Pharmacology articles within Nature Reviews Clinical Oncology

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  • Review Article |

    The blood–brain barrier regulates the movement of various substances between the blood and the brain and therefore has a crucial role in ensuring normal brain function. In both primary brain tumours and brain metastases, the blood–brain barrier is modified to the blood–tumour barrier (BTB), resulting in altered permeability; however, the BTB continues to restrict the penetration of many therapeutic agents into intracranial tumours. Here, Patricia Steeg describes the current knowledge of BTB structure and function and discusses how this knowledge can be translated into improvements in cancer therapy and patient outcomes.

    • Patricia S. Steeg

  • Editorial |

    Phase I trials form the foundations of evidence-based oncology. Here, we explore the ethical controversies surrounding how participation in such trials should be presented to patients.

  • Review Article |

    FGFR alterations can be detected in a small subset of many different cancer types. Inspired by the successes with other targeted therapies, preliminary attempts to target FGFR-altered cancers have been hampered by low response rates and acquired resistance. In this Review, the author describes the development of FGFR inhibitors thus far, and provides guidance on future research priorities.

    • Masaru Katoh

  • News & Views |

    In the RADIANT study, no difference in disease-free survival was observed for patients with non-small-cell lung cancer (NSCLC) treated with erlotinib versus placebo in the adjuvant setting. Further biomarker studies are awaited to determine whether patients with NSCLC can benefit from adjuvant therapy with tyrosine kinase inhibitors.

    • Fred R. Hirsch
    •  & Paul A. Bunn Jr

  • Review Article |

    Identification of the optimal dose remains a key challenge in drug development. The standard approach that is based on identifying the maximum tolerated dose does not take into account important aspects of clinical pharmacology for newer targeted agents. The authors discuss adaptations to dose-finding trials for molecularly-targeted agents that enable more-efficient trials in the future in terms of costs and, most importantly, optimal patient benefit.

    • Ron H. J. Mathijssen
    • , Alex Sparreboom
    •  & Jaap Verweij

  • News & Views |

    The marriage of medicinal chemistry, molecular biology and medicine is perhaps best exemplified by the evolution of selective oestrogen-receptor modulators (SERMs). Translational studies might be useful for predicting the myriad clinical responses to SERMs, contributing to improvements in women's health.

    • V. Craig Jordan

  • Review Article |

    With increasing numbers of anticancer drugs requiring testing, new adaptive model-based phase I trial designs can improve on current practice by exploring a wider range of dose combinations than standard phase I methods. In this Review, the authors describe the methods available as well as the opportunities and challenges faced in dual-agent phase I trials.

    • Jennifer A. Harrington
    • , Graham M. Wheeler
    •  & Duncan I. Jodrell

  • Review Article |

    Agents targeting the PI3K/AKT/mTOR pathway have been shown to be safe and effective in treating a number of tumour types. This Review outlines the background to these inhibitors and discusses the second-generation inhibitors of this pathway. The authors propose that the way forward for the development of inhibitors of the PI3K/AKT/mTOR pathway might be a systems biology approach and biomarker-driven studies.

    • Jordi Rodon
    • , Rodrigo Dienstmann
    •  & Josep Tabernero

  • Review Article |

    Combination strategies of molecular-targeted agents (MTAs) are being used in the hope of optimizing antitumour efficacy and to minimize the development of resistance, but very little effort is focused on molecular vulnerabilities of normal tissues. This Review discusses the main toxicities and the lack of tolerability of some common MTA combinations, and highlights what steps can be introduced for new preclinical testing paradigms for the assessment of chronic toxicities.

    • Sook Ryun Park
    • , Myrtle Davis
    •  & Shivaani Kummar

  • Year in Review |

    In 2012, we increased our knowledge of the molecular portrait of breast cancer. The BOLERO-2 and CLEOPATRA trials led to the approval of everolimus and pertuzumab; and the EMILIA trial will likely result in the approval of T-DM1. Some of these findings represent a paradigm shift in the way we think about the biology and management of breast cancer.

    • Mariana Chavez-MacGregor
    •  & Ana Maria Gonzalez-Angulo

  • News & Views |

    A phase II trial comparing dual MAPK pathway inhibition by combining BRAF and MEK inhibitors with BRAF inhibition alone showed increased progression-free survival and reduced incidence of secondary malignancies in patients with mutant BRAF V600 melanoma. This trial provides strong support for developing combinations hitting the same pathway in melanoma.

    • Keiran S. M. Smalley
    •  & Vernon K. Sondak

  • Review Article |

    Tumour dormancy is when cancer sleeps undetected for periods that can last up to decades. The therapeutic potential of inducing or maintaining this dormant period is clear. This Review describes the mechanisms of dormancy and uses genitourinary cancers as models to demonstrate how dormancy principles could be exploited clinically.

    • Jonathan A. Hensel
    • , Thomas W. Flaig
    •  & Dan Theodorescu

  • News & Views |

    The large randomized study by Crook et al. demonstrated that intermittent administration of androgen deprivation therapy should be considered the standard of care when patients with moderate and well-differentiated localized prostate cancer are treated for rising PSA levels after definitive radiotherapy.

    • Timur Mitin
    • , Jason A. Efstathiou
    •  & William U. Shipley

  • News & Views |

    The VELOUR and VITAL studies recently demonstrated ziv-aflibercept improved overall survival in patients with metastatic colorectal cancer (mCRC), including those previously treated with bevacizumab, but did not improve overall survival in non-small-cell lung cancer. Thus, VEGF-directed agents might be useful throughout the continuum of care in mCRC, but biomarkers are needed to identify patients likely to benefit.

    • Jeffrey M. Clarke
    •  & Herbert I. Hurwitz

  • News & Views |

    An update of the COU-AA-301 study confirms a survival advantage with abiraterone–prednisone compared to prednisone in post-docetaxel patients with metastatic castration-resistant prostate cancer. We place these data in the context of earlier disease states and other novel agents and explore practical issues concerning the future use of abiraterone.

    • Oliver Sartor
    •  & Sumanta K. Pal

  • Perspectives |

    PET or SPECT, is that the question? Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) are both tomographic techniques that enable 3D-localization of the tumour and can be combined with CT for hybrid imaging; but is one better that the other? In oncology imaging nothing is black or white, and Rod Hicks and Michael Hofman provide us with an in-depth analysis of the advantages and disadvantages of each technique.

    • Rodney J. Hicks
    •  & Michael S. Hofman

  • News & Views |

    Addition of aprepitant, an NK-1 receptor antagonist, to dexamethasone and a 5-HT3 receptor antagonist contributes substantially to emetic control in patients receiving 5-day cisplatin-containing chemotherapy, a new trial shows. Some needs in antiemetic therapy remain unmet, including control of emesis with multiple-day chemotherapy and control of nausea.

    • Richard J. Gralla

  • News & Views |

    Two novel agents targeting the androgen receptor signalling axis, even after chemotherapy treatment, have been demonstrated to be effective in patients with metastatic castration-resistant prostate cancer (CRPC). Enzalutamide is the newest approved treatment that improves survival in this lethal and morbid disease.

    • Che-Kai Tsao
    •  & William K. Oh

  • News & Views |

    Compared with anastrozole alone, the combination of fulvestrant and anastrozole significantly improved time without disease progression and extended the median overall survival of women with endocrine-responsive metastatic breast cancer; offering a new standard-of-care for these women. Unfortunately, information about the efficacy of the combination in the adjuvant setting is not available.

    • Aron Goldhirsch
    •  & Richard D. Gelber

  • Review Article |

    Aspirin has been widely reported to be associated with cancer prevention, and now its use as a cancer therapy option is being explored. In this Review, the authors discuss evidence from trials that suggest that aspirin initiation after the diagnosis of colorectal cancer improves survival. The issues of dosage, duration, toxicity and patient selection are also described.

    • Whay Kuang Chia
    • , Raghib Ali
    •  & Han Chong Toh

  • News & Views |

    The small EVEREST trial has shown that the concept of guiding cetuximab dose escalation using the clinical parameter of acneiform skin rash is safe. However, as no significant increase of cetuximab efficacy could be observed, data from the ongoing EVEREST II trial must be awaited before dose escalation can be considered for clinical use.

    • Sebastian Stintzing
    •  & Heinz-Josef Lenz

  • News & Views |

    Gemtuzumab ozogamicin was withdrawn from the market after being evaluated in combination with chemotherapy in the frontline treatment of patients aged 18 to 60 years with acute myeloid leukaemia (AML). More-recent randomized trials demonstrate that low doses of gemtuzumab added to cytarabine and anthracycline-based chemotherapy benefit patients with better-risk AML.

    • Farhad Ravandi
    •  & Hagop Kantarjian

  • News & Views |

    Demonstration of the clinically significant activity of bevacizumab in advanced-stage ovarian cancer has attracted a great deal of interest. Here, we summarize the two positive phase III trials that led to EMA approval of bevacizumab as first-line therapy and discuss the optimum use of the drug in this disease.boxed-text

    • Susana Banerjee
    •  & Stan B. Kaye

  • Review Article |

    The current system for the development of anticancer drugs is not fit for purpose. In this Review article, this system is examined from the perspective of the drug company, offering a fresh look at development from target identification up to registration.

    • Eric H. Rubin
    •  & D. Gary Gilliland

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