Review Articles in 2020

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.

Despite the introduction of novel therapies, lung cancer remains the leading cause of cancer-related mortality worldwide. Randomized controlled trials of low-dose CT-based lung cancer screening in high-risk populations have shown a reduction in mortality. The authors of this Review discuss these studies and present the Screening Planning and Implementation RAtionale for Lung cancer (SPIRAL), a framework to define the scope of future implementation research on lung cancer screening.

Despite several major therapeutic advances, multiple myeloma (MM) remains largely incurable, indicating a need for novel therapies. Thus, considerable research interest exists in chimeric antigen receptor (CAR) T cells targeting BCMA, which is almost universally expressed on MM cells. In this Review, the authors describe the clinical experience with anti-BCMA CAR T cells and discuss several new directions of future research that might prolong the responses of patients receiving these therapies.

Technological advances have enabled the analysis of whole genomes, leading to the identification of causal factors that present new opportunities to prevent cancer. The authors of this Review discuss relevant findings in cancer genetics and genomics from the perspective of global cancer prevention and present a conceptual framework for the translation of such findings into clinical practice and evidence-based policies.

Natural killer (NK) cells have an innate potential to kill cancerous cells and considerable effort is being focused on innovative approaches to leverage these cells for cancer therapy. Herein, the authors discuss the variety of NK cell-based therapies that are being developed for the treatment of diverse cancers and identify future avenues for NK cell therapy research.

Tumour budding is hypothesized to reflect the invasive and metastatic capacities of cancers and is accordingly associated with unfavourable patient outcomes. Herein, Lugli and colleagues describe the pathobiological characteristics of this phenomenon, including its associations with epithelial–mesenchymal transition and features of the tumour microenvironment, and review the evidence demonstrating the value of tumour budding as a prognostic biomarker across various solid cancers.

The number of adults aged ≥65 years with cancer is rapidly growing; these individuals continue to have worse outcomes than younger adults with cancer. The authors of this Review summarize the unique challenges of treating older adults with cancer owing to competing health and ageing-related conditions, and describe the current guidelines as well as investigational studies underway to improve the outcomes of these patients.

ROS1 fusions can be identified across a range of malignancies and confer a high level of sensitivity to ROS1 tyrosine kinase inhibitors. Herein, the authors discuss the non-malignant and malignant biology of ROS1, the diagnostic approaches to identifying ROS1 fusions and the current therapeutic concepts relating to ROS1 fusion-positive cancers, including the resistance mechanisms that have emerged with current ROS1 inhibitors.

The efficacy of chemotherapy in patients with cancer is now known to have an immunogenic component. Nonetheless, chemotherapy alone often fails to provide durable disease remission in most patients. The development of immune checkpoint inhibitors has created an opportunity to combine immunogenic chemotherapies with these agents in order to optimize patient outcomes. In this Review, the authors describe the mechanisms of synergy between chemotherapy and immune checkpoint inhibitors, summarize the available clinical data on these effects and highlight the most promising areas for future research.

TGFβ released by cancer cells and other cells in the tumour microenvironment enables cancer cell invasion and dissemination, stem cell properties and therapeutic resistance as well as generating an immunosuppressive environment. The authors of this Review introduce the mechanisms underlying TGFβ signalling in tumours and their microenvironment and discuss approaches to inhibit these signalling mechanisms, in particular in the context of cancer immunotherapy.

Photodynamic and photothermal therapies hold promise in the local treatment of cancer although, arguably, their full potential has not yet been achieved. Herein, the authors review the current clinical progress of these phototherapies and discuss the bioengineering approaches that are being explored to overcome challenges and thereby improve such treatments.

Most systemic cancer therapies are administered at doses at or close to the maximum tolerated dose until disease progression. However, this approach usually leads to treatment resistance and fails to take into account several potentially relevant evolutionary principles. In this Review, the authors describe how existing approaches to cancer therapy might be optimized by incorporating an understanding of evolutionary dynamics into cancer therapy.

Immune-checkpoint inhibition has transformed the treatment of patients with advanced-stage cancers. Nonetheless, the specific antigens targeted by T cells that are activated or reactivated by these agents remain largely unknown. In this Review, the authors describe the characterization and classification of tumour antigens including descriptions of the most appropriate detection methods, and discuss potential regulatory issues regarding the use of tumour antigen-based therapeutics.

Therapies are being developed to treat cancers on the basis of specific molecular alterations and markers of immune phenotypes that transcend specific tumour histologies. The authors summarize the development and testing of approved histology-agnostic therapeutic agents, present data on other agents under development and discuss the challenges intrinsic to histology-agnostic drug development in oncology, including biological, regulatory, design and statistical considerations.

Signalling induced by extracellular adenosine (eADO) can suppress antitumour immunity through multiple mechanisms. Herein, the authors review the pathophysiological functions of eADO in cancer and the related prognostic implications. They discuss the associated opportunities for eADO pathway-targeted immunotherapy, highlighting potential limitations and the scope for combination and biomarker-based strategies. The data emerging from oncology clinical trials of the diverse range of therapies that have been developed to target the eADO signalling pathway are also described.

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.

Important research efforts are being made to develop therapeutic strategies targeting the tumour microenvironment in pancreatic adenocarcinoma. The authors of this Review describe the apparent contradiction between preclinical studies and clinical outcomes observed to date, presenting more sophisticated strategies under active investigation.

International treatment guidelines for chronic myeloid leukaemia incorporate recommendations for attempting discontinuation of treatment with tyrosine-kinase inhibitors (TKIs) with the aim of a treatment-free remission (TFR). The authors of this Review discuss how results of clinical studies of TFR can guide routine practice, address the development of predictors of outcome after TKI discontinuation and present strategies that warrant further consideration to enable more patients to enter TFR.

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.

Haematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for several haematological malignancies. Improvements in HSCT methodologies have considerably reduced treatment-related morbidity and mortality, thus broadening eligibility and placing increased emphasis on the prevention of disease relapse. In this Review, the authors discuss approaches to dissecting the biology of HSCT and exploiting the biological insights to enhance the graft-versus-tumour response, in particular with adoptive cell therapies and other immune-directed therapies, whilst minimizing graft-versus-host disease.