Drug discovery articles within Nature Reviews Clinical Oncology

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  • 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

  • Review Article |

    Most studies for identifying biomarkers for oestrogen receptor-α (ERα)-positive breast cancer have been performed using material from consecutive series of patients treated with tamoxifen. Consequently, the predictive value of any biomarker identified is confounded by its prognostic value. In this Review, the authors discuss how different biomarkers might enable the prediction of broad endocrine or agent-specific resistance.

    • Karin Beelen
    • , Wilbert Zwart
    •  & Sabine C. Linn

  • Review Article |

    This Review describes current strategies and future approaches to improve T cell-based therapies to treat post-transplant lymphoproliferative disease, a serious and often life-threatening complication that is associated with Epstein-Barr virus and can occur after haematopoietic stem-cell or solid organ transplantation.

    • Catherine M. Bollard
    • , Cliona M. Rooney
    •  & Helen E. Heslop

  • News & Views |

    A qualitative study indicates that there is a positive selection bias towards favourable economic analysis of targeted therapies, when these are funded by the manufacturer. At a time of increasing budgetary constraints and public scrutiny of the relationship between industry and the professions, we need a more mixed economy of funding for this field.

    • David Kerr
    •  & Ahmed Elzawawy

  • 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

  • Review Article |

    In this Review, Tentler et al. present the opportunities and challenges of using patient-derived tumour xenograft models in oncology drug development, provide specific disease examples, and describe concepts regarding predictive biomarker development and future applications.

    • John J. Tentler
    • , Aik Choon Tan
    •  & S. Gail Eckhardt

  • 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

  • Review Article |

    Despite advances in treating multiple myeloma with the proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide, most patients eventually relapse. In this Review, the authors discuss how next-generation inhibitors and immunotherapy agents have been developed based on an improved understanding of the biology of the disease, and highlight the challenges associated with these therapeutic approaches.

    • Anuj Mahindra
    • , Jacob Laubach
    •  & Kenneth Anderson

  • Opinion |

    In terms of drug development, the main driving force should be optimized benefit–risk to patients; however, no drug can be of real benefit unless it has achieved approval from the regulatory agencies. This Perspectives allows us a peek behind the door of one of those agencies (EMA) and outlines the hurdles that exist and that need to be overcome before we can have an efficient, biomarker-driven drug development program. Points for discussion in the community are raised and suggestions are put forward.

    • Bertil Jonsson
    •  & Jonas Bergh

  • Opinion |

    Antiangiogenic therapies have secured a role in the treatment of multiple cancers. However, the success of this targeted therapy is not as great as originally anticipated. In this Perspectives article, the authors use data from clinical trials to uncover where some of the problems with this therapy lie, discuss exciting recently published data and look to what the next steps should be.

    • Gordon C. Jayson
    • , Daniel J. Hicklin
    •  & Lee M. Ellis

  • Opinion |

    The increasing reliance on hazard ratios for the assessment of clinical trial data prompted this Perspectives article, designed to outline the uses and misuses of this popular statistical value. The authors use real trial data and synthetic examples to explain how the hazard ratio is derived and why the numerical value of a survival measure should also be published alongside it.

    • Krastan B. Blagoev
    • , Julia Wilkerson
    •  & Tito Fojo

  • Review Article |

    This Review article approaches the area of targeted therapies from two angles: efficacy and side effects. The authors outline the successes that have been achieved in treating cancer with targeted therapies and also discuss the pitfalls and quality of life issues that still need to be addressed.

    • Dorothy M. K. Keefe
    •  & Emma H. Bateman

  • Review Article |

    If a targeted therapy demonstrates convincing efficacy in early clinical testing, can randomized phase III trials be avoided? Sharma and Schilsky discuss when it is reasonable to consider foregoing randomized phase III trials before drug approval and also highlight the caveats. They explore the consequences of such an approach and propose criteria that the drugs must meet to be approved without a phase III trial.

    • Manish R. Sharma
    •  & Richard L. Schilsky

  • Opinion |

    The use of therapy that is truly targeted to the needs and biological requirements of an individual patient is an aim for many in the oncology field. Jackson and Sood discuss the implications of targeted therapies on patients and the health-care system and discuss methods that might be used to maximize efficiency, cost effectiveness and patient survival.

    • David B. Jackson
    •  & Anil K. Sood

  • News & Views |

    Cancer medicine frequently balances probability of cure against morbidity of treatment. A recent trial in patients with Hodgkin lymphoma compared two regimens of different intensity and toxicity and examined not only the immediate results, but also the broader algorithm of care, factoring in the effects of salvage treatment and high-dose therapy.

    • Sean H. Lim
    •  & Peter W. M. Johnson

  • Opinion |

    Phase I trials have evolved from simple dose-finding studies to studies that provide therapeutic opportunities for patients where no standard therapy is available; however, various factors have hampered patient recruitment on phase I trials. The authors discuss how matching patients with specific genetic aberrations to specific therapies will improve drug attrition rates and improve patient outcomes.

    • Ignacio Garrido-Laguna
    • , Manuel Hidalgo
    •  & Razelle Kurzrock

  • Review Article |

    The treatment of microscopic metastatic disease is based on the assumption that micrometastases and overt metastases will respond to the same interventions; however, clinical observations illustrate this assumption is incorrect. The authors discuss our existing understanding of the metastatic cascade, emerging therapeutic targets involved in the metastatic process, and how novel anti-metastatic therapies might be developed for clinical use.

    • Lida A. Mina
    •  & George W. Sledge Jr

  • Case Study |

    Oral poly(ADP)-ribose polymerase (PARP) inhibitors have been shown to have great promise in the treatment of cancer inBRCA mutation carriers. This case provides evidence that these agents are efficacious in patients with PTEN deficiency but no BRCAmutations, opening up a new patient cohort for this treatment.

    • Martin D. Forster
    • , Konstantin J. Dedes
    •  & L. Rhoda Molife

  • News & Views |

    The treatment of multiple myeloma has evolved rapidly with the use of the immunomodulatory agents thalidomide and lenalidomide as well as the proteasome inhibitor bortezomib. Cavo and colleagues recently reported results of a landmark phase III study comparing thalidomide–dexamethasone with bortezomib–thalidomide–dexamethasone in newly diagnosed multiple myeloma.

    • Jacob Laubach
    • , Paul G. Richardson
    •  & Kenneth Anderson

  • News & Views |

    The recent failure of bevacizumab in the adjuvant setting has forced us to consider what has gone wrong. It is possible that with careful analysis and novel biomarkers, we may not yet have to lay bevacizumab to rest.

    • David J. Kerr
    •  & Annie M. Young

  • Review Article |

    Many clinical trials of targeted therapies have produced disappointing results, indicating that many challenges must be addressed to advance this field. The authors discuss the importance of novel statistical designs, the need for biopsy sampling in clinical trials and appropriate biomarker identification for improving treatment outcomes.

    • Ignacio I. Wistuba
    • , Juri G. Gelovani
    •  & Roy S. Herbst

  • Review Article |

    New techniques, such as crystallography and three-dimensional modeling, can be used to assist the development of selective targeted agents for cancer treatment. In this Review, Pierotti and colleagues discuss the molecular features of KIT and PDGFRA receptor tyrosine kinases, which are druggable targets in gastrointestinal stromal tumors. The authors focus on the major challenge in kinase drug discovery—the emergence of resistance—and discuss techniques for predicting and preventing this adverse event.

    • Marco A. Pierotti
    • , Elena Tamborini
    •  & Silvana Pilotti

  • Review Article |

    The progression-free survival benefits from approved antiangiogenic drugs are modest and are frequently not accompanied by overall survival improvements. Recent disappointing clinical trial results (for example AVANT) have highlighted questions about the basis of drug resistance, the limitations of predictive preclinical models, and whether antiangiogenic therapy may lead to more invasive or metastatic tumor behavior.

    • John M. L. Ebos
    •  & Robert S. Kerbel

  • Review Article |

    For the treatment of early-stage breast cancer, a provocative question is whether some patients can safely be spared chemotherapy? This Review addresses this question by discussing a range of clinicopathological, biomarker and genomic techniques that may help to guide current clinical practice.

    • Philippe L. Bedard
    •  & Fatima Cardoso

  • Opinion |

    A number of biomarkers that predict clinical outcome in response to gemcitabine treatment have been identified. These markers could be used in the clinic to personalize treatment, thereby improving efficacy and reducing adverse effects. The authors of this article describe how treatment can be tailored according to the pharmacogenetics and pharmacokinetics of each patient. In particular, evaluating the status of the liver enzyme cytidine deaminase holds promise as a strategy to optimize therapy.

    • Joseph Ciccolini
    • , Cédric Mercier
    •  & Nicolas André

  • Review Article |

    Selectively targeting cancer stem cells with novel therapeutics is gaining importance because disease recurrence after treatment-induced remissions is a major cause of morbidity and mortality. This Review discusses the pathways that are active during development, specifically the Wnt, Notch, and Hedgehog pathways, and the clinical development of therapeutic agents that target these pathways.

    • Naoko Takebe
    • , Pamela J. Harris
    •  & S. Percy Ivy

  • Review Article |

    Synthetic lethality has emerged as a novel approach to treat cancer. Inhibitors of poly (ADP-ribose) polymerase, a target that has synthetic lethality withBRCAmutations, have already shown promise in clinical trials. The authors of this Review describe the clinical application of synthetic lethality for patients with breast cancer, and discuss biomarkers that can be used to select patients who will respond to this therapy. Other potential genes that could be involved in synthetic lethality, and are thus new targets, are also explored.

    • Farah L. Rehman
    • , Christopher J. Lord
    •  & Alan Ashworth

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