Arnab Ghosh, M.D., Ph.D.
Postdoctoral Research Fellow, Memorial Sloan Kettering Cancer Center, New York, NY
Neovascularization in GVHD and Growth of Tumors in Recipients of allo-BMT
"In many blood cancers, allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents the only treatment with the potential for cure. Graft-versus-host disease (GVHD), however, afflicts between 30-80 percent of patients receiving allo-HSCT and remains a major cause of death. The primary cause of GVHD is known to be linked to donor T cells, which can recognize host cells as foreign and attack indiscriminately, often targeting both cancer cells and normal tissues. Our recent studies in mouse models have demonstrated a previously unknown association between growth of new blood vessels and development of GVHD. We found that organs involved with GVHD have evidence of new vessel growth, and that mice with GVHD have increased numbers of circulating cells called endothelial progenitor cells (EPCs), which are recruited in the formation of new vessels. Reducing numbers of EPCs by anti-VE Cadherin antibody E4G10 resulted in decreased formation of new vessels as well as decreased GVHD. Importantly, the ability of donor T cells to attack cancer cells was not compromised by the antibody treatment. In this project, using mouse models, I will characterize the link between the growth of new vessels and GVHD. In addition, I will determine how the growth of new vessels affects growth and spread of cancer cells, and their interactions with T cells in the context of HSCT. Receiving the Judah Folkman Fellowship is a great honor and will be valuable support for this project. We hope that our approach would reveal a fresh understanding of the GVHD process. Further, we hope to understand how new blood vessel formations in the recipients of bone marrow transplantation affect the development and spread of cancerous cells."
Top of Page
Keli M. Turner, M.D.Resident, University of Maryland, Baltimore, MD
Inhibition of IL-1 as a Novel Target in Pancreatic Adenocarcinoma
"Cancer is the leading cause of death in the United States for all individuals under the age of 85 years. Pancreatic adenocarcinoma, the most common type of pancreatic cancer, is the fourth leading cause of cancer death in the United States. It is one of the most aggressive and deadly cancers known; at five years after diagnosis, 95 percent of patients will have succumbed to this disease. Based on this data, it is clear that the discovery of effective agents for the treatment of patients with pancreatic cancer is desperately needed. In searching for novel therapies in the battle against pancreatic cancer, our lab has shown that a molecule called interleukin-1 beta (IL-1β) is produced in tumors from certain patients with pancreatic cancer. IL-1β is a member of the interleukin-1 protein family. IL-1 has been shown to play a role in various inflammatory conditions and there is emerging data suggesting that over-production of IL-1 in tumors promotes tumor growth and spread outside of the host organ. It is believed that IL-1 mediates tumor growth and metastasis by affecting the production of other molecules, namely those that regulate the growth of blood vessels in the tumor such as vascular endothelial growth factor (VEGF) or interleukin-8 (IL-8). In addition to demonstrating that certain pancreatic tumors overexpress IL-1β, our lab has shown that inhibiting the IL-1 receptor using an IL-1 receptor antagonist in pancreatic cancer cell lines that overproduce IL-1β leads to the inhibition of the production of VEGF. These findings are important as it is believed that inhibiting the growth of blood vessels in a tumor will lead to the regression of that tumor. Our objective is to study the effects of IL-1 on pancreatic cancer growth using both laboratory experiments and animal models. We will also study how IL-1 receptor stimulation and IL-1 inhibition affects tumor blood vessel growth by examining the levels of VEGF and IL-8 in our experiments. What makes our approach to the study of the IL-1 receptor especially unique is that we will use a commercially available IL-1β antibody called Canakinumab in our studies. This drug is used in the treatment of patients with a rare autoinflammatory syndrome called Cryopyrin Associated Periodic Syndrome and works by binding IL-1β such that it cannot bind the IL-1 receptor. If our studies prove that IL-1 blockade inhibits the growth of pancreatic cancer, we will have a new understanding of this disease. Moreover, if Canakinumab proves effective in these studies, it can be ushered into clinical trials as it is already an FDA-approved compound. The Judah Folkman Anti-Angiogenesis Research Fellowship will be utilized to support this research which I hope will not only provide new insight for the treatment of pancreatic cancer but will also provide a new compound to be evaluated as a potential cure for this disease. I would like to thank the AACR for this award and I am truly honored to have received this fellowship. I would also like to thank my mentor Dr. H. Richard Alexander for his guidance and support in this research endeavor."
Top of Page
2008 GRANTEE
Zoe Cournia, Ph.D.Investigator, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
MIF Inhibition as a Means to Suppress Tumor Growth and Angiogenesis
"Macrophage migration inhibitory factor (MIF) is a tautomerase released by T-cells and macrophages, and acts as an immunoregulatory and proinflammatory cytokine. MIF is implicated in multiple aspects of tumor growth, including control of cell proliferation and promotion of angiogenesis. Deactivation of MIF by antibodies or inhibition of MIF binding its receptor, CD74, reduces cellular proliferation and attenuates tumor growth and angiogenesis. The aim of this preclinical project is to target and deactivate the MIF protein by small molecule inhibitors through a joint computational and experimental study. This goal will be achieved by computational structure-based drug design, synthesis of potential leads and
in vitro assaying for (a) MIF-CD74 inhibition and (b) tautomerase inhibition. Following the assays, the potent compounds will be further optimized with computational methods and re-assayed for enhanced inhibition activity. Apart from presenting an excellent opportunity for an efficient anti-cancer therapy, potent MIF inhibitors will improve our understanding of the MIF enzymatic activity and hence its implication in angiogenesis of tumor cells and metastases. In view of our limited knowledge of MIF biochemistry, we also propose to investigate the MIF tautomerization mechanism. Overall, the AACR Judah Folkman Fellowship will help to uncover new anti-cancer leads for further exploration through
in vivo studies and animal models, as well as gain a fundamental understanding of MIF biochemistry. The proposed studies constitute a unique synergy between the Jorgensen laboratory, well-renowned for their computational drug design efforts, and the collaborating experimental Bucala group at Yale University. "I feel truly honored to be the first recipient of the AACR Judah Folkman Fellowship for Cancer Research in Angiogenesis. I would like to express my gratitude to my current mentor, Dr. Jorgensen, for his continuing support, inspiration and confidence in my capabilities. I feel extremely privileged in being able to work with him in such an outstanding environment that fosters my development as a scientist in cancer research."