This is a revised application that received a score of 175 (25th percentile) in its initial review. Over the past decade we have developed a new way of regulating blood cell production. Our method is based on the ectopic expression of modified growth factor receptors. Lacking an extracellular domain, these receptors are insensate to endogenous ligands, but are instead activated by artificial ligands called chemical inducers of dimerization (CIDs). Ectopic expression of a modified derivative of the thrombopoietin receptor (F36VMpl) in hematopoietic stem cells and their progeny allows for CID-dependent blood cell production, predominantly red blood cells, from mice, dogs and humans. Here we propose to apply F36VMpl regulated red cell production to a recently recognized and potentially enormous unmet medical need. Erythropoietin (Epo) is the biggest drug in all of oncology. However, three published Phase III clinical trials (the Henke study in head and neck cancer, the BEST study in breast cancer and the Wright study in non-small cell lung cancer) and two as yet unpublished Phase III studies, all report a statistically significant, Epo-associated worsening of survival which, in the published studies, was primarily due to tumor progression. There is currently no way of knowing which patients are at risk for Epo-induced tumor progression. We hypothesize that the risk of Epo-induced tumor progression is confined to patients with erythropoietin receptor (EpoR) positive tumors. These observations are immediately relevant to Epo's use in oncology today, however we believe they also open the door to a therapeutic opportunity, using our alternative method for controlling red cells, thereby circumventing Epo. Using CIDs to commandeer red cell production might allow for the complete ablation of Epo signaling, analogous to androgen blockade for prostate cancer or estrogen ablation for breast cancer. We therefore believe that this approach may provide not only a new treatment for cancer-related anemia, but for cancer itself.
Our specific aims are to 1) optimize assays for measuring EpoR expression in clinical cancer specimens using a unique repository of breast cancer samples;2) correlate EpoR expression with clinical outcome in patients with head and neck cancer and non-small cell lung cancer;3) test whether CID treatment can circumvent anemia associated with cancer chemotherapy in a dog model.
In this proposal we seek to better understand a recently recognized clinical problem: erythropoietin induced tumor progression, and to develop two types of interventions that address this problem. First, we will develop a diagnostic assay to predict which patients are most susceptible to erythropoietin induced tumor growth. Second, we propose a new strategy for treating tumors that is based on erythropoietin blockade.
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|Miller, Chris P; Lowe, Kimberly A; Valliant-Saunders, Karine et al. (2009) Evaluating erythropoietin-associated tumor progression using archival tissues from a phase III clinical trial. Stem Cells 27:2353-61|