Posted July 18, 2013
Yogen Saunthararajah, M.D., Cleveland Clinic Foundation
Advanced Technology/Therapeutic Development Award
Aggressive leukemia therapies can result in both therapy-resistant cancers and cytotoxicity in normal tissues, degrading the quality of life for the patient. Dr. Yogen Saunthararajah believed that a target could be identified that was essential for the cancer cell but not for normal stem cells. His laboratory previously demonstrated that depletion of DNA methyl-transferase enzyme 1 (DNMT1) in leukemia stem cells causes them to mature and stop dividing, while depletion of DNMT1 in hematopoietic stem cells (normal blood stem cells) increases their growth. He proposed to use an existing DNMT1 inhibitor compound, 5-aza-2'deoxycytidine (decitabine), to translate this research finding into a treatment solution. The specificity of this treatment to leukemia cells precluded the lengthy recovery times usually required for normal cells to regrow. This allowed the drug to be administered with an increased frequency and at lower doses orally.
With funding from a Fiscal Year 2008 Advanced Technology/Therapeutic Development Award, Dr. Saunthararajah examined alternative treatment schedules for decitabine in human leukemia patients. Lower doses and alternative administration of decitabine were utilized, and they were sufficient to deplete DNMT1 without inducing cytotoxicity/apoptosis in normal cells. The lack of toxicity allowed an increase in the frequency of drug administration, which resulted in more cancer cells being targeted for cell death during treatment. Additionally, at the lower doses no patients required anti-nausea medicines or suffered from chemotherapy-induced hair loss.
Dr. Saunthararajah developed an oral form of decitabine with an increased half-life by combining it with tetrahydrouridine and is preparing to study this medicine in clinical trials. He hopes that decitabine will soon be used as a complement or alternative to existing drugs to treat leukemia patients.
Publications:
Lavelle D, Vaitkus K, Ling Y, et al. 2012. Effects of tetrahydrouridine on pharmacokinetics and pharmacodynamics of oral decitabine. Blood 119(5):1240-1247.
Triozzi PL, Aldrich W, Achberger S, et al. 2012. Differential effects of low-dose decitabine on immune effector and suppressor responses in melanoma-bearing mice. Cancer Immunol Immunother 61(9):1441-1450.
Aldrich W, Alcazar O, Negrotto S, et al. 2011. Modification of decitabine for epigenetic-differentiation objectives mediates anti-melanoma activity. Int J Cancer (1):18-29.
Hu Z, Negrotto S, Gu X, et al. 2010. Decitabine maintains hematopoietic precursor self-renewal by preventing repression of stem cell genes by a differentiation-inducing stimulus. Mol Cancer Ther 9(6):1536-1543.
Links:
Public and Technical Abstracts: Next Generation DNMT1 Depletion Therapy for Leukemia