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

点击翻译按钮获取中文摘要

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.