Charles Swanton, MD, FRCP, PhD

2012-2013 BCRF Project:
Modern technologies are increasingly revealing the tremendous diversity between breast cancers from different patients, despite similar characteristics under the microscope in the pathology department. Furthermore, in-depth analysis of tumors from individual patients has revealed that each individual cancer cell may be subtly different from neighboring cells. 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 research builds on his laboratory's earlier work that focuses on the mechanisms that lead to the generation of tumor diversity in breast cancer. By understanding the mechanical processes within a breast cancer cell that lead to differences between tumor cells, Dr. Swanton's team hopes in the future to be able to block the generation of diversity through pharmacologic intervention and improve personalized-cancer medicine approaches and, ultimately, the clinical outcome for patients suffering from breast cancer.

Mid-year Progress: The overall aim of this project is to explore the mechanisms leading to tumor diversity, in particular "chromosomal instability," in breast cancer and how it relates to prognosis and drug response. Specifically the main aims are to: 1) define thresholds of chromosomal instability associated with poor clinical outcome; 2) define a mechanistic basis for chromosomal instability in breast cancer with a focus on ER-negative disease; and 3) assess the importance of chromosomal instability in disease progression from pre-invasive to metastatic disease by combining cytogenetic and sequencing techniques.

Work from Dr. Swanton's laboratory has previously shown that chromosomal instability is associated with poor clinical outcome in breast cancer patients but that this association is dependent on the degree of instability. For aim 1, Dr. Swanton's laboratory is assessing the relationship between outcome and chromosomal instability on a large scale (approximately 3,600 breast cancer samples) and has now measured CIN in two-thirds of the cohort. Once the cohort is complete, they will analyze the data and correlate the degree of CIN with clinical outcome. For aim 2, the researchers have selected a small subset of genes located on chromosomal regions lost in both ER-positive and ER-negative high-grade breast cancers and are now assessing their involvement in chromosomal instability using siRNA technologies in a panel of breast cancer cell lines. For aim 3, they have matched samples from primary and metastatic cases and are looking at chromosomal instability during cancer progression.

Bio:
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.