Articles in 2019

RNA epigenetic drug development enters a new era, as companies start revealing targets and evidence of preclinical efficacy.

Cell plasticity has emerged as a mode of targeted therapy evasion in various cancers. This Review discusses the different mechanisms that drive tumour cell plasticity and the potential therapeutic strategies to target them in order to achieve more durable clinical responses.

In 2009, Merck & Co.’s PD1-blocking antibody pembrolizumab was in development limbo. A decade on, the immuno-oncology drug is Merck’s crown jewel, with more than 20 approvals in 15 tumour types and revenues that are expected to reach US$10 billion this year. For Roger Perlmutter — an immunologist, president of Merck Research Laboratories and executive vice-president of Merck & Co. — this success was not always a sure thing. On the fifth anniversary of the FDA’s approval of pembrolizumab, he spoke with Asher Mullard about remaining immuno-oncology opportunities and questions.

Nearly ten compounds from zebrafish screens are in or about to enter the clinic, and zebrafish 'avatars' are gaining traction as a tool to guide treatment plans for patients with cancers and rare diseases.

The European Medicines Agency and the US Food and Drug Administration have committed to engaging patients in their regulatory processes to promote patient-focused medicinal product development, as well as improve transparency and trust in the regulatory system. Here, we highlight exchanges of experience between the agencies and some impacts on patient engagement.

Precursor mRNA processing, which includes the removal of introns by splicing and the formation of 3′ ends by cleavage and polyadenylation, is frequently altered in tumours. This Review describes small molecules and oligonucleotides that modulate the spliceosome and are now in clinical trials for the treatment of cancer.

Nucleic acid sensors (NASs) are essential for the preservation of cellular and organismal homeostasis, with dysregulated NAS signalling contributing to the pathology of a variety of conditions, including infectious diseases, autoimmune disorders and malignancy. Here, Galluzzi and colleagues discuss recent progress in the development of therapeutic NAS modulators and highlight obstacles faced in their clinical development.

Fibrosis features in numerous chronic diseases, such as non-alcoholic steatohepatitis and heart failure, and no existing therapies can prevent or reverse this abnormal deposition of extracellular matrix, which leads to organ dysfunction. Here, Liu and colleagues describe how this energy-intensive process could be targeted by therapies that interfere with metabolism, including the metabolic implications of drugs directed at transforming growth factor-β and the deposition of extracellular matrix.