Emerging DNA methylation inhibitors for cancer therapy: challenges and prospects
Por:
Gonzalez-Fierro A., Dueñas-González A.
Publicada:
2 ene 2019
Resumen:
Introduction: There is evidence of the association of DNA methylation
alterations with cancer development and progression. Areas covered: This
review will briefly discuss the basis of epigenetics and the clinical
results of first-generation DNA methyltransferase inhibitors (DNMTi) in
myelodysplastic syndrome (MDS) and solid tumors, as well as the limited
clinical information on second-generation DNMTi. Expert opinion:
Azacitidine and decitabine are FDA-approved for the treatment of MDS but
show limited activity against solid tumors despite inducing gene
promoter demethylation, gene reactivation, and global demethylation.
Nevertheless, no data consistently shows that the response to these
drugs is associated with any DNA methylation marker. It is key to
increase clinical exploratory trials with existing and novel
demethylating agents incorporating `omics' technologies to identify DNA
methylation `drivers' or ``patterns' unique to specific malignancies and
then proceed to clinical trials in highly selected patients. Ongoing
studies with novel DNMTi would inform whether these agents overcome the
pharmacological limitations of current DNMTi and improve their efficacy.
Interestingly, solid preclinical data indicate that acquired DNA
hypermethylation impedes PD-1 blockade-mediated T-cell rejuvenation and
this phenomenon can be reverted with decitabine; moreover, this drug
synergizes CTLA-4 blockade in vivo. This promising research avenue is
now clinically being tested.
Filiaciones:
Gonzalez-Fierro A.:
Division of Basic Research, Instituto Nacional de Cancerología, México City, Mexico
Inst Nacl Cancerol, Div Basic Res, Mexico City, DF, Mexico
Dueñas-González A.:
Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México UNAM/Instituto Nacional de Can cerología, México City, Mexico
Univ Nacl Autonoma Mexico, Inst Nacl Can Cerol, Inst Invest Biomed, Mexico City, DF, Mexico
|