Carlos L. Arteaga, MD

Most estrogen receptor positive (ER+) breast cancers depend on female hormones to grow and spread. Many of them initially respond to anti-estrogen therapies, such as letrozole (an aromatase inhibitor), tamoxifen, and raloxifene; however, many of these cancers become resistant to anti-estrogen therapies over time. With BCRF funding, Dr. Arteaga and colleagues have continued to investigate mechanisms of acquired resistance to estrogen deprivation and hormone dependence in breast cancer. They have developed several ER cell lines that acquire resistance to estrogen deprivation and have found in these cells that the PI3K/AKT pathway was upregulated. The researchers noted that these cells were exquisitely sensitive to PI3K pathway inhibitors and as a result, they initiated clinical trials using letrozole in combination with two novel drugs under development, the pan-PI3K inhibitor BKM120 and the dual PI3K/TOR inhibitor BEZ235. They also have identified IGF-IR, InsR, CDK4, and PLK1 as molecules that can dispense with hormone dependence and, as such, contribute to escape from anti-estrogen therapies. In 2012-2013, Dr. Arteaga's team will continue to investigate how the targeting of these kinases in combination with endocrine therapies will abrogate escape from estrogen deprivation and benefit patients with ER+ breast cancer.

Mid-year Progress: Dr. Arteaga's team has previously found that ER+ breast cancer cells and tumors deprived of estrogen maintain estrogen-independent ER function. This suggests that a drug that induces degradation of ER, such as fulvestrant or a more potent ER downregulator (degrader) would be more effective than an aromatase inhibitor (AI) or would be highly complementary with an AI in patients with ER+ breast cancer. Dr. Arteaga's team has shown that the oral ER downregulator ARN-673 is superior to fulvestrant against human breast tumors grown in the laboratory. This drug is about to enter phase I clinical trials with Vanderbilt as one of the three sites where patients will be enrolled. Dr. Arteaga's team is currently testing the combination of fulvestrant, BKM120 and the Src inhibitor dasatinib in laboratory models bearing ER+ xenografts that also have PIK3CA and LYN mutations. Since some ER+ breast cancer cells maintain ER transcriptional activity despite estrogen deprivation, Dr. Arteaga's team is now identifying kinase signaling pathways that promote estrogen-independent ER transcription and cell growth. Preliminary data that the researchers anticipate will be included in the next progress report suggest PLK1 is a main kinase associated with this escape. Since Src and PLK1 inhibitors are also in clinical development, combinations including these drugs can also be tested in preclinical models and later examined in clinical trials.

Bio:
Carlos L. Arteaga obtained his M.D. degree with honors in 1980 at the University of Guayaquil in Guayaquil, Ecuador. He trained in Internal Medicine and Medical Oncology at Emory University (Atlanta, GA) and the University of Texas Health Sciences Center in San Antonio, TX, respectively. He joined the Vanderbilt faculty in 1989 where he now holds the Donna S. Hall Chair in Breast Cancer Research and serves as Professor of Medicine and Cancer Biology in the Division of Hematology-Oncology in the Department of Medicine. Arteaga is Associate Director for Clinical Research at the NCI-designated Vanderbilt-Ingram Comprehensive Cancer Center (VICC) and directs the Breast Cancer Program of the VICC. He has over 250 publications in the areas of signaling by growth factor receptors and oncogenes in breast tumor cells as well as the development of molecular therapeutics and biomarkers of drug action in breast cancer. Arteaga directs the NCI-funded Vanderbilt Breast Cancer SPORE where he leads a number of investigator-initiated clinical trials. He is funded by NCI, ACS, the DOD Breast Cancer Research Program, Stand Up 2 Cancer/AACR, and the Komen and Breast Cancer Research Foundations. He is certified by the American Board of Internal Medicine in Internal Medicine and in Medical Oncology. In 1998 he was elected into the American Society of Clinical Investigation (ASCI) and in 2005 into the Association of American Physicians (AAP). He serves (or has served) as member of the NCI Parent Committee for Review of Cancer Centers (Subcommittee A; 2004-2008), the Board of Scientific Advisors of the National Cancer Institute (1999-2004), the Breast Cancer Core Committee of the Eastern Cooperative Oncology Group (ECOG), and the Board of Directors of the American Association for Cancer Research (AACR; 2004-2007). He co-chaired the Developmental Therapeutics Committee of ECOG and chaired the Special Conferences Committee of the AACR (2002-2008). Arteaga is the recipient of the 2003 AACR Richard & Hinda Rosenthal Award and more recently received the 2007-2012 ACS Clinical Research Professorship Award, the 2009 Gianni Bonadonna Award from the American Society of Clinical Oncology (ASCO), and the 2011 Brinker Award for Scientific Distinction from the Susan G. Komen for the Cure Breast Cancer Foundation. He has chaired the AACR Special Conference Advances in Breast Cancer Research in 2003, 2005, 2007, and 2009. He is Deputy Editor of Clinical Cancer Research and Associate Editor or member of the Editorial Board of Cancer Cell, theJournal of Mammary Gland Biology & Neoplasia, Breast Cancer Research, Molecular Cancer Therapeutics, Journal of Clinical Oncology (past), Clinical Proteomics, and Cancer Biology & Therapy.