Research Highlight |
Featured
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Review Article |
Cell-state dynamics and therapeutic resistance in melanoma from the perspective of MITF and IFNγ pathways
The authors of this Review propose a new model in which dynamic fluctuations of protein expression at the single-cell level and longitudinal reshaping of the cellular state at the cell-population level explain the process of therapeutic resistance development in patients with melanoma.
- Xue Bai
- , David E. Fisher
- & Keith T. Flaherty
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Review Article |
Vessel co-option in cancer
Despite much hope, anti-angiogenic agents have largely failed to achieve the promise demonstrated in preclinical models. In this Review, the authors discuss an alternative hypothesis — vessel co-option — that might explain many of these failures and describe the evidence for a role of this largely overlooked aspect of tumour biology.
- Elizabeth A. Kuczynski
- , Peter B. Vermeulen
- & Andrew R. Reynolds
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Review Article |
The beginning of the end for conventional RECIST — novel therapies require novel imaging approaches
The development of more-targeted cancer therapies has not been matched by more-targeted imaging methods. This discrepancy has, in some scenarios, resulted in inaccurate assessments of the effects of novel therapies. In this Review, the authors describe potential novel imaging approaches that could be adopted to enable improvements in imaging-based monitoring of treatment responses and resistance.
- Mirjam Gerwing
- , Ken Herrmann
- & Moritz Wildgruber
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Review Article |
Beyond 5 years: enduring risk of recurrence in oestrogen receptor-positive breast cancer
Women with early-stage oestrogen receptor (ER)-positive (ER+) breast cancer remain at risk of distant recurrence for at least 15 years after discontinuation of 5 years of standard endocrine therapy. The authors of this Review discuss the epidemiology and mechanisms underlying late recurrence and examine several models used for risk prognostication and for estimating the presence of minimal residual disease.
- Juliet Richman
- & Mitch Dowsett
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Review Article |
Cancer immunoediting and resistance to T cell-based immunotherapy
The mechanisms of resistance to immunotherapy seem to broadly overlap with the immunoediting process whereby cancers evade detection by the immune system. The authors of this Review discuss these interactions as well as the strategies that can be used to overcome therapeutic resistance
- Jake S. O’Donnell
- , Michele W. L. Teng
- & Mark J. Smyth
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Review Article |
State-of-the-art strategies for targeting the DNA damage response in cancer
Inhibition of poly(ADP-ribose) polymerase (PARP) is the paradigmatic example of synthetic lethal therapy and is predicated on exploiting DNA repair deficiencies that are a hallmark of cancer. In this Review, the authors review the progress made to date with PARP inhibitors and describe the expanding landscape of novel anticancer therapies targeting the DNA damage response. Potential predictive biomarkers, mechanisms of resistance and combinatorial strategies are discussed.
- Patrick G. Pilié
- , Chad Tang
- & Timothy A. Yap
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Research Highlight |
BCC identity switch breaks restraints of Hedgehog pathway inhibition
- David Killock
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Review Article |
NTRK fusion-positive cancers and TRK inhibitor therapy
TRK fusion proteins are pathognomonic in certain rare tumour types and present in a small subset of diverse cancer types, including some common cancers; TRK inhibitors have promising efficacy in the treatment of these cancers, in a histology-agnostic manner. In this Review, the biology of TRK signalling and TRK fusions, strategies to target these drivers, the unique safety profile of TRK inhibitors and mechanisms of and strategies to overcome acquired resistance to these agents are discussed.
- Emiliano Cocco
- , Maurizio Scaltriti
- & Alexander Drilon
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Research Highlight |
Signatures IMPRES and might turn the TIDE in predicting responses
- David Killock
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Review Article |
Making the first move in EGFR-driven or ALK-driven NSCLC: first-generation or next-generation TKI?
The clinical management of patients with non-small-cell lung carcinoma has greatly evolved owing to the development of tyrosine-kinase inhibitors (TKIs) targeted against the driver mutations of this disease. The authors of this Review describe the existing evidence on the sequential administration of TKIs and the use of next-generation TKIs upfront.
- Gonzalo Recondo
- , Francesco Facchinetti
- & Luc Friboulet
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Research Highlight |
Uncovering the clonal basis of response and resistance to IDH2 inhibition in AML
- David Killock
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News & Views |
Next-generation sequencing for measuring minimal residual disease in AML
The prognostic significance of residual disease, measured by flow cytometry or PCR-based assays, has been established in patients with acute myeloid leukaemia (AML). The results of a recent study involving almost 500 patients in morphological remission demonstrate that detection of persistent mutations using next-generation sequencing provides information complementary to that obtained using the established methods and offer insights into AML evolution.
- Roland B. Walter
- & Frederick R. Appelbaum
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Review Article |
Treatment resistance in urothelial carcinoma: an evolutionary perspective
Patients with advanced-stage urothelial carcinoma typically receive chemotherapy and might also receive immune-checkpoint inhibitors following disease progression. However, the majority of patients will ultimately develop resistance to treatment. In this Review, the authors describe the evolutionary mechanisms of treatment resistance in patients with urothelial carcinoma.
- Panagiotis J. Vlachostergios
- & Bishoy M. Faltas
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Review Article |
Targeting the PI3K pathway in cancer: are we making headway?
The PI3K–AKT–mTOR pathway has key roles in tumorigenesis and is dysregulated in most cancers. Consequently, numerous drugs that target key nodes of this pathway have been developed, although few of these agents have been approved for the treatment of cancer. Herein, the authors review the current experience with anticancer therapies that target the PI3K–AKT–mTOR pathway, discuss the challenges that have limited the clinical translation of these agents, and provide perspectives for the future development of these drugs.
- Filip Janku
- , Timothy A. Yap
- & Funda Meric-Bernstam
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Editorial |
CAR T cells — what have we learnt?
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Review Article |
Tumour heterogeneity and resistance to cancer therapies
The onset of acquired resistance to treatment is virtually inevitable in patients with solid tumours. In this Review, the authors describe the role of tumour heterogeneity in the development of acquired resistance, potential treatment strategies that take into account the heterogeneity of patient's tumours, and how a better understanding of tumour heterogeneity might improve the outcomes of patients.
- Ibiayi Dagogo-Jack
- & Alice T. Shaw
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Research Highlight |
Liquid biopsy provides highly sensitive detection of RAS mutations
- Peter Sidaway
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Review Article |
Fusions in solid tumours: diagnostic strategies, targeted therapy, and acquired resistance
A wide range of gene fusions have been detected in solid tumours, and the products of these fusions, some of which result in constitutive activation of kinase signalling, can be targeted using tyrosine-kinase inhibitors. However, the development of acquired resistance is almost inevitable. In this Review, the authors describe strategies used to diagnose and treat patients with fusion-positive cancers.
- Alison M. Schram
- , Matthew T. Chang
- & Alexander Drilon
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Editorial |
Context: the grey matter of cancer
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Review Article |
Antibody–drug conjugates in glioblastoma therapy: the right drugs to the right cells
Few therapeutic options are currently available for patients with glioblastoma, which are associated with a poor prognosis. Therapies with monoclonal antibodies, alone or linked to cytotoxic payloads, are currently being explored in these patients. Herein, the authors summarize therapeutic strategies based on antibody–drug conjugates (ADCs), targeted against EGFR, and discuss key aspects such as the blood–brain barrier, resistance mechanisms, and the development of specific biomarkers.
- Hui K. Gan
- , Martin van den Bent
- & Andrew M. Scott
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Review Article |
Monitoring immune-checkpoint blockade: response evaluation and biomarker development
Patients receiving anticancer therapies based on immune-checkpoint blockade (ICB) often experience clinical benefits from such treatments, but unconventional patterns of response can be observed, emphasizing the importance of using a specific approach to evaluating responses to immunotherapy. Herein, the authors review the biological mechanisms underlying the response patterns associated with ICB, describe strategies for the assessments of such responses, and highlight the ongoing efforts to identify biomarkers to guide treatment with ICB.
- Mizuki Nishino
- , Nikhil H. Ramaiya
- & F. Stephen Hodi
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Opinion |
Evolution of lymphoma staging and response evaluation: current limitations and future directions
Accurate detection and monitoring of treatment responses is an essential element of the management of patients with lymphoma. In this Perspectives, the authors describe the evolution of lymphoma staging criteria and highlight unaddressed questions, which, if answered, will substantially improve the management of patients with lymphoma.
- Joel Cunningham
- , Sunil Iyengar
- & Bhupinder Sharma
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Review Article |
Unravelling the biology of SCLC: implications for therapy
For three decades, the treatment of small-cell lung cancer (SCLC) has remained essentially unchanged, and patient outcomes remain dismal. In the past 5 years, however, advances in our understanding of the disease, at the molecular level, have resulted in the development of new therapeutic strategies, encompassing immunotherapies and novel molecularly targeted agents. Herein, authors review the breakthroughs that hold the promise to improve SCLC outcomes.
- Joshua K. Sabari
- , Benjamin H. Lok
- & Charles M. Rudin
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News & Views |
Hiding in plain sight: immune escape in the era of targeted T-cell-based immunotherapies
Adoptive cellular therapy (ACT) is now considered a bona fide treatment modality within the evolving field of anticancer immunotherapy. Great advances have enabled the adoptive transfer of tumour-selective lymphocytes for the treatment of a variety of malignancies. Unfortunately, this selectivity has led to the emergence of antigen-loss variants. New strategies need to be employed to minimize the incidence of this phenomenon, enabling the full potential of ACT to be realized.
- Anthony F. Daniyan
- & Renier J. Brentjens
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News & Views |
Exploiting synthetic lethality to improve cancer therapy
The success of cancer therapies is hampered by a paucity of suitable drug targets and the rapid development of therapy resistance. The concept of synthetic lethality provides a potential solution to these constraints via the identification of novel therapeutic vulnerabilities, as exemplified in two recent studies.
- Diede Brunen
- & René Bernards
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Immunoediting defines prognosis
Gut bacteria modulate responses to PD-1 blockade
CRISPR unveils T-cell-resistance mechanisms in tumours
Tracing tumour evolution
Dual targeting to defeat resistance
Unravelling intertwined second-line options
Reversal of fortunes for TKI resistance
Fitness depends on KRAS imbalance