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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA153019-01
Application #
7988648
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Merritt, William D
Project Start
2010-08-01
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
1
Fiscal Year
2010
Total Cost
$319,990
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Konopleva, Marina; Thall, Peter F; Yi, Cecilia Arana et al. (2015) Phase I/II study of the hypoxia-activated prodrug PR104 in refractory/relapsed acute myeloid leukemia and acute lymphoblastic leukemia. Haematologica 100:927-34
Benito, Juliana; Zeng, Zhihong; Konopleva, Marina et al. (2013) Targeting hypoxia in the leukemia microenvironment. Int J Hematol Oncol 2:279-288
Battula, V Lokesh; Chen, Ye; Cabreira, Maria da Graca et al. (2013) Connective tissue growth factor regulates adipocyte differentiation of mesenchymal stromal cells and facilitates leukemia bone marrow engraftment. Blood 122:357-66
Benito, Juliana; Shi, Yuexi; Szymanska, Barbara et al. (2011) Pronounced hypoxia in models of murine and human leukemia: high efficacy of hypoxia-activated prodrug PR-104. PLoS One 6:e23108