Targeted therapies articles within Nature Reviews Clinical Oncology

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  • News & Views |

    The much anticipated results from two phase III studies evaluating the clinical efficacy of poly(ADP-ribose) polymerase (PARP) inhibition in patients with advanced-stage breast cancer harbouring a germline mutation in BRCA1/2 have established new therapeutic opportunities and yet, have left us with several ongoing questions.

    • Shani Paluch-Shimon
    •  & Fatima Cardoso

  • News & Views |

    Opposing results of the monarchE and PALLAS trials investigating the role of adjuvant treatment with the CDK4/6 inhibitors abemaciclib and palbociclib, respectively, in patients with hormone receptor-positive, HER2-negative early stage breast cancer have recently been presented. Herein, potential reasons why these two drugs that have similar efficacy in the metastatic setting have produced disparate results in the adjuvant setting are discussed.

    • Giuseppe Curigliano

  • Review Article |

    Nuclear import and export proteins, such as exportin 1(XPO1), regulate the transport of proteins and other molecules into and out of the nucleus, including several tumour suppressor proteins. The dysregulation of nuclear export can be observed in several types of haematological and solid tumours, providing a rationale for a novel form of targeted therapy. In this Review, the authors describe the development of XPO1 inhibitors, from basic research to clinical approval.

    • Asfar S. Azmi
    • , Mohammed H. Uddin
    •  & Ramzi M. Mohammad

  • Perspective |

    Genotyping is recommended for all patients with metastatic non-squamous non-small-cell lung cancers (NSCLC), both to enable patients to receive targeted therapies and to avoid therapies they are unlikely to benefit from. However, obtaining tumour biopsy material for genotyping is often challenging and is unfeasible in some patients, indicating the need to incorporate liquid biopsy approaches. In this Perspective, the authors provide guidance on how analysis of ctDNA from liquid biopsy samples in patients with metastatic NSCLC prior to first-line therapy has the potential to extend the benefits of genotyping to virtually all patients.

    • Charu Aggarwal
    • , Christian D. Rolfo
    •  & David R. Gandara

  • Comment |

    Single-arm phase II trials can provide compelling results that facilitate the approval of a new therapy. Designing and interpreting single-arm studies based on four principles — instinct, comparative analysis, statistical soundness and like-for-like comparisons — can provide indications as to which drugs are most likely to provide improved therapeutic options for patients.

    • Robert H. Glassman
    • , Grace Kim
    •  & Marc J. Kahn

  • Consensus Statement
    | Open Access

    The analysis of ctDNA obtained from low-volume blood samples has the potential to transform the management of patients with colorectal cancer. Nevertheless, research priorities and minimum standards for sample collection and analysis in this area are currently missing. In this Position Paper, the NCI Colon and Rectal–Anal Task Forces provide a set of recommendations designed to address these challenges and accelerate the implementation of ctDNA in the management of patients with colorectal cancer.

    • Arvind Dasari
    • , Van K. Morris
    •  & Scott Kopetz

  • Review Article |

    Therapies targeting MET-overexpressing cancers have limited efficacy. However, owing to advances in detection methods, therapies targeting MET-dependent tumours harbouring MET amplifications, activating mutations or fusions are emerging. In this review, the authors describe emerging data on this new class of targeted therapies.

    • Robin Guo
    • , Jia Luo
    •  & Alexander Drilon

  • News & Views |

    Mature results of the PROfound study demonstrate that the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib prolongs progression-free survival compared with second-generation hormonal therapies in men with metastatic castration-resistant prostate cancer harbouring BRCA1, BRCA2 or ATM mutations. However, a closer look at the efficacy of olaparib on a gene-by-gene basis suggests that its activity is most pronounced in BRCA2-mutant prostate cancers and might not be equally active in all homologous recombination repair-deficient cancers.

    • Emmanuel S. Antonarakis

  • Review Article |

    Despite improvements in diagnostic strategies, cancer of unknown primary — metastatic cancer in patients in whom the primary tumour remains undetected — continues to account for around 1–2% of all cancers. In this Review, Rassy and Pavlidis discuss insights into the biology of CUP and shifts in the clinical management of this enigmatic disease entity in the era of precision medicine.

    • Elie Rassy
    •  & Nicholas Pavlidis

  • Review Article |

    The authors of this Review present the main pathways that regulate apoptosis as well as other signalling pathways that interact with them, highlighting actionable molecular targets for anticancer therapy. They also provide an overview of therapeutic agents exploiting apoptosis currently in clinical translation and known mechanisms of resistance to these agents.

    • Benedito A. Carneiro
    •  & Wafik S. El-Deiry

  • Review Article |

    Cancer cells, like non-malignant cells, are dependent on folate uptake for growth. However, cancer cells are much more reliant on folate receptors (FRs) and particularly FRα for folate uptake than non-malignant cells. In this Review, the authors describe the available data on the role of FRα as a biomarker and as a target of imaging probes, and of targeted therapies in patients with solid tumours.

    • Mariana Scaranti
    • , Elena Cojocaru
    •  & Udai Banerji

  • News & Views |

    The survival outcomes of the FLAURA trial support osimertinib as the new first-line standard of care for patients with EGFR-mutated advanced-stage non-small-cell lung cancer in health-care systems that can afford its cost. However, the low crossover rate is a flaw of this study. Knowledge of mechanisms of resistance to provide tailored treatment is the new challenge preventing a continued paradigm shift in this disease.

    • Jordi Remon
    •  & Gilberto Lopes

  • Review Article |

    Brain metastases are a frequent manifestation of several common solid tumour types, including lung cancer, breast cancer and melanoma. Although the presence of brain-metastatic disease continues to be associated with poor outcomes, advances in surgery, radiotherapy and systemic therapies that can permeate the blood–brain barrier are beginning to improve patient outcomes. In this Review, the authors provide an overview of contemporary advances in the management of brain metastases over the past decade.

    • John H. Suh
    • , Rupesh Kotecha
    •  & Eric L. Chang

  • News & Views |

    In 2018, the SOLO1 trial set a new standard of care with maintenance olaparib substantially extending progression-free survival (PFS) in women with newly-diagnosed BRCA1/2-mutated advanced-stage ovarian cancer. Herein, we summarize trials of first-line poly(ADP-ribose) polymerase (PARP) inhibition beyond BRCA1/2 mutations, including combination strategies, and discuss the optimum use of PARP inhibition in advanced-stage ovarian cancer.

    • Susana N. Banerjee
    •  & Christopher J. Lord

  • Viewpoint |

    Regulatory approval of new cancer medicines can have important consequence for patients with advanced-stage and/or rare cancers who have exhausted all standard-of-care therapies. However, evidence that new medicines are safe and effective can also take time to accrue, and approval with a lack of evidence may cause unnecessary harm to patients. In this Viewpoint, we asked two leading oncologists involved in clinical drug development, an expert in regulatory science and prescription drug policy, and a prominent patient advocate, to provide their opinions on the current approach to cancer drug approvals.

    • Razelle Kurzrock
    • , Hagop M. Kantarjian
    •  & Ellen V. Sigal

  • Comment |

    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

  • Review Article |

    HER2-targeted therapy has greatly improved the outcomes of patients with HER2-positive breast cancer, with a range of agents now approved or in late-stage clinical development. In the era of precision medicine, efforts are being made to further improve patient outcomes by personalizing HER2-targeted treatment regimens, primarily though escalation or de-escalation of therapy according to the disease biology. In this Review, the authors provide an overview of the current landscape of HER2-targeted therapy and discuss the evidence supporting such tailored therapeutic strategies.

    • Kristina Goutsouliak
    • , Jamunarani Veeraraghavan
    •  & Rachel Schiff

  • Review Article |

    Virtually all patients with resectable pancreatic ductal adenocarcinoma (PDAC) will have disease progression, which is generally associated with dismal outcomes. However, novel targeted therapies and immunotherapies, selected based on the genomic and/or clinical features of patients’ tumours are beginning to improve the outcomes in subsets of patients. In this Review, the authors describe progress in novel therapies for patients with PDAC.

    • Christopher Nevala-Plagemann
    • , Manuel Hidalgo
    •  & Ignacio Garrido-Laguna

  • Comment |

    New molecular insights occasionally lead to the rapid development of therapeutic agents that improve the outcomes of patients with cancer; however, these breakthroughs can be followed by extensive, empirically driven and often unsuccessful efforts at extending the drug to other indications or combinations. Herein, we describe the clinical development of imatinib, a paradigm of rapid molecularly driven drug development, and advocate for a balanced portrayal of the potential of molecularly targeted therapies for cancer.

    • Benjamin G. Carlisle
    • , Tiger Zheng
    •  & Jonathan Kimmelman

  • News & Views |

    BRCA1/2 mutations and poly (ADP-ribose) polymerase (PARP) inhibitors are paradigmatic of synthetic lethal therapy. However, the activity of PARP inhibitors seems to vary considerably across BRCA1/2-mutant cancers and new insights into the tumour-lineage dependency of this synthetic lethal relationship might explain why BRCA1/2 mutations are not tumour-agnostic biomarkers of a response to PARP inhibitors.

    • Nicola J. Curtin
    • , Yvette Drew
    •  & Sweta Sharma-Saha

  • Review Article |

    The use of epigenetic drugs (epi-drugs) as single agents according to a ‘one size fits all’ approach has generally resulted in disappointing therapeutic activity. In this Review, the mechanisms by which epi-drugs can modulate the sensitivity of cancer cells to other diverse forms of anticancer therapy are described, and completed and ongoing clinical trials relating to combination therapies incorporating epi-drugs are discussed. In addition, clinical trial designs and drug development strategies aimed at optimizing the development of such combinations are outlined.

    • Daphné Morel
    • , Daniel Jeffery
    •  & Sophie Postel-Vinay

  • Review Article |

    HER2-targeted therapies have dramatically improved the outcomes in women with HER2-positive breast cancer. Furthermore, genetic sequencing studies have revealed HER2 alterations in a range of other cancers, including gastric cancer, colorectal cancer and non-small-cell lung cancer. In this Review the authors describe the available data on HER2-targeted therapies beyond breast cancer.

    • Do-Youn Oh
    •  & Yung-Jue Bang

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