George W. Sledge, Jr., MD

2012-2013 BCRF Project:
Dr. Sledge's team has for many years focused on the subject of anti-angiogenic (anti-VEGF) therapy, which seeks to stymie the growth and development of blood vessels in breast cancers. They have identified molecular targets associated with the resistance to this form of therapy and have examined whether amplification and deletion of the VEGF gene occurs in human breast cancers, and are examining what effect this may have on patient outcome. In addition to continuing work in this area, Dr. Sledge's team will focus the majority of their 2012-2013 efforts on tumor dormancy and metastasis suppression, the therapeutic targeting of which they believe is crucial to decrease the mortality rate in breast cancer.

The development of metastasis is a complex process, and it appears that metastatic tumor cells may be switched to a dormant state, which can prevent the occurrence of the final stage of metastasis, mainly metastatic colonization. Dr. Sledge's team will further examine the role of metastasis suppressor genes (MSGs), which recently have been observed to act as regulators of dormancy and metastasis. As well, they will determine whether existing therapeutic agents, such as metformin (a widely prescribed diabetes drug that has been associated with anti-breast cancer properties) affect the expression levels of MSGs. They will also continue to use a novel approach, designated as "Connectivity Map (CMAP)," which connects gene expression profiles into potential therapeutics in their analyses. They further will determine whether reexpression of these MSGs will switch metastatic breast cancer cell lines to a dormant, inactive state of disease using therapeutic agents.

In another related collaboration, Dr. Sledge's team is working with fellow BCRF grantee, Dr. Bryan Schneider (also at Indiana University) on hypertension and anti-VEGF therapy. Based on earlier studies, Drs. Sledge and Schneider found multiple provocative associations with hypertension, the most common toxicity specific to an anti-VEGF therapy called bevacizumab (Avastin). They recently completed whole-genome genotyping on an additional 1,169 patients participating in the E5103 (cohort 2) clinical trial. They will now validate the multiple provocative associations from the first 2,204 patients (cohort 1) in the additional 1,169 patients (cohort 2). They will also perform a meta-analysis on all 3,373 patients with genotyping in the E5103 study. The signature of top associations from the meta-analysis in E5103, will be further validated in the metastatic setting in a separate clinical trial, E2100. Drs. Sledge and Schneider also plan to explore the association between germline genetic variation with a variety of other chemotherapy-induced toxicities in the E5103 study. Specifically, they will evaluate for associations with congestive heart failure (CHF), a rare but potentially devastating complication from doxorubicin. Provocative associations will be validated in independent data sets.

Mid-year Progress: Dr. Sledge's group has focused on anti-angiogenic therapy and its resistance mechanisms in breast cancer both in laboratory models and in human studies. They have identified novel targets responsible for resistance to anti-VEGF therapy. Inhibition of these targets in combination with the anti-VEGF therapy will improve the sensitivity to these agents and predict benefits of therapy in the clinic. Finally, they continue to explore tumor dormancy, implicated in the late relapse of breast cancer.

Bio:
Dr. George W. Sledge, Jr. was appointed Chief of Oncology in the Department of Medicine at Stanford University Medical Center in January 2013. Prior to joining Stanford, Dr. Sledge was co-Director of the breast cancer program at the Indiana University Cancer Center, where he was a Professor of Medicine and Pathology at the Indiana University Simon Cancer Center. He held the Ballve-Lantero Endowed Chair while at Indiana University.

Dr. Sledge specializes in the study and treatment of breast cancer and directed the first large, nationwide study on the use of paclitaxel to treat advanced breast cancer. His recent research focuses on novel biologic treatments for breast cancer. He has published over 250 articles in medical journals about breast cancer and chaired several nationwide clinical trials involving new breast cancer treatments. His work spans both laboratory and clinic.

Dr. Sledge serves as Editor-in-Chief of the journal Clinical Breast Cancer and is Immediate Past President of the American Society of Clinical Oncology (ASCO). He served as chairman of the Breast Committee of the Eastern Cooperative Oncology Group from 2002-2009, where he played an important role in the development of several nationwide clinical trials. He has also served as chair of ASCO's Education Committee, as a member of the Department of Defense Breast Cancer Research Program's Integration Panel, as a member of the Food and Drug Administration's Oncology Drug Advisory Committee (ODAC), and currently as a member of the External Advisory Committee for The Cancer Genome Atlas (TCGA) project.

Dr. Sledge received the 2006 Komen Foundation Brinker Award for Scientific Distinction in 2006, The Breast Cancer Research Foundation Jill Rose Award and the William L. McGuire Award from the San Antonio Breast Cancer Symposium in 2010.