Targeting hypoxic bone marrow microenvironment in Acute Myeloid Leukemia (AML)

描述（由申请人提供）：治疗急性髓性白血病（AML）的主要挑战是克服对化疗的耐药性。我们已经表明，白血病患者的骨髓（BM）是高度缺氧的，并且BM缺氧促进了对通常用于治疗AML的药物的耐药性。这些数据提供了使用低氧激活的前药消除低氧壁龛内的AML细胞的基本原理。在我们的临床前模型中，利用新型缺氧激活的前药PR 104显著降低了白血病负荷并治愈了移植有人白血病的小鼠。在正在进行的实体瘤临床试验中，PR 104的主要毒性是骨髓抑制;这种毒性表明PR 104可能在AML中具有活性。基于这些发现，我们将在复发或难治性AML患者中进行I/II期临床试验，以研究PR 104的安全性和抗白血病疗效。该试验将利用新的统计设计，根据每位患者的AML病史（如既往缓解持续时间和年龄）确定“个性化”剂量。我们设计了可选的实验室研究来测量白血病细胞中的BM缺氧和缺氧反应，以研究这些标志物是否可以在选择患者特异性剂量的PR 104时增加临床特征。如果成功，这种靶向低氧微环境的方法，单独或与其他化疗或靶向药物联合，可能会显著影响AML治疗，并最终改善患者的预后。 公共卫生相关性：急性髓性白血病（AML）患者复发后的预后仍然很差。PR 104是一种新型的低氧激活剂，在低氧白血病骨髓微环境中被代谢为细胞毒衍生物。在这项研究中，我们将研究PR 104在复发或难治性AML患者中的安全性和抗白血病疗效。

DESCRIPTION (provided by applicant): The main challenge in the treatment of acute myeloid leukemia (AML) is overcoming resistance to chemotherapy. We have shown that bone marrow (BM) in leukemia patients is highly hypoxic, and that BM hypoxia promotes resistance to drugs commonly used to treat AML. These data provide a rationale for use of hypoxia-activated prodrugs to eliminate AML cells within hypoxic niches. In our preclinical models, utilization of the novel hypoxia-activated prodrug PR104 has significantly decreased leukemia burden and cured mice transplanted with human leukemia. In the ongoing clinical trials in solid tumors, the principal toxicity of PR104 is bone marrow suppression; such toxicity indicates PR104 may be active in AML. Based on these findings, we will conduct Phase I/II clinical trial in patients with relapsed or refractory AML to investigate the safety and anti-leukemia efficacy of PR104. This trial will utilize novel statistical design to determine "individualized" doses based on each patient's AML history such as previous remission duration and age. We have designed optional laboratory studies to measure BM hypoxia and hypoxic responses in leukemic cells to study whether these markers can add to clinical characteristics in selecting patient-specific doses of PR104. If successful, this approach of targeting hypoxic microenvironment, alone or in combination with other chemotherapeutic or targeted agents, may significantly impact AML therapy and ultimately improve outcomes of patients. PUBLIC HEALTH RELEVANCE: The prognosis of acute myeloid leukemia (AML) patients upon relapse remains poor. PR104 is a novel hypoxia-activated agent, which is metabolized into cytotoxic derivatives in hypoxic leukemic bone marrow microenvironment. In this study, we will investigate the safety and anti-leukemia efficacy of PR104 in patients with relapsed or refractory AML.