TY - JOUR
T1 - The Promise of Retinoids in the Treatment of Cancer
T2 - Neither Burnt Out Nor Fading Away
AU - Nagai, Yuya
AU - Ambinder, Alexander J.
N1 - Publisher Copyright:
© 2023 by the authors.
PY - 2023/7
Y1 - 2023/7
N2 - Since the introduction of all-trans retinoic acid (ATRA), acute promyelocytic leukemia (APL) has become a highly curable malignancy, especially in combination with arsenic trioxide (ATO). ATRA’s success has deepened our understanding of the role of the RARα pathway in normal hematopoiesis and leukemogenesis, and it has influenced a generation of cancer drug development. Retinoids have also demonstrated some efficacy in a handful of other disease entities, including as a maintenance therapy for neuroblastoma and in the treatment of cutaneous T-cell lymphomas; nevertheless, the promise of retinoids as a differentiating therapy in acute myeloid leukemia (AML) more broadly, and as a cancer preventative, have largely gone unfulfilled. Recent research into the mechanisms of ATRA resistance and the biomarkers of RARα pathway dysregulation in AML have reinvigorated efforts to successfully deploy retinoid therapy in a broader subset of myeloid malignancies. Recent studies have demonstrated that the bone marrow environment is highly protected from exogenous ATRA via local homeostasis controlled by stromal cells expressing CYP26, a key enzyme responsible for ATRA inactivation. Synthetic CYP26-resistant retinoids such as tamibarotene bypass this stromal protection and have shown superior anti-leukemic effects. Furthermore, recent super-enhancer (SE) analysis has identified a novel AML subgroup characterized by high expression of RARα through strong SE levels in the gene locus and increased sensitivity to tamibarotene. Combined with a hypomethylating agent, synthetic retinoids have shown synergistic anti-leukemic effects in non-APL AML preclinical models and are now being studied in phase II and III clinical trials.
AB - Since the introduction of all-trans retinoic acid (ATRA), acute promyelocytic leukemia (APL) has become a highly curable malignancy, especially in combination with arsenic trioxide (ATO). ATRA’s success has deepened our understanding of the role of the RARα pathway in normal hematopoiesis and leukemogenesis, and it has influenced a generation of cancer drug development. Retinoids have also demonstrated some efficacy in a handful of other disease entities, including as a maintenance therapy for neuroblastoma and in the treatment of cutaneous T-cell lymphomas; nevertheless, the promise of retinoids as a differentiating therapy in acute myeloid leukemia (AML) more broadly, and as a cancer preventative, have largely gone unfulfilled. Recent research into the mechanisms of ATRA resistance and the biomarkers of RARα pathway dysregulation in AML have reinvigorated efforts to successfully deploy retinoid therapy in a broader subset of myeloid malignancies. Recent studies have demonstrated that the bone marrow environment is highly protected from exogenous ATRA via local homeostasis controlled by stromal cells expressing CYP26, a key enzyme responsible for ATRA inactivation. Synthetic CYP26-resistant retinoids such as tamibarotene bypass this stromal protection and have shown superior anti-leukemic effects. Furthermore, recent super-enhancer (SE) analysis has identified a novel AML subgroup characterized by high expression of RARα through strong SE levels in the gene locus and increased sensitivity to tamibarotene. Combined with a hypomethylating agent, synthetic retinoids have shown synergistic anti-leukemic effects in non-APL AML preclinical models and are now being studied in phase II and III clinical trials.
KW - APL
KW - ATRA
KW - CYP26
KW - differentiation therapy
KW - non-APL AML
KW - RARα
KW - retinoid
KW - tamibarotene
UR - http://www.scopus.com/inward/record.url?scp=85169847877&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85169847877&partnerID=8YFLogxK
U2 - 10.3390/cancers15143535
DO - 10.3390/cancers15143535
M3 - Review article
C2 - 37509198
AN - SCOPUS:85169847877
SN - 2072-6694
VL - 15
JO - Cancers
JF - Cancers
IS - 14
M1 - 3535
ER -