Grant: Project Grant

Anemia (a low number of red blood cells or low amount of hemoglobin in blood) affects many cancer patients undergoing chemotherapy, leading to fatigue, weakness, shortness of breath and other symptoms, which severely reduce the patients' quality of life. Cancer-related anemia is also associated with shorter survival times. While treating anemia with the hormone erythropoietin (EPO) has been highly successful, the use of EPO in cancer-related anemia is sometimes considered unsafe since it also encourages tumor growth. Previous research has shown that the desired response to EPO (red blood cell production) likely occurs via a different mechanism than the undesired tumor-promoting effects. That is, the stimulation of red blood cell production depends on a cell surface receptor called EPOR, while tumor-stimulating effects depend on other cell surface receptors unrelated to EPOR. These observations suggest that the development of molecules capable of stimulating only the desirable EPOR-dependent responses may provide novel avenues for a more effective treatment of cancer-related anemia. We have developed a rapid and efficient method to engineer protein variants of EPO and antibodies that attach to EPOR. This involves searching through large collections of EPO-like variants or antibodies for molecules that attach to EPOR and stimulate its activity. The effect of these novel molecules on EPOR activation is assessed in cultured cells and screened in cultured tumor cells to identify molecules that do not stimulate tumor growth. The proposed project builds on current knowledge from available anemia treatments by creating novel, improved molecules that will stimulate production of red blood cells via an EPO-dependent mechanism, but unlike natural EPO, they will not stimulate other pathways that lead to undesired side effects. Therefore, this project has the potential to greatly improve the quality of life and survival for cancer patients.