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Breast cancer is a heterogeneous disease with different molecular drivers regulating its growth, survival and treatment response. Drug development efforts have resulted in agents against new molecular targets that are active against only those tumors with the targeted molecular alteration or phenotype. The authors critically discuss the recently established and investigational strategies for the treatment of the main breast cancer subtypes.

A CRISPR–CAS9 screen, analysis of patient data, and functional in vivo and in vitro experiments identify a critical role for ARID1A in determining breast luminal cell identity and endocrine therapeutic response in estrogen-receptor-positive breast cancer.

Estrogen-deprivation strategies with aromatase inhibitors are superior to tamoxifen in the adjuvant, neoadjuvant and advanced breast-cancer settings in postmenopausal patients. Short-term hormonal resistance especially in the HER2-positive patient population, however, is a significant issue with these endocrine agents. The authors discuss the progress made in our understanding of resistance to endocrine therapy, and provide insights regarding the management of patients with hormone receptor-positive/HER2-positive advanced breast cancer.

Neural stem cells in the adult mammalian brain derive from proliferating precursors that are spared as dormant reservoirs during development. Here, the authors show that autophagy is required for neural stem cells to transition to the adult quiescent state.

Matthew Freedman and colleagues show that a region on 8q24 associated with colorectal cancer risk functions as an enhancer and undergoes long-range interactions with MYC. They further show that alleles at the risk-associated SNP bind differentially to TCF7L2, a transcription factor in the Wnt pathway.

2010 has been another prolific year in breast cancer research with a number of original observations bringing us closer to personalized care. Studies with novel targeted agents in defined breast cancer subgroups have revealed exciting developments and highlight the importance of patient selection.

The crosstalk between the transcriptional activity of β-catenin and FOXO3a reveals unexpected pro-metastatic cooperative effects of these pathways through concurrent modulation of cell adhesion and motility programs. In tumors with high FOXO3a and β-catenin activity, the proapoptotic effect of FOXO3a is subverted and the pro-proliferative effect of β-catenin is also dampened, but pro-metastatic pathways are activated. These findings suggest that caution should be exerted when using targeted inhibitors that activate FOXO3a in tumors with high β-catenin activity, as coactivation of both pathways also correlates with more aggressive disease in humans.

This Perspectives article describes how phase I trials assessing the efficacy of targeted therapies should examine not only safety and toxicity, but also the appropriate patient population. Based on the experience of their own academic institution, Rodón and colleagues explain how to build a pre-screening programme in early drug development.

Targeting the Erbb family of receptor tyrosine kinases, specifically ERBB1 (EGFR) and ERBB2, has led to successful cancer therapies. However, many patients will progress on these therapies. As we learn more about this pivotal receptor family, can we devise better methods of targeting it?

Head and neck squamous cell carcinomas (HNSCC) often harbourPIK3CAmutations but PI3Kα inhibitors can cause some side effects. Here, the authors develop P-selectin targeted nanoparticles to enhance tumour-specific delivery of a PI3Kα inhibitor to HNSCC PDX and orthotopic xenograft models.

TheTP53gene is mutated in 50% of reported cancer cases and the p53 pathway is often partially inactivated in the remaining 50%. Clinical trials assessing agents that exploit the p53 system are ongoing. This Review discusses the mechanism of action of these treatments and the future of p53-based therapy.

In a basket trial design, the efficacy of the pan-HER kinase inhibitor neratinib is tested in patients with 21 different tumour types, and responses are determined by mutation and tissue type, and are restricted to HER2-mutant cancers.

One way of discovering genes with key roles in cancer development is to identify genomic regions that are frequently altered in human cancers. Here, high-resolution analyses of somatic copy-number alterations (SCNAs) in numerous cancer specimens provide an overview of regions of focal SCNA that are altered at significant frequency across several cancer types. An oncogenic function is also found for the anti-apoptosis genes MCL1 and BCL2L1, which reside in amplified genome regions in many cancers.

TGF-β signaling is commonly aberrantly activated in gliomas and other tumors and can exert a pro-oncogenic function. The authors identify a new mechanism for upregulation of TGF-β signaling in cancer. The deubiquitinase USP15 is shown to be able to bind the TGF-β receptor complex, counteract its degradation and potentiate its stimulation of downstream mediators. USP15 is amplified in human glioblastoma and could represent a therapeutic target, as its downregulation impairs the growth of glioblastoma cells in vivo.

Cancer genomic data sets contain a wealth of data that can be used to predict prognosis and further understand disease. Here, the authors integrate multiple genomics data types to identify transcriptional dysregulation in response to somatic mutations.

There have been great advances in the treatment of patients with breast cancer, with novel targeted agents having a great impact on treatment at all stages of the disease trajectory. In this Review, the treatment options for patients with metastatic disease are discussed—focussing on agents that target breast cancer cells, breast cancer stem cells and the breast microenvironment.

Sarat Chandarlapaty and colleagues report the identification of mutations in the ESR1 gene affecting the ligand-binding domain of the encoded estrogen receptor in 20% of metastatic hormone-resistant breast cancers. They determine that the mutant receptor has a hormone-independent active state that likely promotes resistance to estrogen-depriving therapies.

How best to serve patients' interests in large clinical trials? Martine Piccart, Aron Goldhirsch and their colleagues argue that maintaining academic independence is essential to early breast cancer trials.

A high-diversity Amazonian system reveals the influence of mammalian diversity on the carbon cycle, mediated through vertebrate feeding events.

When the tyrosine kinase inhibitor imatinib (Gleevec) was found to induce high remission rates in patients with chronic myeloid leukemia, this was hailed as a success for targeted tumor therapy. Since then, the repertoire of cancer types that respond to such inhibitors has expanded and researchers are beginning to grapple with the problem of acquired drug resistance. The activating kinase mutations targeted by these drugs can be viewed as the Achilles heel of cancer—they promote malignant progression, yet can turn cancer into a therapeutically exploitable disease.

A review of drug resistance in cancer analyses each biological determinant of resistance separately and discusses existing and new therapeutic strategies to combat the problem as a whole.

Analysis of more than 17,000 tumours suggests that the contribution of germline and somatic mutations in the BRCA1 and BRCA2 genes to oncogenesis depends on tumour lineage.

mTOR complex 1 signalling regulates polyamine metabolism and thereby promotes tumorigenesis, through regulation of the stability of a key enzyme, AMD1.

A study of genome evolution in a metastatic breast cancer bearing an activating PIK3CA mutation, following treatment with the PI(3)Kα inhibitor BYL719, shows that all metastatic lesions, when compared to the pre-treatment tumour, had lost a copy of PTEN; parallel genetic evolution of separate sites with different PTEN genomic alterations had led to a convergent PTEN-null phenotype resistant to PI(3)Kα inhibition.

Agents targeting the PI3K/AKT/mTOR pathway have been shown to be safe and effective in treating a number of tumour types. This Review outlines the background to these inhibitors and discusses the second-generation inhibitors of this pathway. The authors propose that the way forward for the development of inhibitors of the PI3K/AKT/mTOR pathway might be a systems biology approach and biomarker-driven studies.