Studying Erythropoietin Receptor Presence and Function in Human Cancer Specimens

Background: Erythropoietin, EPO, is the main regulator and stimulator of bone marrow erythropoiesis, and is responsible for growth and differentiation of the erythroid cell lineage. The cloning of the gene, led to the production of the recombinant product, rHuEPO. rHuEPO has successfully served over the last couple of decades for both research and clinical application. The product has been shown to improve the anemia of end-stage renal disease, cancer-related anemia, as well as other types of anemia and/or blood loss. Improved anemia by rHuEPO is characterized by increased hemoglobin (Hb) and hematocrit (Hct) levels, reduced blood transfusion requirements and an improved quality of life. Thus, the use of rHuEPO has become a routine daily practice in hematology and oncology, with millions of cancer patients with or without anemia treated with rHuEPO. Indeed, rHuEPO has become a blockbuster (over an annual billion dollar sales) and the most common biological product in the market.

In 2003, reports have suggested that breast cancer, and Head and Neck cancer patients, treated with rHuEPO had a shorter survival than patients who had not been treated with the hormone. These reports were followed by several others. However, other reports, including ours, led to different conclusions. Meta-analysis also failed to provide a definitive answer.

Three potential mechanisms, none of them proven so far, have been proposed to explain potential poor prognosis among rHuEPO-treated cancer patients:

1. Stimulation of EPO receptors (EPO-R), existing on the surface of the tumor cells.
2. High level of Hb and Hct, leading to viscosity and thrombotic-like complications.
3. Increased angiogenesis induced by rHuEPO promoting tumor progression. As expected, these conflicting reports elicited a controversy among the clinical hematologic-oncologic communities, reduced the use of the product and led the FDA Oncology Drug Advisory Committee (ODAC) to publish an alert. The American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH), as well as the European Organization for Research and Treatment of Cancer (EORTC), published strict guidelines, defining who are the patients and under what circumstances rHuEPO should be or should not be administered.

With our long-time collaborator, Prof. D. Neumann, Sackler Faculty of Medicine, TAU, we have established a European international consortium, with top basic scientists and clinical investigators, with the general aim to study the topic further. Recently, the consortium, led by Prof. Neumann has been notified that the EU has recognised the importance of the project and has decided to fund it with the prestigious FP7 research grant.