Catherine Smith, MD

Asst Professor In Residence
Departments of Medicine
Hematology/Oncology
+1 415 476-9553

My laboratory focuses on identification of therapeutic resistance mechanisms and novel treatment strategies for acute myeloid leukemia (AML). We have a particular emphasis on AML associated with mutations in Fms-like Tyrosine Kinase-3 (FLT3). FLT3 is mutated in ~30% of AML, with constitutively activating FLT3 internal tandem duplication (ITD) mutations conferring a poor prognosis. We employ a prototypical “bedside to bench and back” approach to the problem of cancer drug resistance, founded on the belief that the ultimate pathway to improved cancer therapy begins with translational studies that utilize samples from patients who have undergone therapy in real time. This strategy allows us to interrogate how tumors can evolve under the selective pressure of cancer therapy and allows us to devise ways to circumvent these evolutionary adaptations.

We have the following specific research focuses at the current time:
1) Rational discovery and screening of novel FLT3 inhibitors coupled with analysis of resistance mechanisms to clinically relevant FLT3 inhibitors currently in clinical trials.
2) Identification and validation of non-FLT3 dependent mechanisms of FLT3 inhibitor resistance through genomic analysis of patients treated on FLT3 inhibitor clinical trials.
3) Study of the role of AML genetic tumor heterogeneity in response and resistance to FLT3 inhibitor therapy.
4) Understanding the molecular mechanism of recurrent cyclin D3 mutations in mediating resistance to FLT3 inhibitor therapy.

Primary Thematic Area: 
Cancer Biology & Cell Signaling
Secondary Thematic Area: 
None
Research Summary: 
Genetic Determinants of Resistance to AML Therapy

Websites

Featured Publications: 

Characterizing and Overriding the Structural Mechanism of the Quizartinib-Resistant FLT3 "Gatekeeper" F691L Mutation with PLX3397.

Cancer discovery

Smith CC, Zhang C, Lin KC, Lasater EA, Zhang Y, Massi E, Damon LE, Pendleton M, Bashir A, Sebra R, Perl A, Kasarskis A, Shellooe R, Tsang G, Carias H, Powell B, Burton EA, Matusow B, Zhang J, Spevak W, Ibrahim PN, Le MH, Hsu HH, Habets G, West BL, Bollag G, Shah NP

Overcoming myelosuppression due to synthetic lethal toxicity for FLT3-targeted acute myeloid leukemia therapy.

eLife

Warkentin AA, Lopez MS, Lasater EA, Lin K, He BL, Leung AY, Smith CC, Shah NP, Shokat KM

Crenolanib is a selective type I pan-FLT3 inhibitor.

Proceedings of the National Academy of Sciences of the United States of America

Smith CC, Lasater EA, Lin KC, Wang Q, McCreery MQ, Stewart WK, Damon LE, Perl AE, Jeschke GR, Sugita M, Carroll M, Kogan SC, Kuriyan J, Shah NP

Activity of ponatinib against clinically-relevant AC220-resistant kinase domain mutants of FLT3-ITD.

Blood

Smith CC, Lasater EA, Zhu X, Lin KC, Stewart WK, Damon LE, Salerno S, Shah NP

Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia.

Nature

Smith CC, Wang Q, Chin CS, Salerno S, Damon LE, Levis MJ, Perl AE, Travers KJ, Wang S, Hunt JP, Zarrinkar PP, Schadt EE, Kasarskis A, Kuriyan J, Shah NP