Faculty ProfilesCatherine Smith, MD
513 Parnassus Avenue
San Francisco, CA 94117
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.
Education and Training
|Location||Degree or Training||Specialty||Date|
|Duke University||M.D.||School of Medicine||05/2002|
CCND3, FLT3, acute myeloid leukemia, drug resistance, targeted therapyRelated Web Sites
In the News
- An Achilles Heel of AML (Apr 15, 2012)
Recent Articles (22)
Smith CC, Paguirigan A, Jeschke GR, Lin KC, Massi E, Tarver T, Chin CS, Asthana S, Olshen A, Travers KJ, Wang S, Levis MJ, Perl AE, Radich JP, Shah NP. Heterogeneous resistance to quizartinib in acute myeloid leukemia (AML) revealed by single cell analysis. Blood. 2017 May 10.
Minson KA, Smith CC, DeRyckere D, Libbrecht C, Lee-Sherick AB, Huey MG, Lasater EA, Kirkpatrick GD, Stashko MA, Zhang W, Jordan CT, Kireev D, Wang X, Frye SV, Earp HS, Shah NP, Graham DK. The MERTK/FLT3 inhibitor MRX-2843 overcomes resistance-conferring FLT3 mutations in acute myeloid leukemia. JCI Insight. 2016 Mar; 1(3):e85630.
Mannis GN, Martin TG, Damon LE, Logan AC, Olin RL, Flanders MD, Ai WZ, Gaensler KM, Kaplan LD, Sayre PH, Smith CC, Wolf JL, Andreadis C. Long-term outcomes of patients with intermediate-risk acute myeloid leukemia treated with autologous hematopoietic cell transplant in first complete remission. Leuk Lymphoma. 2016 Jul; 57(7):1560-6.
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. Characterizing and Overriding the Structural Mechanism of the Quizartinib-Resistant FLT3 "Gatekeeper" F691L Mutation with PLX3397. Cancer Discov. 2015 Jun; 5(6):668-79.
Frett B, McConnell N, Smith CC, Wang Y, Shah NP, Li HY. Computer aided drug discovery of highly ligand efficient, low molecular weight imidazopyridine analogs as FLT3 inhibitors. Eur J Med Chem. 2015 Apr 13; 94:123-31.
Mannis GN, Andreadis C, Logan AC, Damon LE, Benet LZ, Ai WZ, Gaensler KM, Kaplan LD, Koplowicz YB, Linker CA, Olin RL, Sayre PH, Smith CC, Sudhindra A, Venstrom JM, Wolf JL, Martin TG. A phase I study of targeted, dose-escalated intravenous busulfan in combination with etoposide as myeloablative therapy for autologous stem cell transplantation in acute myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2015 Jun; 15(6):377-83.
Warkentin AA, Lopez MS, Lasater EA, Lin K, He BL, Leung AY, Smith CC, Shah NP, Shokat KM. Overcoming myelosuppression due to synthetic lethal toxicity for FLT3-targeted acute myeloid leukemia therapy. Elife. 2014; 3.
Chatterjee A, Ghosh J, Ramdas B, Mali RS, Martin H, Kobayashi M, Vemula S, Canela VH, Waskow ER, Visconte V, Tiu RV, Smith CC, Shah N, Bunting KD, Boswell HS, Liu Y, Chan RJ, Kapur R. Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis. Cell Rep. 2014 Nov 20; 9(4):1333-48.
Keller JW, Andreadis C, Damon LE, Kaplan LD, Martin TG, Wolf JL, Ai WZ, Venstrom JM, Smith CC, Gaensler KM, Hwang J, Olin RL. Hematopoietic cell transplantation comorbidity index (HCT-CI) is predictive of adverse events and overall survival in older allogeneic transplant recipients. J Geriatr Oncol. 2014 Jul; 5(3):238-44.
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. Crenolanib is a selective type I pan-FLT3 inhibitor. Proc Natl Acad Sci U S A. 2014 Apr 8; 111(14):5319-24.
Verstovsek S, Tam CS, Wadleigh M, Sokol L, Smith CC, Bui LA, Song C, Clary DO, Olszynski P, Cortes J, Kantarjian H, Shah NP. Phase I evaluation of XL019, an oral, potent, and selective JAK2 inhibitor. Leuk Res. 2014 Mar; 38(3):316-22.
Collins BH, Holzknecht ZE, Lynn KA, Sempowski GD, Smith CC, Liu S, Parker W, Rockey DC. Association of age-dependent liver injury and fibrosis with immune cell populations. Liver Int. 2013 Sep; 33(8):1175-86.
Smith CC, Lasater EA, Zhu X, Lin KC, Stewart WK, Damon LE, Salerno S, Shah NP. Activity of ponatinib against clinically-relevant AC220-resistant kinase domain mutants of FLT3-ITD. Blood. 2013 Apr 18; 121(16):3165-71.
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. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature. 2012 May 10; 485(7397):260-3.
Smith CC, Shah NP. Tyrosine kinase inhibitor therapy for chronic myeloid leukemia: approach to patients with treatment-naive or refractory chronic-phase disease. Hematology Am Soc Hematol Educ Program. 2011; 2011:121-7.