The broad goal of the proposed research project is to identify and characterize molecular mechanisms of resistance to AC220, a clinically active investigational inhibitor of FLT3 in acute myeloid leukemia (AML).
The specific aims are to: 1) identify and characterize on-target (FLT3- dependent) mechanisms of acquired resistance to AC220 and other clinically promising FLT3 TKIs in vitro and in primary AML isolates and 2) identify and characterize off-target (FLT3- independent) mechanisms of primary and acquired resistance to AC220 and other effective FLT3 inhibitors in vitro and in primary AML isolates. This research focuses on AML, which afflicts more than 10,000 Americans annually, the majority of whom die of their disease within a short time. It is anticipated that the proposed research will: 1) improve our understanding of the importance of FLT3 as a therapeutic target in AML, 2) identify drug-resistant mutations that can be targeted in the future, and 3) identify ways in which AML cells can bypass inhibition of FLT3. A new investigator will carry out the research project at UCSF. The research design includes molecular biology studies as well as structural studies, and in addition, translational studies of primary samples isolated from AML patients undergoing treatment with FLT3 inhibitors.

Public Health Relevance

This research project is relevant to the health needs of those in the US and abroad. Specifically, it addresses the shortcomings of an active targeted therapy for a proportion of patients with acute myeloid leukemia and could benefit the lives of thousands of individuals. Furthermore, its focus on the molecular mechanisms responsible for disease resistance will improve our understanding of leukemia biology and be applicable to other cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA166616-02
Application #
8460491
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Forry, Suzanne L
Project Start
2012-04-17
Project End
2017-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$301,352
Indirect Cost
$106,302
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Nybakken, G E; Canaani, J; Roy, D et al. (2016) Quizartinib elicits differential responses that correlate with karyotype and genotype of the leukemic clone. Leukemia 30:1422-5
Frett, Brendan; McConnell, Nick; Smith, Catherine C et al. (2015) Computer aided drug discovery of highly ligand efficient, low molecular weight imidazopyridine analogs as FLT3 inhibitors. Eur J Med Chem 94:123-31
Smith, C C; Lin, K; Stecula, A et al. (2015) FLT3 D835 mutations confer differential resistance to type II FLT3 inhibitors. Leukemia 29:2390-2
Smith, Catherine C; Zhang, Chao; Lin, Kimberly C et al. (2015) Characterizing and Overriding the Structural Mechanism of the Quizartinib-Resistant FLT3 ""Gatekeeper"" F691L Mutation with PLX3397. Cancer Discov 5:668-79
Ciceri, Pietro; Müller, Susanne; O'Mahony, Alison et al. (2014) Dual kinase-bromodomain inhibitors for rationally designed polypharmacology. Nat Chem Biol 10:305-12
Warkentin, Alexander A; Lopez, Michael S; Lasater, Elisabeth A et al. (2014) Overcoming myelosuppression due to synthetic lethal toxicity for FLT3-targeted acute myeloid leukemia therapy. Elife 3:
Smith, Catherine C; Lasater, Elisabeth A; Zhu, Xiaotian et al. (2013) Activity of ponatinib against clinically-relevant AC220-resistant kinase domain mutants of FLT3-ITD. Blood 121:3165-71
Smith, Catherine C; Wang, Qi; Chin, Chen-Shan et al. (2012) Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature 485:260-3