Erythropoietin Blockade for the Treatment of Cancer

促红细胞生成素阻断治疗癌症

基本信息

批准号：
7692926
负责人：
C. Anthony Blau
金额：
$ 40.83万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-25 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7692926
关键词：
Ablation Address Advisory Committees Androgens Anemia Antibodies Archives Biological Biological Assay Blood Cells Boxing Canis familiaris Cell Therapy Cells Chemicals Chemotherapy-Oncologic Procedure Clinical Clinical Data Clinical Treatment Custom Data Detection Diagnostic Dimerization Doxorubicin EPOR gene Ectopic Expression Engineering Erythrocytes Erythropoietin Erythropoietin Receptor Estrogens Extracellular Domain Goals Growth Growth Factor Receptors Head and Neck Cancer Hematopoietic Hematopoietic stem cells Human Immune Intervention Ligands Malignant Neoplasms Malignant neoplasm of prostate Mass Spectrum Analysis Measurement Measures Medical Messenger RNA Methods Modeling Mus Non-Small-Cell Lung Carcinoma Outcome Participant Patients Pharmaceutical Preparations Phase III Clinical Trials Plague Predisposition Production Proteins Publishing Quantitative Reverse Transcriptase PCR Recombinant Erythropoietin Reporting Risk Sampling Series Signal Transduction Signaling Molecule Source Specimen Survival Rate Testing Therapeutic Transcript Transforming Growth Factors Treatment-Related Cancer Work base cancer cell cancer therapy cellular transduction chemotherapy conditioning human MPL protein malignant breast neoplasm meetings oncology preclinical study public health relevance receptor repository small molecule tumor tumor growth tumor progression vector

项目摘要

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.