A phase I study of ABT-510 plus bevacizumab in advanced solid tumors.

Our laboratory focuses on transforming growth factor-ß (TGF-ß) superfamily signal transduction pathways, and specifically, the role of these pathways in cancer biology. The TGF-ß superfamily is comprised of a number of polypeptide growth factors, including TGF-βs, bone morphogenetic proteins (BMPs) and activin) that regulate growth, differentiation and morphogenesis in a cell and context specific manner. TGF-ß and the TGF-ß signaling pathway have a dichotomous role in cancer biology, as both tumor-suppressor genes (presumably as regulators of cellular proliferation, differentiation and apoptosis) and as tumor promoters (presumably as regulators of cellular motility, adhesion, angiogenesis and the immune system). This dichotomy of TGF-ß function remains a fundamental problem in the field both in terms of understanding the mechanism of action of the TGF-ß pathway, and directly impacting our ability to target this pathway for the chemoprevention or treatment of human cancers. Resistance to the tumor suppressor effects of TGF-ß is also a common feature of epithelial-derived human cancers (breast, colon, lung, pancreatic, prostate), however, mechanisms for TGF-ß resistance remain undefined in the majority of cases. TGF-ß regulates cellular processes by binding to three high affinity cell surface receptors, the type I, type II, and type III receptors. Recent studies by our laboratory and others have established the type III TGF-ß receptor (TßRIII)  as a critical mediator/regulator of TGF-ß signaling. Specifically we have demonstrated that regulating TßRIII expression levels is sufficient to regulate TGF-ß signaling, and that decreased TßRIII expression is a common phenomenon in human cancers, resulting in cancer progression. TßRIII is also shed from the surface to generate soluble TßRIII, which we have demonstrated has a role in creating an immunotolerant tumor microenvironment. The role of TßRIII and soluble TßRIII in the tumor immune microenvironment is currently being investigated using a multidisciplinary approach.

Activin receptor-like kinase 4 (ALK4) is a type I transforming growth factor-β (TGF-β) superfamily receptor that mediates signaling for several TGF-β superfamily ligands, including activin, Nodal and GDF5. We have demonstrated that mutation or copy number loss of ALK4 occurs in 35% of pancreatic cancer patients, with loss of ALK4 expression associated with a poorer prognosis. ALK4 has also been identified in an unbiased screen as a gene whose disruption enhances Ras mediated pancreatic tumorigenesis in vivo. We have demonstrated that loss of ALK4 expression increases canonical TGF-β signaling to increase cancer invasion and metastasis in vivo. We are currently investigating the mechanism by which loss of ALK4 regulates TGF-β signaling, how it may effect other signaling pathways, and how to use this knowledge to treat pancreatic cancer patients with loss of ALK4 function.

Dr. Andrew Nixon is Professor of Medicine in the Department of Medicine/Division of Medical Oncology at Duke University. He holds a BS in chemistry from Miami University, a PhD in biochemistry from Wake Forest University, and an MBA with a focus on healthcare management from Duke University/Fuqua School of Business. He is a nationally recognized expert in the development of cancer biomarkers and correlative science, with extensive experience leading large multi-center biomarker analyses. Dr. Nixon serves in various leadership roles within the National Cancer Institute (NCI), working with diverse multi-disciplinary teams focused on improving cancer patient outcomes through biomarker science. He serves as the national co-chair for the NCI Core Correlative Sciences Committee which adjudicates the use of biospecimens collected throughout the NCI National Clinical Trial Network (NCTN). Within the NCI-NCTN Alliance cooperative group, Dr. Nixon has multiple leadership positions including serving on the Alliance Board of Directors, co-chair of the Immuno-Oncology Committee, co-chair for Gastrointestinal Correlative Research, and has been an executive member of the Translational Research Program since its inception. Additionally, within the NCI-NCTN NRG cooperative group, he serves as a member of the Gynecologic Translational Science Committee and on the Gynecological Oncology Group - Partners Investigator Council Translational Research Subcommittee. Dr. Nixon is an American Society for Clinical Oncology (ASCO) Ambassador and has chaired various committees and led scientific and educational sessions at national conferences. Recently, Dr. Nixon has focused his research on cellular senescence and biomarkers of aging and early carcinogenesis. He serves as Principal Investigator for a large multi-center NIH grant to develop high-resolution tissue maps and biomarkers of cellular senescence as a part of the Senescence Network (SenNet) Consortium.

Classification and Predictive Models
Design and Analysis of Biomarker Clinical Trials
Genomics
Pathway Analysis