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2003
Xiao-Feng Yang, MD, PhD
Baylor College of Medicine
"Novel Antigen targets for Immunotherapy in the Myeloproliferative Diseases"
Polycythemia Vera (PV) is a malignant blood cell disease similar to chronic myeloid leukemia (CML). Despite progress, PV therapeutics still needs to be improved. Good responses to the drug interon-a (IFN-a) indicate that host immune system plays an important role in controlling PV. Our proposal will investigate, in the context of IFN-a therapy, the hypothesis that PV tumor cells express a set of specific proteins molecules (tumor antigens) that are capable of eliciting immune responses leading to remission of PV, which may be similar to, if not the same as, the antigens that mediate anti-tumor immunity in other MPD like CML. We have found two new tumor antigens called CML66 and CML28. These two antigens cannot be found in normal tissues but can be easily found in a variety of tumors suggesting they are tumor-specific. The goal of this proposal focuses on the potential for novel tumor antigens and other potential PV-associated antigens to serve as targets for immunotherapy of PV and other blood tumors.
Ruben Mesa, MD
Mayo Clinic, Rochester, NY
"Novel therapies for Myelofibrosis with Myeloid Metaplasia"
Myelofibrosis with myeloid metaplasia (MMM) is a bone marrow stem cell disese that results in anemia, splenic enlargement, fatigue, acute leukemia, and death. There isno curative or palliative therapy for MMM, nor is there tissue culture oranimal model for investigation of new agents. We have prevopusly examined the effects of potential new therapies on hematopoietic progenitors from MMM patients in vitro. Based on these studies, a Phase II mutli-center clinical trial of R115777 in MMM is ongoing. We now propose a three-pronged approach to identify potential new therapies for the disease. First, we will screen a spectrum of investigational drugs to identify agents that might be appropriate for future clinical trials. Second, we will investigate the reason a novel drug, 17-allylamino-17-demethoxygeldanamycin (17-AAG), is effective in killing MMM-derived cells in vitro. Finally, we will use the new techniques of "proteonimcs" (a method of studying all of the proteins in a cell at once) to identify proteins that are uniquely increased or decreased in MMM cells compared to normal counterparts to gain further insight into MMM pathogenesis. Support of this project will hopefully lead directly to clinical trials of new and targeted therapies for MMM patients.
Richard D'Andrea, MD
Child Health Research Institute, Australia
"Identification of Growth Factor Receptor Mutations in Polycythemia Vera"
Polycythemia vera (PV) is a mature onset, myeloproliferative disorder, characterized by increased numbers of red blood cells and white blood cells. In PV, blood precursor cells in the bone marrow are hypersensitive to several growth factors or hormones, a mechanism thought to contribute to their increased growth. We have previously shown that alteration to a cell surface receptor for on of these growth factors can lead to similar altered growth factor responses and to a PV-like disease in mouse models. We have been screening PV patients for genetic alterations in the gene for this receptor and have detected a sequence change within a critical region of the gene. To investigate this further, we propose to screen larger numbers of PV patients and normal subjects for the presence of this altered sequence to determine its importance for the disease. We then have several assays in which to test the receptor responses affected by this change. In a second approach to identifying other genetic changes that contribute to PV, we propose to use a novel cloning technique to isolate genes from a PV patient that confer altered growth factor responses on normal cells.
Ron Hoffman, MD
University of Illinois at Chicago
"Organizational grant for International MPD Research Consortium in application
for $25 million grant from NCI"
Vahid Afshar-Kharghan, MD
Baylor College of Medicine
"Continuation of 2002 Grant"
One of the most important complications of myeloproliferative disorders is the organ damage caused by occlusion of blood vessels such as stroke or heart attack. Bleeding is also a common problem among patients with myeloproliferative disorders. Currently, we cannot predict which patient will develop a thrombotic (occlusion of blood flow) or hemorrhagic complication. The number and function of blood cells (including platelets) are abnormal in patients with myeloproliferative disorders. Platelets play an important role in the formation of blood clots and cessation of bleeding in normal individuals. In patients with myeloproliferative disorders, in addition to having an abnormal platelet count, platelet function is frequently altered. The change in platelet function is not similar among all patients with myeloproliferative disorders. Some of these patients have platelets that have less activity compared to normal platelets (hypoactive), while others have platelets that are hyperactive. We propose that the level of platelet activity determines which patients are at a higher risk of thrombosis and which ones are at risk of bleeding complication. We will identify the inherited and acquired factors that modulate platelet function in patients with myeloproliferative disorders, and will try to determine new risk factors that can be used to predict the risk of developing thrombotic or bleeding problems.
