| RoFAR awards grants for the first cycle of applications
Grants totalling over one million Swiss Francs will support innovative research in anemia
RoFAR (Roche Foundation for Anemia Research) announced on 4 December 2004 in San Diego that just six months after the organization was established it has awarded its first research grants totalling 1,383,000 Swiss Francs (about 1,200,000 US Dollars) for medical research in renal and cancer related anemia to physicians in Germany, Italy, the UK and the USA.
Over 70 initial applications for grants have been made to RoFAR during the first cycle of applications. The seven research projects chosen for the first awards meet exacting standards for scientific excellence, feasibility and originality set by the organization's independent Scientific Advisory Board.
Announcing the awards, Dr Jim Armitage, a member of the RoFAR Board of Trustees and a leading oncologist at the University of Nebraska Medical Center, USA, said “I would like to congratulate this, the first group of physicians to receive awards from RoFAR. The research they will embark on over the next two years has the potential to yield information that will move our understanding of anemia into new and important arenas. We wish them every success with their scientific endeavours.”
The first award winners and their fields of research are:
Dr Nancy C. Andrews, Children's Hospital Boston, USA
Hepcidin regulation in the anemia of chronic disease
The anemia of chronic disease (also called the anemia of chronic inflammation) is an acquired condition that affects patients with a variety of inflammatory disorders including infection, arthritis, inflammatory bowel disease, trauma, organ failure and cancer. It can be severe enough to require blood transfusions. However, even milder anemia of chronic disease can impair quality of life and general well being. We previously showed that the anemia of chronic disease results, at least in part, from induction of synthesis of a hormone called hepcidin in response to inflammation. Hepcidin controls how the body uses iron by regulating its absorption through the intestine and its recycling by tissue macrophages. When increased levels of hepcidin are produced both intestinal absorption and iron recycling are blocked, resulting in decreased iron available for erythropoiesis and consequent anemia. The goal of this project is to understand the normal regulation of hepcidin production and changes in regulation in response to inflammation. We hope that this work will provide information to facilitate the development of drugs that can prevent increased expression of hepcidin in inflammation and ameliorate the anemia of chronic disease.
Progress report available: 
Dr Martin Bergmann, Katheterlabor, Franz Volhard Klinik, Germany
Effect of 5,000 IU epoetin beta once weekly subcutaneously (sc.) administered for three months in patients subjected to percutaneous coronary intervention (PCI) displaying reduced LV-ejection fraction due to regional left ventricular wall motion defects
Despite increasing success of interventional methods to restore blood supply to ischemic myocardium, the resultant functional improvement of myocardial contractility is often limited. Epoietin has been shown to protect cardiomyocytes from apoptosis, enhance the level of circulating progenitor cells possibly contributing to restore functional myocardium in previous ischemic areas and increase oxygen supply by increasing the hemoglobin levels. All these effects may enhance myocardial function after percutaneous coronary interventions (PCI). Therefore, the study will test the effect of a once weekly dose of epoietin beta applied subcutaneously beginning at the time of PCI on the recovery of regional wall motion defects at three month. Cardiac function will be precisely assessed by cardiac magnetic resonance imaging.
Progress report available:
Dr Andrew McKie, Life Sciences, Kings College London, UK
Characterisation of a novel intestinal heme transporter
Iron is an essential nutrient required by the body to make the protein hemoglobin in red blood cells which is essential for delivering oxygen to working muscles and other cells. Too little iron in the diet (iron deficiency) leads to anemia causing fatigue. On the other hand too much iron is toxic and can damage vital organs like the heart and liver. Red meat is a good source of iron because it contains a lot of heme iron which is efficiently absorbed by the small intestine. We have now identified the protein responsible for the absorption of heme from the diet. In this application we study the proteins involved. One aim will be to develop synthetic dietary supplements based on the structure of heme which would be suitable for treatment of iron deficiency anemia in vegetarian communities.
Progress report available:
Final report available:
Dr Marco Merlano, Division of Medical Oncology, S. Croce General Hospital, Cuneo, Italy
In vitro analysis of tumor response to radiation in oxic and hypoxic conditions
Dr Cristiana Lo Nigro received the award on behalf of Dr Merlano.
Despite therapeutic improvements and efforts to develop more efficacious therapies, the majority of Head and Neck Squamous Cell Carcinoma (HNSCC) patients face a poor prognosis. Therefore, the primary goal of current treatment is improvement of quality of life (QOL) and prolongation of survival. Anemia frequently occurs in HNSCCs and has been associated with decreased QOL, impaired treatment outcomes and shortened survival. Furthermore, anemia is a causative factor of tumor hypoxia, which compromises the efficacy of radiotherapy. Thus, correction of anemia seems to have a beneficial effect on QOL and outcome. The human recombinant erythropoietin (rHuEPO) has proven efficacy and safety in correcting anemia in numerous clinical studies and over a decade of clinical practice.
The relationship among anemia, hypoxia, transfusion and treatment outcome is complex and there certainly remains a lot of room for discussion about the role of hypoxia for tumor development and radiation response. Nevertheless, understanding the biological mechanisms is important to reach the ability of reversing radioresistance, improving QOL in anaemic patients, cancer control and clinical efficacy of radiation.
The purpose of the presented study is to establish an experimental model and to provide experimental evidences to examine the relationship between hypoxia, EPO/EPOR and EGFR transcription/expression and their effects on the cellular response to radiation; we will investigate different cellular responses after radiation under oxic and hypoxic conditions and compare these findings to what happens when the cells cultured in hypoxia are reported to oxic conditions and then irradiated.
The aim is to better define the biological and molecular bases for the in vitro response to hypoxia and to explore its effects on radiotherapy, in order to add knowledge on the mechanisms underlying the negative effects of anemia on radiotherapy outcome: the identification of the causes of treatment failure may facilitate the development of treatment strategies to improve efficacy and reduce toxicity.
Progress report available:
Dr Peter Mertens, Medizinische Klinik II Universitätsklinikum Aachen, Germany
Mechanisms for erythropoeitin resistance in transformed and non-transformed cells
Recent studies indicate that erythropoietin (EPO) fulfills important functions not only in haematopoiesis, but also related to cell survival of non-transformed and transformed cells under hypoxia. Our goal is to unravel causes of cellular EPO resistance with the focus being on an archetypical stress responsive protein, namely Y-box protein-1 (YB-1). This transcription factor is hypothesized to counteract EPO cytoprotective effects in non-transformed cells at several key levels, including EPO gene transcription, EPO signalling and target gene regulation. Our data indicate that YB-1 itself is regulated under hypoxia. After elucidating whether YB-1 has an immediate effect on the hypoxic response, e.g. by binding to specific DNA regulatory elements within the EPO gene, further results deal with the effects of manipulated cellular YB-1 levels (up and down) on EPO signalling and cell survival. For tumour cells an increased nuclear YB-1 content has been described, which is associated with poor outcome due to metastasis formation. An underlying mechanism may be counteracted EPO regulation with the initiation of a hypoxia cell program. Such a response includes the upregulation of target genes relevant for angiogenesis and metastasis formation. Our approach is to test for the EPO response in dependency of YB-1 expression levels, that will be manipulated by molecular biology tools.
The in-depth understanding of EPO resistance for mesenchymal cells as well as tumour cells may provide the rational for specific interventions. These may include targeting of YB-1 under both conditions, to sensitize cells to EPO and thereby increase the survival of mesenchymal cells under hypoxia, and to shut off the “angiogenesis program” of tumour cells responsible for metastasis formation in a wide range of tumours, like breast and lung cancer.
Progress report available:
Dr Chris Vulpe, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, USA
Characterization of a family of putative mammalian heme chaperones
Iron is an essential nutrient that is required for a wide range of biochemical reactions in the body. One of the important roles of iron is in heme which is used by a variety of proteins including hemoglobin, cytochromes important for mitochondrial function and P450s involved in chemical detoxification. Despite the importance of heme and the recent progress in understanding iron metabolism in both yeast and mammals, the distribution of heme from the mitochondria to the organelles and proteins that require it has remained a central intractable enigma of mammalian metal metabolism. We have identified a family of eukaryotic proteins that very likely represent the long elusive heme chaperones which deliver heme to apo-proteins. We propose to characterize the mammalian members of this family of proteins and investigate the mechanisms of heme transport and delivery. Understanding of heme metabolism is vital to the understanding iron deficiency, the most common nutritional disorder in the world, and the resulting anemia. This study will provide insight into the clinical consequences include impaired psychomotor and cognitive development in children, increased morbidity in anemic mothers and diminished work capacity in affected adults and possibly lead to therapeutic interventions.
Progress report available:
Applications for the second cycle of awards closed on the 21st November and awards for this cycle will be made in May 2005. Physicians can already apply for awards for the third cycle of funding; the deadline for letters of intent for this cycle is 19 June 2005.
|