Strategies to overcome resistance to common chemotherapy regimens are necessary to improve upon the currently dismal prognosis of acute myeloid leukemia (AML) patients with refractory disease or who have relapsed following initial achievement of complete remission (CR). One such novel strategy is to down-regulate ribonucleotide reductase (RNR), an enzyme that reduces nucleoside to deoxynucleosides for incorporation into newly synthesized DNA and, when over expressed in leukemia cells, induces resistance to cytarabine arabinoside (Ara-C), a nucleoside analog and backbone component of several up-front and salvage regimens in AML. In preclinical studies, we showed that GTI-2040, a 20-mer oligonucleotide complementary to the R2 component of RNR mRNA, decreased levels of its target and inhibited RNR function in AML cells. We propose here to test the combination of GTI-2040 with high dose Ara-C (HiDAC) in refractory/relapsed AML. This approach has already shown promise (i.e., evidence of clinical response and relatively low toxicity) in an initial phase I trial of a similarly, intensively treated high risk AML population. Although assessment of disease response was not a primary objective of this trial, a significant correlation between target down-regulation and achievement of CR was observed. The current proposal seeks to establish definitively the response rate to combination of GTI-2040 with HiDAC in refractory/relapsed AML and correlates it with plasma pharmacokinetics (PK), intracellular concentration and trafficking of the antisense, reduction in R2 expression levels and inhibition of the RNR function (i.e. depletion of dNTP ratios). We will achieve these goals through the following specific aims: 1) To conduct a Phase II clinical trial of GTI-2040 in combination with HiDAC in refractory/relapsed AML and determine the overall response rate (complete remission plus complete remission with incomplete count recovery) and the one year relapse rate and survival;2) To conduct PK studies and determine the plasma and intracellular levels of GTI-2040 and correlate them with toxicity, clinical response, and post- treatment changes in R2 expression and RNR function;and 3) To conduct pharmacodynamic (PD) correlative studies and determine how serial post-treatment R2 mRNA and protein levels and RNR function compare with untreated baseline and correlate with plasma and intracellular concentrations of GTI-2040, toxicity and disease response. The overall goal of this study is to validate an effective salvage regimen that will allow relapsed/refractory AML patients to achieve high CR/CRi rates, proceed to allogeneic stem cell transplant and/or extend survival.
Acute myeloid leukemia (AML), one of the most common and lethal types of leukemia in the Western Hemisphere, is often resistant to standard chemotherapy, and novel strategies to overcome chemoresistance and improve the outcome of these patients are highly needed. In this proposal, GTI- 2040, an antisense compound that decreases expression and inhibits the function of ribonucleotide reductase (RNR), an enzyme involved in chemoresistance of leukemia cells, is combined with high dose cytarabine (Ara-C), an essential component of several chemotherapy regimens for AML. The goals of this study are to decrease chemoresistance to Ara-C and improve clinical responses in AML patients with refractory or relapsed disease. Studies to understand the mechanisms through which GTI-2040 reduces and inhibits respectively the expression and function of RNR and leads to clinical responses are critical aspects of this proposal.
| Aimiuwu, Josephine; Wang, Hongyan; Chen, Ping et al. (2012) RNA-dependent inhibition of ribonucleotide reductase is a major pathway for 5-azacytidine activity in acute myeloid leukemia. Blood 119:5229-38 |
| Alachkar, Houda; Xie, Zhiliang; Marcucci, Guido et al. (2012) Determination of cellular uptake and intracellular levels of Cenersen (Aezea(ýý), EL625), a p53 antisense oligonucleotide in acute myeloid leukemia cells. J Pharm Biomed Anal 71:228-32 |
| Chen, Ping; Aimiuwu, Josephine; Xie, Zhiliang et al. (2011) Biochemical modulation of aracytidine (Ara-C) effects by GTI-2040, a ribonucleotide reductase inhibitor, in K562 human leukemia cells. AAPS J 13:131-40 |
