CHEK1 and WEE1 Inhibition as Therapeutic Strategies in AML

  • Tibes, Raoul, (PI)

Project: Research project

Description

DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) is one of the deadliest cancers and cure rates have not improved for four decades. Patients with poor risk cytogenetics have 0-5 % survival at 2-3 years and only 40% to 50% of older patients achieve a complete remission to upfront therapy. Cytarabine (AraC) has been the most active single agent in AML therapy, however the majority of patients still relapse and die of refractory disease. The ability o circumvent AraC resistance would be crucial in improving initial responses and preventing resistance and relapse. In RNAi screens we identified CHEK1 and WEE1 kinases as the two most potent sensitizers to AraC. CHEK1 and WEE1 have complementary functions as sensors and downstream effectors of DNA damage signals, resulting in G2/M and S-Phase checkpoint activation with cell cycle arrest. A Phase 1 trials of AraC plus the CHEK1 inhibitor MK8776 in AML was completed and showed a remarkable 33% complete remission (even higher at higher MK8776 doses) and 50% overall response rate in highly relapsed and refractory AML patients indicating that CHEK1 inhibition combined with AraC could overcome chemoresistance in AML cells. We are co-leading a follow up study, a CTEP randomized Phase 2 trial of AraC versus AraC + MK8776 (CHEK1 inhibitor) in 99 AML patients. It will now be crucial to identify those patients responding to AraC + MK8776 and we propose to develop biomarkers that will correlate with sensitivity or resistance to AraC + MK8776 in AML patients. For this goal we will build on our previous successful biomarker results from another trial in which expression of a panel of DNA repair and cell cycle checkpoint proteins predicted response to a CHEK1-G2/M checkpoint targeting drug in combination with the DNA damaging agent cisplatin. These proteins enriched with additional CHEK1 and WEE1 effectors will be analyzed in samples from patients treated on the Phase 1 and 2 trial of AraC + MK8776 to develop predictive biomarkers of response to the combination. Given the complementary functions of CHEK1 and WEE1 we will further characterize the therapeutic potential of complete cell cycle checkpoint and DNA repair inhibition with the small molecule CHEK1 and WEE1 inhibitors MK8776 and MK1775, in vitro and ex vivo in primary AML patient samples. Successful results will support a clinical trial f these novel non-cytotoxic drugs. Finally to identify completely new targets and molecular vulnerabilities in AML we will conduct the first High-throughput RNA interference sensitizer screen with AraC and the Anthracycline Daunorubicin to inform novel combination strategies and regimens for AML induction therapy as well as to develop predictive biomarkers of response to induction therapy.
StatusFinished
Effective start/end date7/1/136/30/18

Funding

  • National Institutes of Health: $344,450.00
  • National Institutes of Health: $344,450.00
  • National Institutes of Health: $334,116.00
  • National Institutes of Health: $344,450.00

Fingerprint

Acute Myeloid Leukemia
Cell Cycle Checkpoints
Biomarkers
Therapeutics
RNA Interference
DNA Repair
S Phase Cell Cycle Checkpoints
M Phase Cell Cycle Checkpoints
Recurrence
Cell Cycle Proteins
Daunorubicin
Anthracyclines
Cytarabine
Myeloid Cells
Drug Combinations
MK-8776
Cytogenetics
Cisplatin
DNA Damage
Phosphotransferases