Erythropoietin Blockade for the Treatment of Cancer

描述(申请人提供)：这是一份修改后的申请，在最初的审查中得到了175(第25个百分位数)的分数。在过去的十年里，我们开发了一种调节血细胞生产的新方法。我们的方法是基于修饰的生长因子受体的异位表达。这些受体缺乏胞外结构域，对内源性配体不敏感，而是被称为化学二聚化诱导剂(CID)的人造配体激活。在造血干细胞及其后代中异位表达血小板生成素受体的修饰衍生物(F36VMpl)，可以从小鼠、狗和人类产生依赖CID的血细胞，主要是红细胞。在这里，我们建议将F36VMpl调节的红细胞生产应用于最近认识到的潜在的巨大未满足的医疗需求。促红细胞生成素(EPO)是所有肿瘤学中最大的药物。然而，三项已发表的第三阶段临床试验(针对头颈癌的Henke研究、针对乳腺癌的最佳研究和针对非小细胞肺癌的Wright研究)以及两项尚未发表的第三阶段研究，都报告了与促红细胞生成素相关的统计学意义上的存活率恶化，在已发表的研究中，这主要是由于肿瘤的进展。目前还没有办法知道哪些患者存在促红细胞生成素诱导的肿瘤进展的风险。我们假设EPO诱导肿瘤进展的风险仅限于促红细胞生成素受体(EPOR)阳性的肿瘤患者。这些观察结果与今天EPO在肿瘤学中的使用直接相关，然而我们相信它们也打开了治疗机会的大门，使用我们控制红细胞的替代方法，从而绕过EPO。使用CID来征用红细胞产生可能允许完全消融EPO信号，类似于前列腺癌的雄激素阻断或乳腺癌的雌激素消融。因此，我们认为，这种方法不仅可能为癌症相关性贫血提供一种新的治疗方法，而且可能为癌症本身提供一种新的治疗方法。我们的具体目标是1)利用乳腺癌样本的独特资料库优化检测EPOR在临床癌症标本中的表达的方法；2)将EPOR的表达与头颈癌和非小细胞肺癌患者的临床预后相关联；3)在犬模型中测试CID治疗是否可以避免癌症化疗相关的贫血。公共卫生相关性：在这项建议中，我们试图更好地了解最近认识到的一个临床问题：促红细胞生成素诱导的肿瘤进展，并开发两种类型的干预措施来解决这一问题。首先，我们将开发一种诊断方法来预测哪些患者最容易受到促红细胞生成素诱导的肿瘤生长的影响。第二，我们提出了一种基于促红细胞生成素阻断的治疗肿瘤的新策略。

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and neck cancer, the BEST study in breast cancer and the Wright study in non-small cell lung cancer) and two as yet unpublished Phase III studies, all report a statistically significant, Epo-associated worsening of survival which, in the published studies, was primarily due to tumor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.