Research

The Brekken laboratory is part of the Division of Surgical Oncology and is located in the Hamon Center for Therapeutic Oncology Research on the 8th floor of the Simmons Biomedical Research Building (NB) on the North campus of UT Southwestern. The broad interest of the lab is to study the microenvironment of tumors with a particular emphasis on extracellular matrix (ECM) deposition and remodeling, regulation and manipulation of tumor angiogenesis, and the testing of novel therapy.

To study the tumor microenvironment we use models of pancreatic, breast, and lung cancer. Pancreatic cancer is particularly well-suited for evaluation of ECM deposition and remodeling as it is a highly desmoplastic disease. Breast cancer is also well suited for these studies and has been used frequently by investigators to study cell trafficking and angiogenesis. Lung cancer is a strength of the Hamon Center and we have utilized these resources to study pathways associated with therapy resistance.

    Matricellular proteins are a class of ECM-related proteins that control the interaction of cells with the ECM and/or deposition of structural ECM proteins (e.g., collagens, elastin).SPARC (also known as osteonectin) is a prominent member of the matricellular class of proteins. SPARC is known to orchestrate collagen deposition and we have documented that it is required for appropriate host response to tumor growth and control of the activation of latent TGFβ. Current studies are focused on demonstrating that SPARC is a critical control point for collagen signaling.

    Matricellular Proteins as Modulators of Cell-ECM Interaction in Cancer Flowchart

    We have demonstrated previously that fibulin-5 (Fbln5) competes with fibronectin for binding to integrin α5β1. Absence or blockade of Fbln5 results in elevated ligation of the integrin by fibronectin, which stimulates the production of reactive oxygen species (ROS). We are deciphering the signaling pathways that lead to ROS production and are also exploring the physiologic consequences of fibronectin-mediated integrin-induced ROS generation.

    We are exploring actively numerous novel targets for the therapy of pancreas and breast cancer.

    One novel target is anaplastic lymphoma kinase (ALK). ALK can be oncongenic when fused with other genes (e.g, EML4-ALK in lung cancer). However, we have identified that ALK activity in tumor-associated macrophages drives a pro-metastatic macrophage phenotype and further inhibition of ALK in macrophages can augment that activity of other therapy such as anti-VEGF strategies. The Mary Kay Foundation has recently funded our Lab to explore the use of ALK as a marker of breast cancer progression and as a target for therapy.

    Anti-inflammation Angiogenesis Immune tolerance Metastasis

    We are interested in creating new drugs that act by homing in on blood vessels in cancers and destroying them. This stops the flow of blood to the cancer, and the cancer cells then die because they are starved of oxygen and nutrients. For this strategy to work, differences had to be found between cancer blood vessels and blood vessels in healthy tissues. We made the remarkable discovery that a fatty lipid molecule, phosphatidylserine, becomes exposed on the outer surface of cancer blood vessels where it can serve as a target for the new drugs.

    Microscopic view of Chemotherapy or irradiation induces phosphatidylserine exposure on endothelial cells<br />
(L-R: 0 hr, 8 hr, 16 hr, 24 hr)

    Chemotherapy or irradiation induces phosphatidylserine exposure on endothelial cells 
    (L-R: 0 hr, 8 hr, 16 hr, 24 hr)

    Phosphatidylserine (PS) is largely absent from the surface of most cells under normal conditions. PS becomes exposed on tumor blood vessels in response to stress conditions in the tumor microenvironment. To target cell surface PS, we raised monoclonal antibodies that recognize anionic phospholipids. Some of the antibodies bind directly to PS while others bind to lipids complexed with beta2-glycoprotein I, a common blood protein. We have found that the antibodies localize specifically to tumor blood vessels after injection into mice bearing various types of solid tumors. In contrast, the antibodies do not localize to blood vessels in normal tissues. Treatment of tumor-bearing mice with one of the antibodies, 2aG4, results in up to 90% tumor growth retardation in multiple tumor models. 2aG4 enhances the antitumor effects of common radio- and chemo-therapeutic strategies. In vitro and in vivo studies indicate that 2aG4 acts by provoking innate immune reactions that destroy tumor blood vessels. In addition, the antibody blocks PS-mediated immunosuppressive signals that would normally prevent immune cells from being able to recognize tumor cells as foreign. The antibody therefore reactivates tumor immunity which further helps to control tumor growth and spread. A semi-human version of 2aG4, called bavituximab, has been produced in collaboration with our pharmaceutical company partners, Peregrine Pharmaceuticals, Inc. Randomized phase IIb studies of bavituximab combined with chemotherapy are  in progress in patients suffering from advanced lung or pancreatic cancer. Trials are also underway in patients with liver cancer and breast cancer.

    Prolonged survival time and cures in rats bearing orthotopic F98 tumors treated with irradiation and 2aG4 (chart)

    Prolonged survival time and cures in rats bearing orthotopic F98 tumors treated with irradiation and 2aG4

    Vascular endothelial growth factor (VEGF) is a primary stimulant of angiogenesis in normal and tumor tissue. Inhibition of VEGF activity results in a decrease in microvessel density, which increases hypoxia in the target tissue. Hypoxia has numerous effects on the tumor microenvironment, including induction of EMT and alterations in metabolism. We are actively working on animal models that recapitulate anti-VEGF-induced hypoxia to determine the critical factors that drive 1) resistance to anti-VEGF and 2) changes in tumor cell phenotype after anti-VEGF therapy.

    Angiogenesis Flowchart