Charles Swanton, MD, FRCP, PhD
Chair, Personalized Cancer Medicine
CR-UK Group Leader
Translational Cancer Therapeutics Laboratory
University College London Cancer Institute
London, United Kingdom
2013-2014 BCRF Project:
In-depth analysis of solid tumors from individual patients has revealed that no two biopsies share the same characteristics and each individual tumor cell may be subtly different. Such diversity both between and within individual tumors presents difficulties for the modern era of “personalized medicine” and the development of new drugs. Of even greater concern is emerging evidence that breast tumors with greater diversity have worse clinical outcome. Dr. Swanton’s BCRF-funded study builds on work from his laboratory, which focuses on the mechanisms that lead to the generation of tumor diversity, and therefore heterogeneity, as well as a novel mutation analysis approach his team has developed to allow for the study of the genetic heterogeneity within individual tumors using multi-region sequencing. By understanding the mechanical processes within a breast cancer cell that lead to differences between tumor cells, Dr. Swanton hopes in the future to be able to block the generation of diversity through pharmacologic intervention, and to improve personalized-cancer medicine approaches and ultimately the clinical outcome for patients suffering from breast cancer.
The overall aim of this project is to explore the mechanisms leading to tumor diversity in breast cancer, and how this relates to prognosis and drug response. Specifically the main aims are to: 1) define thresholds of chromosomal instability (CIN) associated with clinical outcome; 2) define a mechanistic basis for CIN in breast cancer with a focus on ER-negative disease; and 3) assess the importance of CIN in disease progression from pre-invasive to metastatic disease by combining cytogenetic and sequencing techniques. For aim 1, Dr. Swain and his team are assessing the relationship between outcome and CIN, having now measured CIN in a large cohort of breast cancers. This data is presently being analyzed. For aim 2 they have selected a small subset of genes located in regions lost in high-grade breast cancers. They are validating whether the loss of function of these genes allows tolerance of aneuploidy using siRNA technologies in a panel of breast cancer cell lines. For aim 3, they are preparing the studies covering sample collection from matched primary and metastatic cases and post-mortem for submission to the IRB and regulatory bodies.
Dr. Swanton completed the MD PhD program at University College London and his doctorate in the laboratory of Nic Jones at the Imperial Cancer Research Fund Laboratories where he established the subversion of cell cycle control by the Kaposi's Sarcoma Herpes virus encoded K-Cyclin (Swanton et al. Nature 1997). He has continued his interest in cell cycle disruption in cancer and its therapeutic applications and was made a Member of the Royal College of Physicians, as well as Fellow of the Society of Biologists.
Dr. Swanton was awarded a Cancer Research UK (CR-UK) clinician scientist fellowship at the CR-UK London Research Institute with Professor Julian Downward. During this fellowship, Dr. Swanton established multi-drug sensitivity mechanisms associated with common cytotoxics used in oncological practice and identified that regulators of mitotic arrest and ceramide metabolism were important determinants of taxane response and preliminary evidence demonstrating the association of chromosomal instability with taxane resistance in vivo.
Dr. Swantonwas appointed CR-UK/MRC Group leader of the Translational Cancer Therapeutics Laboratory at the CR-UK London Research Institute and consultant medical oncologist at the Royal Marsden Hospital in the Breast and Drug Development Units in 2008 where he is aiming to better direct novel therapeutics to patients with specific breast cancer molecular subtypes within clinical trials.