Decitabine and Arsenic Trioxide for Myelodysplastic Syndrome(MDS)
Status:
Unknown status
Trial end date:
2020-11-01
Target enrollment:
Participant gender:
Summary
This is a prospective,controlled and multi-institution trial.The aim is to identify if using
decitabine and Arsenic Trioxide(ATO) as the therapy of Myelodysplastic Syndrome(MDS) has
better relapse free survival and complete response than using decitabine alone.
TP53 mutation is commonly associated with poor cancer patient prognosis yet no mutant p53
(mp53)-targeting regimen was clinically established. Particularly, p53 mutation is associated
with extremely poor prognosis in myelodysplastic syndromes (MDS) and acute myeloid leukemia
(AML) patients.
Decitabine (DAC) is a FDA approved drug for MDS treatment. In two independent clinical trials
reported recently, DNA demethylating drug DAC treatment yielded a surprisingly high rate of
complete remission (CR) in mp53-harboring AML/MDS patients (Welch, NEJM, 2016; Chang, BJH,
2017). Notably, all of the mp53-expressing patients in the two clinical studies relapsed
quickly.
Arsenic trioxide (ATO) is a FDA approved drug for M3-AML treatment. Despite of the observed
efficacy in treating non-APL patients, ATO is not yet approved for non-APL cancer treatment.
ATO plays key role in regulating both wild-type p53 (wtp53) and mp53. Our published and
unpublished data suggest ATO potentially hijacks nuclear iASPP-mediated STRaND pathway via
exposing iASPP's RaDAR nuclear import code (Lu, Cancer Cell, 2013; Lu, Cell, 2014; Lu, Nat
Rev Mol Cell Biol, 2016; Lu, unpublished). Our unpublished data also suggests a key role of
ATO in regulating mp53 (Lu, The 17th International p53 Workshop, 2017). ATO is widely
reported to be able to degrade and thus inhibit mp53's oncogenic function (Hamadeh, BBRC,
1999)(Liu, Blood, 2003). ATO suppressed cancer cell growth by targeting mp53 for degradation
by Pirh2 degradation pathway (Yang, JBC, 2011; Yan, PLOS one, 2014);
Here we explore the potential of combination of DAC and ATO in improving the mp53-harboring
AML/MDS patients' relapse free survival (RFS) and the ability to thoroughly eliminate mp53
subclone. Basic researches aiming to explore the mechanisms how mp53 cells responds to DAC
and/or ATO treatment and how mp53 cells develop resistance to DAC and/or ATO will be coupled.
We designate trials aiming for a better treatment regimen for mp53 patients as
'PANDA-Trials'.