma refractory to anti-PD-1 antibodies validate preclinical evidence that this approach can improve the gut microbiota and overcome resistance to ICIs; however, many questions remain.
- Arielle Elkrief
- & Bertrand Routy
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Review Article |
Exploring the NK cell platform for cancer immunotherapy
Natural killer (NK) cells have an innate potential to kill cancerous cells and considerable effort is being focused on innovative approaches to leverage these cells for cancer therapy. Herein, the authors discuss the variety of NK cell-based therapies that are being developed for the treatment of diverse cancers and identify future avenues for NK cell therapy research.
- Jacob A. Myers
- & Jeffrey S. Miller
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Review Article |
Tumour budding in solid cancers
Tumour budding is hypothesized to reflect the invasive and metastatic capacities of cancers and is accordingly associated with unfavourable patient outcomes. Herein, Lugli and colleagues describe the pathobiological characteristics of this phenomenon, including its associations with epithelial–mesenchymal transition and features of the tumour microenvironment, and review the evidence demonstrating the value of tumour budding as a prognostic biomarker across various solid cancers.
- Alessandro Lugli
- , Inti Zlobec
- & Iris D. Nagtegaal
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Review Article |
The adenosine pathway in immuno-oncology
Signalling induced by extracellular adenosine (eADO) can suppress antitumour immunity through multiple mechanisms. Herein, the authors review the pathophysiological functions of eADO in cancer and the related prognostic implications. They discuss the associated opportunities for eADO pathway-targeted immunotherapy, highlighting potential limitations and the scope for combination and biomarker-based strategies. The data emerging from oncology clinical trials of the diverse range of therapies that have been developed to target the eADO signalling pathway are also described.
- Bertrand Allard
- , David Allard
- & John Stagg
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Review Article |
Roles and mechanisms of alternative splicing in cancer — implications for care
Alternative splicing enables the regulated generation of multiple mRNA and protein products from a single gene. This Review outlines the splicing process and its alterations in cancer before highlighting related opportunities for the development of innovative therapeutic approaches.
- Sophie C. Bonnal
- , Irene López-Oreja
- & Juan Valcárcel
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Review Article |
T cell-engaging therapies — BiTEs and beyond
The use of bispecific antibodies to engage cells of the immune system that are cytotoxic to cancer cells is a major focus of cancer immunotherapy, with approvals for the treatment of acute lymphoblastic leukaemia. Here, the authors review the clinical results obtained with bispecific antibodies to date. They also discuss the challenges associated with this therapeutic approach and the proposed solutions aimed at preventing or minimizing toxicities, countering immune escape and broadening the indications for these treatments.
- Maria-Elisabeth Goebeler
- & Ralf C. Bargou
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Perspective |
Harnessing cancer immunotherapy during the unexploited immediate perioperative period
Surgery remains a key pillar of cancer therapy, particular for those with curable, localized disease. The immediate perioperative period (days before and after surgery) is associated with various psychological and physiological stresses and associated factors, including inflammatory mediators, that might promote cancer progression and thus determine long-term outcomes. Herein, the authors present the hypothesis and supporting evidence that the use of certain types of immunotherapy, together with interventions to abrogate stress–inflammatory responses, in conjunction with surgery might improve the overall success of cancer treatment.
- Pini Matzner
- , Elad Sandbank
- & Shamgar Ben-Eliyahu
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Comment |
The roles of patient groups in fostering cancer research
As more patients with oncogene-driven non-small-cell lung cancer are treated with targeted therapies, they are joining forces online to form groups that provide support, education and advocacy focused on specific oncogenes. Herein, we discuss how the involvement of these groups in patient-partnered research can benefit both patients and lung cancer research.
- Merel Hennink
- , Geert Vandeweyer
- & Janet Freeman-Daily
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Review Article |
Engineering strategies to overcome the current roadblocks in CAR T cell therapy
Chimeric antigen receptor (CAR) T cell therapy, the first approved therapeutic approach with a genetic engineering component, holds substantial promise in the treatment of a range of cancers but is nevertheless limited by various challenges, including toxicities, intrinsic and acquired resistance mechanisms, and manufacturing issues. In this Review, the authors describe the innovative approaches to the engineering of CAR T cell products that are providing solutions to these challenges and therefore have the potential to considerably improve the safety and effectiveness of treatment.
- Sarwish Rafiq
- , Christopher S. Hackett
- & Renier J. Brentjens
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Review Article |
Targeting signalling pathways and the immune microenvironment of cancer stem cells — a clinical update
Cancer stem cells (CSCs) are implicated in cancer development, progression and resistance to treatment; therefore, the signalling pathways that mediate the CSC phenotype are attractive therapeutic targets. In this Review, the authors provide an update on the progress in targeting the Notch, WNT, Hedgehog and Hippo signalling pathways. Additionally, they discuss the interactions of CSCs with the immune system, the roles of CSC-related signalling pathways in immune cells and novel approaches to CSC-directed immunotherapy.
- Joseph A. Clara
- , Cecilia Monge
- & Naoko Takebe
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News & Views |
Tinkering in the garage — tuning CARs for safety
The adoptive transfer of T cells expressing a chimeric antigen receptor (CAR) is an effective therapy for patients with relapsed or refractory CD19+ B cell malignancies, but can cause life-threatening toxicities. Herein we discuss a recent study suggesting that alterations to the design of anti-CD19 CARs can reduce cytokine release and the incidence of treatment-related complications.
- Alexander I. Salter
- & Stanley R. Riddell
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Correspondence |
Assembling the brain trust: the multidisciplinary imperative in neuro-oncology
- Ethan B. Ludmir
- , Anita Mahajan
- & Mary Frances McAleer
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Correspondence |
Reply to ‘Assembling the brain trust: the multidisciplinary imperative in neuro-oncology’
- Kenneth Aldape
- , Kevin M. Brindle
- & Richard J. Gilbertson
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Consensus Statement
| Open AccessChallenges to curing primary brain tumours
Brain cancer encompasses a diverse range of complex malignancies, many of which are associated with a poor prognosis and require more effective treatments. In this Position Paper, an international panel of clinicians and laboratory-based scientists convened by Cancer Research UK identify and discuss seven challenges that must be overcome if we are to cure all patients with a brain tumour.
- Kenneth Aldape
- , Kevin M. Brindle
- & Richard J. Gilbertson
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Editorial |
Notes from 2017, hopes for 2018
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Comment |
Tumour microenvironment: informing on minimal residual disease in solid tumours
Patients with resectable solid tumours can harbour minimal residual disease (MRD) after initial treatment, which is a potential source for subsequent metastatic relapse. The interaction between disseminated tumour cells (DTCs) and the new microenvironment in which they reside determines whether DTCs remain dormant or progress into overt metastases. We highlight the promise of liquid biopsies to inform on MRD.
- Klaus Pantel
- & Catherine Alix-Panabières
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Review Article |
EMT, CSCs, and drug resistance: the mechanistic link and clinical implications
According to the cancer stem cell (CSC) paradigm, a minor subpopulation of cancer cells with stem-cell properties predominantly underlies tumour progression, therapy resistance, and disease recurrence. Notably, epithelial-to-mesenchymal transition (EMT) is implicated in these processes, and CSCs typically show markers of EMT-programme activation. Herein, the authors outline our current understanding of the links between the EMT programme, the CSC phenotype, metastasis, and drug resistance, and discuss the potential for therapeutic targeting of these facets of tumour biology.
- Tsukasa Shibue
- & Robert A. Weinberg
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Review Article |
Tumour-associated macrophages as treatment targets in oncology
Tumour-associated macrophages (TAMs) are key drivers of tumour-promoting inflammation and cancer progression, and are important determinants of responsiveness to a range of therapies. Herein, the authors summarize the roles of TAMs in cancer, and discuss the potential of TAM-targeted therapeutic strategies to complement and synergize with other anticancer treatments.
- Alberto Mantovani
- , Federica Marchesi
- & Paola Allavena
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Opinion |
A second chance for telomerase reverse transcriptase in anticancer immunotherapy
Telomerase reverse transcriptase (TERT) is expressed constitutively in tumour cells throughout the evolution of many cancers; therefore, this potential tumour self-antigen has been an important target for anticancer vaccines over the past 10 years, but only modest benefits from this approach have been observed in clinical trials. In this Perspectives, Maurizio Zanetti reviews these studies, and highlights advances in our knowledge that warrant further development and refinement of TERT immunotherapy.
- Maurizio Zanetti
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Review Article |
Opportunities and challenges of radiotherapy for treating cancer
Although dramatic changes in the delivery of radiation therapy have occurred, the impact of radiobiology on the clinic has been far less substantial. New advances are uncovering some of the mechanistic processes that underlie the differences between the tumour and host tissue characteristics. The authors of this Review focus on how these processes might be targeted to improve the outcome of radiotherapy for patients.
- Dörthe Schaue
- & William H. McBride
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Review Article |
Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update
Cancer stem cell (CSC) populations are increasingly recognized in most malignancies and are hypothesized to contribute to cancer proliferation, relapse, and metastasis. Thus, the highly conserved stem-cell signal transduction pathways involved in development and tissue homeostasis that are frequently active in CSCs represent prime targets for targeted therapies against this characteristically treatment-resistant and highly tumorigenic cell population. This Review provides a update on the clinical development of therapies targeting Wnt, Notch, and Hedgehog, three prominent stem-cell signalling pathways that are upregulated in CSCs.
- Naoko Takebe
- , Lucio Miele
- & S. Percy Ivy
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Review Article |
Translational research in oncology—10 years of progress and future prospects
The landscape of translational oncology has shifted dramatically over the past 10 years, characterized by the introduction of more-sophisticated molecular tools into the clinic and advances are being employed in genomic clinical trials that will examine the feasibility of matching a broad range of systemic therapies to specific molecular tumour characteristics. The authors review selected developments in translational cancer biology, diagnostics, and therapeutics that have occurred over the past decade and offer our thoughts on future prospects for the next few years.
- James H. Doroshow
- & Shivaani Kummar