title: Tosedostat for the treatment of relapsed and refractory acute myeloid leukemia.
abstract: BACKGROUND
  Despite recent improvements in the scientific understanding of leukemia biology, the overall prognosis for adults with acute myeloid leukemia (AML) remains disappointingly poor. Therapeutic options for AML that are relapsed or refractory to front-line chemotherapy are limited, and the development of effective agents for this indication is an unmet need. The aminopeptidase-inhibitor tosedostat (CHR-2797) is a novel metalloenzyme inhibitor that blocks a critical step in the protein degradation and re-synthesizes intracellular pathway. This orally bioavailable agent has shown promising activity in vitro and in early clinical trials for patients with relapsed/refractory AML.
  
  
  METHODS
  This review summarizes the development of tosedostat to date. Specifically, the authors review the literature on its mechanism of action, pharmacoepidemiology and the currently available preclinical and clinical data.
  
  
  CONCLUSIONS
  Tosedostat is an oral agent with a novel mechanism of action. Early trials of tosedostat in relapsed/refractory elderly AML have shown encouraging results in a population with an overall very poor prognosis. This is particularly noted in patients with a prior history of myelodysplastic syndrome (MDS) and hypomethylating-agent (HMA) use. Additional studies of tosedostat in rationally designed combinations with cytarabine and HMAs in advanced MDS and refractory AML populations are ongoing. Furthermore, the safety and efficacy evaluation is similarly ongoing, and patient selection will be an important consideration in the continued development of this promising compound.
authors: University of Texas MD Anderson Cancer Center, Department of Leukemia , 1515 Holcombe Blvd, Unit 0428, Houston, TX 77030 , USA +1 713 794 5783 ; +1 713 745 4612 ; jcortes@mdanderson.org.
authors: Courtney D
authors: CD
authors: DiNardo
authors: Jorge E
authors: JE
authors: Cortes
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D005998:Glycine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; C531970:tosedostat; D005998:Glycine