Milestones in cancer

A study reports germline loss-of-function mutations in the gene encoding a subunit of succinate dehydrogenase (SDH, also known as mitochondrial complex II) in patients with hereditary paraganglioma. SDH, a component of the tricarboxylic acid (TCA) cycle, has a key role in mitochondrial respiration. This is the first of many studies showing the association of loss-of-function mutations in genes encoding SDH subunits or fumarate hydratase (another TCA-cycle enzyme) in tumours, thus showcasing their tumour-suppressor roles and the contribution of mitochondrial respiration defects to tumour formation.

Related article: Mutations in SDHD, a Mitochondrial Complex II Gene, in Hereditary Paraganglioma

Resistance to targeted treatment can be achieved through markedly distinct but functionally convergent approaches, thus showing that certain genes and mutations remain essential drivers of tumour growth and survival. Read more.

By Ilse Valtierra

Leland Hartwell, Tim Hunt and Paul Nurse win the Nobel Prize in Physiology or Medicine “for their discoveries of key regulators of the cell cycle.”

Related article: Press release: The Nobel Prize in Physiology or Medicine 2001

A large epidemiological study of more than 900,000 adults in the United States finds an association between obesity and higher death rates for all cancers combined as well as for specific tumour types.

Related article: Overweight, Obesity, and Mortality from Cancer in a Prospectively Studied Cohort of U.S. Adults

Azacitidine, an inhibitor of DNA methylation and a pioneering epigenetic therapy, becomes the first drug to gain US Food and Drug Administration (FDA) approval for the treatment of myelodysplastic syndrome.

Related article: Approval Summary: Azacitidine for Treatment of Myelodysplastic Syndrome Subtypes

The FDA approves bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, for the treatment of advanced colorectal cancer. This is the first approval of an antiangiogenic agent to treat cancer.

Related article: Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer

A study published by Cristofanilli et al. is the first to use the CellSearch platform to show that the number of circulating epithelial cells in the blood is markedly higher in women with metastatic breast cancer before starting systemic therapy than in women without breast cancer or with benign breast disease. Read more.

By Diana Romero

A trial by Harper et al. provides the first evidence that vaccination against human papilloma virus (HPV) might decrease cervical cancer risk: Cervarix, a bivalent vaccine for HPVs 16 and 18, is found to decrease the risk of associated cervical abnormalities from 4.9% to 0.4%. Read more.

By Peter Sidaway

Two landmark studies by the groups of Alan Ashworth in collaboration with KuDOS Pharmaceuticals Ltd., and of Thomas Helleday and Nicola Curtin demonstrate that human cancer cells with mutations in the tumour-suppressor genes BRCA1 and BRCA2 are sensitive to poly(ADP–ribose) polymerase inhibitors. Read more.

By Barbara Marte

Four groups report remarkable in vivo evidence of the existence of oncogene-induced senescence in several mouse and human premalignant tissues. These studies demonstrate that pathways underlying oncogene-induced senescence are dependent on the tumour tissue and oncogenic insult. Read more.

By Linda Gummlich

Warburg believed that the origin of cancer was based purely on metabolic alterations. We know today that Warburg was not quite right: oncogenic signalling fundamentally contributes to malignant transformation, partly by regulating metabolism. Read more.

By Ulrike Harjes

The Cancer Genome Atlas is a large cancer genomics project aiming to catalogue cancer-associated mutations from more than 20,000 matched tumour and normal samples across 33 cancer types. The first interim analysis reports findings from their glioblastoma study.

Related article: Comprehensive genomic characterization defines human glioblastoma genes and core pathways

The first cancer whole-genome sequence, of an acute myeloid leukaemia from a woman in her mid-50s, is published in 2008 by Ley et al. Read more.

By Michael Fletcher

A technique is developed wherein single stem cells or single crypt structures from intestinal crypts can generate ‘organoids’—in vitro structures with the architecture of, and all differentiated cell types present in, organ structures. The development of tumour organoids has since facilitated basic and preclinical studies across many cancer types.

Related article: Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche

IDH1 mutations are frequently observed in glioblastoma. An R132H substitution encoded by a gain-of-function mutation is reported to facilitate the conversion of α-ketoglutarate to the oncometabolite 2-hydroxyglutarate, thus driving tumour initiation and progression.

Related article: Cancer-associated IDH1 mutations produce 2-hydroxyglutarate

Ipilimumab, an antibody to CTLA-4, makes history as the first immune-checkpoint inhibitor to be approved by the FDA, thus validating the approach to immunotherapy originally proposed by James Allison. Read more.

By David Killock

Multiple studies in the past two decades have shown that chimeric antigen receptor (CAR) T cells and TCR T cells have clinical activity, thus advancing the field of adoptive cell therapy, which has seen remarkable results, particularly in B cell malignancies. Read more.

By M. Teresa Villanueva

A study of more than 50,000 people at high risk of lung cancer shows that screening with low-dose helical computed tomography can decrease mortality from lung cancer.

Related article: Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening

A study introduces the concept of ‘senescence surveillance’, wherein premalignant senescent hepatocytes are cleared through a tumour-antigen-directed immune response.

Related article: Senescence surveillance of pre-malignant hepatocytes limits liver cancer development

Two seminal studies reveal the presence of mutations affecting the histone H3 genes in paediatric high-grade gliomas, including glioblastomas. Read more.

By Monica Wang

Gerlinger et al. provide a direct demonstration of multiple genetically related subclones within a solid tumour and their phylogenetic relationships. This study has driven a shift in thinking of tumours in Darwinian terms—from linear to tree-like cancer evolution. Read more.

By Linda Koch

Smart-seq, a method to generate high-coverage transcriptomes from single cells, is used to analyse the full-length messenger-RNA transcriptomes of circulating tumour cells from a patient with melanoma. The study opens the possibility of genome-wide transcriptomic profiling of individual cells.

Related article: Full-length mRNA-Seq from single-cell levels of RNA and individual circulating tumor cells

A study shows that cells lacking p53 are exquisitely sensitive to serine depletion, thus suggesting that removal of this amino acid through dietary changes or pharmacological approaches might have therapeutic potential in treating p53-deficient tumours.

Related article: Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells

The lack of success in identifying RAS inhibitors led many to call RAS undruggable. Then Kevin Shokat’s lab developed a groundbreaking inhibitor of the KRAS G12C mutant, targeting one of the most prevalent RAS alterations in non–small cell lung cancer. Read more.

By Megan Cully

Two seminal studies from the groups of Laurence Zitvogel and Giorgio Trinchieri shed light on the idea that the gut microbiota might influence host responses to cancer therapeutics via the immune system. Read more.

By Anna Dart

A study of colorectal cancer genomics puts forward a model of tumour evolution whereby tumour growth is predominantly driven by an early, mutational ‘Big Bang’ which produces numerous clones, none of which are subject to stringent selection.

Related article: A Big Bang model of human colorectal tumor growth

Sequencing of 243 biopsies of sun-exposed but healthy skin from 4 individuals shows a high burden of somatic mutations, including those known to drive skin cancer.

Related article: High burden and pervasive positive selection of somatic mutations in normal human skin

The FDA announces accelerated approval of the first immunotherapy combination—ipilimumab (an antibody to the immune-checkpoint protein CTLA-4) and nivolumab (an antibody to the immune-checkpoint protein PD-1)—for the treatment of BRAF-wild-type metastatic melanoma.

Related articles: Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma, Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial

Atezolizumab, the first of an emerging class of inhibitors of PD-L1, is approved by the FDA for the treatment of urothelial carcinoma.

Related articles: FDA approves new, targeted treatment for bladder cancer, Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial

Esteva et al. publish a landmark study in the field of computer vision applied to cancer detection. Read more.

By Miguel Foronda

The FDA approves the use of pembrolizumab, a monoclonal antibody to PD-1, for the treatment of unresectable or metastatic microsatellite-instability-high or mismatch-repair-deficient solid tumours. This is the first approval of a treatment on the basis of tumour genomics alone rather than tumour origin.

Related articles: FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication, Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

The FDA approves the use of enasidenib for adult patients with relapsed or refractory acute myeloid leukaemia. The drug, which is the first inhibitor of mutant isocitrate dehydrogenase 2 approved for clinical use, promotes cellular differentiation (rather than cell death) by blocking generation of the metabolite 2-hydroxyglutarate.

Related articles: FDA approves new targeted treatment for relapsed or refractory acute myeloid leukemia, Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia

James P. Allison and Tasuku Honjo win the Nobel Prize in Physiology or Medicine “for their discovery of cancer therapy by inhibition of negative immune regulation.”

Related article: Press release: The Nobel Prize in Physiology or Medicine 2018

A phase I clinical trial of a CAR T cell therapy (bb2121) that targets the B cell–maturation antigen shows an acceptable toxicity profile and signs of antitumour activity in relapsed or refractory multiple myeloma. This trial and others indicate the clinical utility of using CAR T cells to target antigens other than CD19.

Related article: Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma

William Kaelin, Peter Ratcliffe and Greg Semenza win the Nobel Prize in Physiology or Medicine for “for their discoveries of how cells sense and adapt to oxygen availability.”

Related article: Press release: The Nobel Prize in Physiology or Medicine 2019

The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Project reports whole-genome-sequencing data and integrated analyses of more than 2,600 tumour–normal tissue pairs across 38 tumour types.

Related article: Pan-cancer analysis of whole genomes

A phase I/II trial of 11 patients with relapsed or refractory CD19-positive cancers finds that most patients respond to CD19-targeting CAR natural killer (NK) cells and show few major toxicity effects. This trial illustrates the therapeutic potential of CAR expression on non–T cells and suggests that genetically engineered allogeneic NK cells could be used as an ‘off the shelf’ cancer therapy.

Related article: Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors