The broad goal of the proposed application is train Dr. Smith, a candidate with demonstrated potential as a clinical-translational researcher in leukemia into an independent principal investigator capable of effectively mediating the """"""""bedside to bench and back"""""""" translation of genomic data into functional studies that will facilitate the development of clinically effective therapeutics for acute myeloid leukemia. The research plan incorporates the proposed training goals of education and experience in the use of 1) emerging genomic technologies, particularly analysis of next-generation sequencing data, 2) biochemistry and proteomics, with an emphasis on the study of kinase function and 3) cellular models of oncogenic signaling and transformation through the scientific aims of 1) defining and validating genetic changes associated with resistance to clinically active investigational FLT3 inhibitors and 2) defining the molecular impact of quizartinib-resistant FLT3 kinase domain mutations. The application incorporates a combination of coursework, tutorials, mentoring and direct laboratory research experience set in the unparalleled scientific environment of UCSF, a world-renowned research institution with a well-established NCI-funded Comprehensive Cancer, multiple institutional resources and a distinguished community of physician-scientists.
This research focuses on acute myeloid leukemia (AML), which affects more than 10,000 Americans annually, the majority of who die of their disease within a short time. It is anticipated that the proposed research will: 1) improve our understanding of resistance mechanisms to FLT3 inhibitors, 2) identify and test novel therapeutic inhibitors that may be effective in resistant disease. The overall goal of this work is to improve therapeutic outcomes for AML patients in the near future.
|Cortes, Jorge; Perl, Alexander E; Döhner, Hartmut et al. (2018) Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol 19:889-903|
|Perl, Alexander E; Altman, Jessica K; Cortes, Jorge et al. (2017) Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. Lancet Oncol 18:1061-1075|
|Smith, Catherine C; Paguirigan, Amy; Jeschke, Grace R et al. (2017) Heterogeneous resistance to quizartinib in acute myeloid leukemia revealed by single-cell analysis. Blood 130:48-58|
|Minson, Katherine A; Smith, Catherine C; DeRyckere, Deborah et al. (2016) The MERTK/FLT3 inhibitor MRX-2843 overcomes resistance-conferring FLT3 mutations in acute myeloid leukemia. JCI Insight 1:e85630|
|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|
|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|
|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|
|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:|