TY - JOUR
T1 - DNA methyltransferase inhibitor exposure–response
T2 - Challenges and opportunities
AU - Kagan, Amanda B.
AU - Garrison, Dominique A.
AU - Anders, Nicole M.
AU - Webster, Jonathan A
AU - Baker, Sharyn D.
AU - Yegnasubramanian, Srinivasan
AU - Rudek, Michelle A.
N1 - Funding Information:
This work was supported in part by the National Institute of Health grants: UM1CA186691 (M.A.R. and J.A.W.), U24CA247648 (M.A.R., N.M.A., and S.D.B.), P30CA006973 (M.A.R. and S.Y.), T32GM066691 (A.B.K. and D.A.G.), UL1TR003098 (M.A.R.), the OSU Comprehensive Cancer Center Pelotonia foundation (S.D.B.), and the Commonwealth Foundation (M.A.R. and S.Y.).
Publisher Copyright:
© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
PY - 2023/8
Y1 - 2023/8
N2 - Although DNA methyltransferase inhibitors (DNMTis), such as azacitidine and decitabine, are used extensively in the treatment of myelodysplastic syndromes and acute myeloid leukemia, there remain unanswered questions about DNMTi's mechanism of action and predictors of clinical response. Because patients often remain on single-agent DNMTis or DNMTi-containing regimens for several months before knowing whether clinical benefit can be achieved, the development and clinical validation of response-predictive biomarkers represents an important unmet need in oncology. In this review, we will summarize the clinical studies that led to the approval of azacitidine and decitabine, as well as the real-world experience with these drugs. We will then focus on biomarker development for DNMTis—specifically, efforts at determining exposure–response relationships and challenges that remain impacting the broader clinical translation of these methods. We will highlight recent progress in liquid-chromatography tandem mass spectrometry technology that has allowed for the simultaneous measurement of decitabine genomic incorporation and global DNA methylation, which has significant potential as a mechanism-of-action based biomarker in patients on DNMTis. Last, we will cover important research questions that need to be addressed in order to optimize this potential biomarker for clinical use.
AB - Although DNA methyltransferase inhibitors (DNMTis), such as azacitidine and decitabine, are used extensively in the treatment of myelodysplastic syndromes and acute myeloid leukemia, there remain unanswered questions about DNMTi's mechanism of action and predictors of clinical response. Because patients often remain on single-agent DNMTis or DNMTi-containing regimens for several months before knowing whether clinical benefit can be achieved, the development and clinical validation of response-predictive biomarkers represents an important unmet need in oncology. In this review, we will summarize the clinical studies that led to the approval of azacitidine and decitabine, as well as the real-world experience with these drugs. We will then focus on biomarker development for DNMTis—specifically, efforts at determining exposure–response relationships and challenges that remain impacting the broader clinical translation of these methods. We will highlight recent progress in liquid-chromatography tandem mass spectrometry technology that has allowed for the simultaneous measurement of decitabine genomic incorporation and global DNA methylation, which has significant potential as a mechanism-of-action based biomarker in patients on DNMTis. Last, we will cover important research questions that need to be addressed in order to optimize this potential biomarker for clinical use.
UR - http://www.scopus.com/inward/record.url?scp=85162651637&partnerID=8YFLogxK
U2 - 10.1111/cts.13548
DO - 10.1111/cts.13548
M3 - Review article
C2 - 37345219
AN - SCOPUS:85162651637
SN - 1752-8054
VL - 16
SP - 1309
EP - 1322
JO - Clinical and Translational Science
JF - Clinical and Translational Science
IS - 8
ER -