The past 10 years have witnessed a remarkable acceleration in the pace of translational research in oncology. James Doroshow and Shivaani Kummar of the National Cancer Institute, USA, reviewed in the latest issue of the Nature Reviews Clinical Oncology selected developments in translational cancer biology, diagnostics, and therapeutics that have occurred over the past decade and offer their thoughts on future prospects.
The first issue of Nature Clinical Practice Oncology, the forerunner of Nature Reviews Clinical Oncology, which was published 10 years ago, focused on the clinical benefit of treatment with the EGFR inhibitor gefitinib for patients with non-small cell lung cancers harbouring mutations in the EGFR gene.
The demonstration that the mutational status of a solid tumour could predict therapeutic efficacy for a specific agent in a molecularly-defined subset of patients galvanised oncology drug-development programmes, highlighted by the introduction of trastuzumab and imatinib into the clinic.
Advances in translational research in oncology over the past 10 years have been characterised by the application of molecular tools to larger populations of patients with cancer or those who are at increased risk of developing the disease. These advances include the demonstration that risk of recurrence for women with oestrogen receptor (ER)-positive breast cancer and histologically uninvolved lymph nodes receiving tamoxifen could be predicted based on the expression levels of 21 genes.
The application of modern tumour tissue acquisition methods, next-generation DNA sequencing, gene-expression analysis, DNA methylation profiling, proteomic evaluation, and development of big data sets to the understanding of cancer biology in the clinic, exemplified by the work of The Cancer Genome Atlas project and the International Cancer Genome Consortia, as well as the application of large-scale human tumour cell line drug screening, has expanded appreciation of the broad range of specific mutations and other molecular abnormalities that could be examined as potential targets for therapeutics development. Improvements in DNA sequencing also provided the basis for a much more sophisticated appreciation of the evolution of human tumour heterogeneity.
The rapidly expanding knowledge of human DNA repair processes has been exploited to develop inhibitors of certain DNA repair proteins. Enhanced understanding of the control of tumour cell immunity, and technological advances in the molecular engineering of immune cells, has recently been translated into new immunotherapeutic treatment programmes, including antibodies and cell vaccines.
Improvements over the past 10 years in the development of both in vitro and in vivo models of human cancer, including those produced directly from a specific individual's tumour, suggest that in the future oncologists might be able to examine tumour biology on a patient-by-patient basis.
Advances in translational cancer biology
In their review article, the authors evaluate advances in translational cancer biology (namely new molecular models of cancer, model organisms, inflammation and cancer, cancer metabolism, characterisation of tumours and host tissues, human biospecimens, and clinical characterisation of tumours); cancer diagnostics and therapeutics (molecularly targeted therapy and diagnostics, genomic prediction of therapeutic efficacy, proof of mechanism pharmacodynamics, developing predictive biomarkers, therapeutic resistance and therapy combinations, immunologically-based therapy of cancer, functional molecular imaging); and future prospects (clinically-annotated tumour/normal tissues, new therapeutic models, new approaches to therapeutic resistance, prospects and challenges for immunotherapy, imaging molecular pathways in tumours, and clinical molecular characterisation).
The authors summarised that international efforts to sequence the genomes of various human cancers have been broadly deployed in drug discovery programmes. Diagnostic tests that predict the value of the molecularly targeted anticancer agents used in such programmes are conceived and validated in parallel with new small molecule treatments and immunotherapies. This approach has been aided by better preclinical cancer models; an enhanced appreciation of the complex interactions that exist between tumour cells and their microenvironment; the elucidation of interactions between many of the genetic drivers of cancer, including oncogenes and tumour suppressors; and recent insights into the genetic heterogeneity of human tumours. The advances are being employed in the first generation of genomic clinical trials. More extensive molecular characterisation of tumours and their supporting matrices are anticipated to become standard aspects of oncological practice, permitting continuous molecular re-evaluations of tumours on a patient-by-patient and treatment-by-treatment basis.
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Doroshow JH, Kummar S. Translational research in oncology-10 years of progress and future prospects. Nature Reviews Clinical Oncology 2014; 11:649–662. doi:10.1038/nrclinonc.2014.158