Featured
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Review Article |
Strategies to avoid treatment-induced lineage crisis in advanced prostate cancer
Emerging evidence suggests that the prolonged therapeutic use of androgen receptor (AR)-targeting agents in patients with prostate cancer induces histological dedifferentiation and lineage alterations. Roubaud and colleagues propose that AR suppression creates a checkpoint by which potent therapies exert a selective pressure on prostate cancer cells, favouring dedifferentiated and/or treatment-resistant cell lineages. The authors present a new clinical trial strategy in which rapid drug cycling is used to delay the onset of resistance and treatment-induced lineage crisis in patients with prostate cancer.
- Guilhem Roubaud
- , Bobby C. Liaw
- & David J. Mulholland
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Opinion |
Combine and conquer: challenges for targeted therapy combinations in early phase trials
The presence ofde novoresistance or the development of acquired resistance in cancer cells has limited the use of targeted agents. Combinations of targeted treatments can circumvent some mechanisms of resistance to yield clinical benefit. The authors explore the challenges in identifying the best drug combinations and the best combination strategies, as well as the complexities of delivering these treatments to patients.
- Juanita S. Lopez
- & Udai Banerji
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News & Views |
Using ctDNA to track EGFR and KRAS mutations in advanced-stage disease
Analysis of circulating tumour DNA (ctDNA) in blood samples provides a surrogate form of tumour biopsy (liquid biopsy) for determining EGFR and KRAS mutation status in patients with advanced-stage non-small-cell lung cancer. This approach obviates the need for a repeat biopsy, especially for the EGFR T790M mutation, which confers resistance to EGFR inhibition.
- Rafael Rosell
- & Niki Karachaliou
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Year in Review |
Immune-checkpoint blockade — durable cancer control
In 2015, advances in immunotherapy for metastatic melanoma have come to fruition, with phase III data supporting the combination of ipilimumab and nivolumab as first-line therapy. Understanding the mechanisms involved in an effective antitumour immune response are now key to further advances. Several studies published in 2015 have increased our understanding of the complex relationships that exist between our immune system and malignancy.
- Elizabeth I. Buchbinder
- & F. Stephen Hodi
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Year in Review |
Bypassing checkpoints, overcoming resistance, and honing in on new targets
Lung-cancer treatment paradigms continue to advance as we exploit our growing understanding of the genetic basis of both tumorigenesis and therapy resistance. Moreover, ongoing developments with targeted therapies are improving patient outcomes, with two new drugs approved in 2015 for non-small-cell lung cancer and many others showing promise.
- Egbert F. Smit
- & Paul Baas
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Review Article |
The influence of subclonal resistance mutations on targeted cancer therapy
The molecularly targeted therapy paradigm has led to improvements in the management of patients with cancer. Responses to targeted therapies are, however, mostly short-lived, owing to inherent or acquired resistance, which in most cases relates to the outgrowth of pre-existent rare subclones harbouring resistance mutations. Our current understanding of this concept is reviewed herein; how knowledge of pre-existing resistance mechanism obtained through the use of ultra-sensitive sensitive DNA-sequencing assays might be best exploited to improve personalized medicine is discussed.
- Michael W. Schmitt
- , Lawrence A. Loeb
- & Jesse J. Salk
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Review Article |
ESR1 mutations—a mechanism for acquired endocrine resistance in breast cancer
Endocrine resistance will eventually develop in patients with ER-positive breast cancer receiving endocrine therapy. Several studies unveiled gain-of-function mutations in theESR1 gene in approximately 20% of patients with metastatic ER-positive disease who received endocrine therapies. These mutations lead to ligand-independent ER activity that promotes tumour growth, partial resistance to endocrine therapy, and potentially enhanced metastatic capacity. We discuss the contribution of ESR1mutations to the development of acquired endocrine resistance, and evaluate how mutated ER can be detected and targeted to overcome resistance and improve patient outcomes.
- Rinath Jeselsohn
- , Gilles Buchwalter
- & Rachel Schiff
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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 |
Refining the treatment of NSCLC according to histological and molecular subtypes
The recognition of non-small-cell lung cancer (NSCLC) as a heterogeneous disease and ongoing efforts to characterize disease subtypes based on genotype and histology have resulted in dramatic improvements in outcomes for select patient subgroups. However, many challenges remain, not least acquired therapeutic resistance and the related issue of how to best use the available therapies. In this Review, the authors provide an overview of the key developments in NSCLC therapy, describe efforts to tackle therapeutic resistance, and discuss potential strategies to further optimize patient outcomes by stratifying treatments according to particular disease subtypes.
- Anish Thomas
- , Stephen V. Liu
- & Giuseppe Giaccone
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News & Views |
Is docetaxel the 'black widow' of mCRPC drugs?
In the recent MAINSAIL trial, addition of lenalidomide to docetaxel for metastatic castration-resistant prostate cancer (mCRPC) was associated with inferior overall survival and more toxicity; thus, lenalidomide joins a long line of agents that failed to improve the efficacy of docetaxel. The process by which new therapies are advanced to phase III studies, particularly in combination with docetaxel, should be re-examined.
- Bobby C. Liaw
- & William K. Oh
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Research Highlight |
Cancer's vast secretes revealed—secretome changes promote resistance to therapy
- David Killock
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Research Highlight |
Hippo effector YAP1 inhibition—towards a new therapeutic option to overcome drug resistance
- Alessia Errico
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Review Article |
Can oncology recapitulate paleontology? Lessons from species extinctions
The evolutionary biology of cancers and organismal species are similar: in both cases, a genetically diverse population mutates and evolves through natural selection. In addition, driving both species and cancers to extinction is extremely difficult. Nevertheless, greater than 99.9% of species that have lived on Earth are now extinct, and the parallels between tumours and organismal evolution suggest that understanding species extinction through paleontology could teach us much about how to eradicate cancers. In this Review, the selective pressures that have driven species extinct and the characteristics of species that make them resistant to extinction are described, and how these factors can be translated to cancers in order to develop improved approaches to therapy and prognosis is discussed.
- Viola Walther
- , Crispin T. Hiley
- & Carlo C. Maley
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Review Article |
Current treatment landscape for relapsed and/or refractory multiple myeloma
Recent developments in the treatment of multiple myeloma have led to improvements in response rates and to increased survival; however, relapse is inevitable in almost all patients. Currently, there is no standard treatment for patients with relapsed and/or refractory disease. This Review discusses the current treatment landscape for patients with relapsed and/or refractory multiple myeloma and highlights disease-related and patient-related factors that are important considerations for clinicians when selecting an appropriate treatment.
- Meletios A. Dimopoulos
- , Paul G. Richardson
- & Kenneth C. Anderson
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Review Article |
Acquired resistance to TKIs in solid tumours: learning from lung cancer
This Review explores breakthroughs in our understanding and treatment of acquired resistance to tyrosine kinase inhibitors in key molecular subtypes of non-small-cell lung cancer, which may be relevant across multiple different solid malignancies with oncogene-addicted subtypes. The potential of a number of clinical approaches to treat acquired resistance, from new drugs or drug combinations through to the use of more traditional therapies such as radiation or cytotoxic chemotherapy, are highlighted, and the implications for major changes in conducting clinical research in this setting are discussed.
- D. Ross Camidge
- , William Pao
- & Lecia V. Sequist
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Review Article |
Drug rechallenge and treatment beyond progression—implications for drug resistance
There are many circumstances where patients respond to reintroduction of the same therapy (drug rechallenge) following relapse or disease progression during therapy, and in a few cases, when a therapy is continued beyond disease progression. The authors comprehensively describe the available data on rechallenge and continuation beyond progression treatment strategies, discuss the potential mechanisms explaining tumour re-sensitization with reintroduced or continued therapy, and make the case for why drug resistance definitions need to be re-evaluated.
- Elizabeth A. Kuczynski
- , Daniel J. Sargent
- & Robert S. Kerbel
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Research Highlight |
Novel mouse model reveals strategy to delay drug resistance in melanoma
- Lisa Hutchinson
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Correspondence |
The microenvironment and resistance to personalized cancer therapy
- Shigeo Masuda
- & Juan Carlos Izpisua Belmonte
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