Research Summary

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.

Research Funding

  • September 1, 2014 - August 31, 2018 - Investigating Resistance to FLT3 Inhibitors in AML, Principal Investigator. Sponsor: NIH/NCI, Sponsor Award ID: K08CA187577
  • September 1, 2014 - August 31, 2018 - Investigating Resistance to FLT3 Inhibitors in AML, Principal Investigator. Sponsor: NIH/NCI, Sponsor Award ID: K08CA187577
  • September 1, 2014 - August 31, 2018 - Investigating Resistance to FLT3 Inhibitors in AML, Principal Investigator. Sponsor: NIH/NCI, Sponsor Award ID: K08CA187577
  • September 1, 2014 - August 31, 2018 - Investigating Resistance to FLT3 Inhibitors in AML, Principal Investigator. Sponsor: NIH/NCI, Sponsor Award ID: K08CA187577

Education

Yale University, CT, BS, 1998, Chemistry

Duke University, MD, 2002, Medicine

Honors & Awards

  • 2010
    Leukemia and Lymphoma Society Special Fellow in Clinical Research Career Development Award
  • 2010
    European Hematology Association/American Society of Hematology Translational Research Training Program Award
  • 2009
    American Society of Hematology Research Training Award for Fellows, Finalist
  • 2002
    American Medical Women's Association, Inc. Janet M. Glasgow Memorial Achievement Citation Awarded to graduating women medical students who graduate in the top 10% of their class.
  • 2002
    E. E. Owen, M.D. Clinical Scholar Award Awarded to 2 graduating medical students for clinical excellence.
  • 2001
    William G. Anylan Scholarship Awarded to 4th year medical students deserving recognition based on academics, service to the medical school and commitment to the profession.
  • 2000
    Alpha Omega Alpha
  • 2000-2001
    Howard Hughes Medical Institute Research (HHMI) Medical Student Training Fellowship
  • 1998
    Cum Laude, Yale University
  • 1998
    Howard Douglass Moore Prize Awarded for excellence in the field of chemistry at Yale University.
  • 1998
    Michael T. Manzella Award Presented to the senior who through the qualities of kindness, dedication and courage most inspired classmates in Timothy Dwight College at Yale.
  • 1997
    National Institutes of Health (NIH) Summer Research Internship
  • 1996
    Howard Hughes Medical Institute (HHMI) Summer Research Fellowship

Selected Publications

  1. Demaree B, Delley CL, Vasudevan HN, Peretz CAC, Ruff D, Smith CC, Abate AR Joint profiling of DNA and proteins in single cells to dissect genotype-phenotype associations in leukemia.  View on PubMed
  2. Peretz CAC, McGary LHF, Kumar T, Jackson H, Jacob J, Durruthy-Durruthy R, Levis MJ, Perl A, Huang BJ, Smith CC Single-cell DNA sequencing reveals complex mechanisms of resistance to quizartinib.  View on PubMed
  3. Tran TH, Nguyen JV, Stecula A, Akutagawa J, Moorman AV, Braun BS, Sali A, Mullighan CG, Shah NP, Dai Y, Devidas M, Roberts KG, Smith CC, Loh ML The EBF1-PDGFRB T681I mutation is highly resistant to imatinib and dasatinib in vitro and detectable in clinical samples prior to treatment.  View on PubMed
  4. Kennedy VE, Smith CC FLT3 Mutations in Acute Myeloid Leukemia: Key Concepts and Emerging Controversies.  View on PubMed
  5. Ramasamy MN, Minassian AM, Ewer KJ, Flaxman AL, Folegatti PM, Owens DR, Voysey M, Aley PK, Angus B, Babbage G, Belij-Rammerstorfer S, Berry L, Bibi S, Bittaye M, Cathie K, Chappell H, Charlton S, Cicconi P, Clutterbuck EA, Colin-Jones R, Dold C, Emary KRW, Fedosyuk S, Fuskova M, Gbesemete D, Green C, Hallis B, Hou MM, Jenkin D, Joe CCD, Kelly EJ, Kerridge S, Lawrie AM, Lelliott A, Lwin MN, Makinson R, Marchevsky NG, Mujadidi Y, Munro APS, Pacurar M, Plested E, Rand J, Rawlinson T, Rhead S, Robinson H, Ritchie AJ, Ross-Russell AL, Saich S, Singh N, Smith CC, Snape MD, Song R, Tarrant R, Themistocleous Y, Thomas KM, Villafana TL, Warren SC, Watson MEE, Douglas AD, Hill AVS, Lambe T, Gilbert SC, Faust SN, Pollard AJ Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial.  View on PubMed
  6. Alexander E. Perl, Jessica K. Altman, Naoko Hosono, Pau Montesinos, Nikolai A. Podoltsev, Giovanni Martinelli, Catherine C. Smith, Mark Levis, Christoph Röllig, Marco Groß-Langenhoff, Nahla Hasabou, Qiaoyang Lu, Ramon V. Tiu Clinical Outcomes in Patients with Relapsed/Refractory Acute Myeloid Leukemia Treated with Gilteritinib Who Received Prior Midostaurin or Sorafenib.  View on PubMed
  7. Kelly L. Schoenbeck, Sirisha Tummala, Neha G. Goyal, Catherine C. Smith, Neil P. Shah Cognitive Dysfunction Associated with Tyrosine Kinase Inhibitors in Patients with CML in Chronic Phase.  View on PubMed
  8. Amir T. Fathi, Alexander E. Perl, Mark Levis, Catherine C. Smith, Andrew M. Brunner, Koichi Takahashi, Philip C. Amrein, Hanno R. Hock, Gabriela S. Hobbs, Rupa Narayan, Jenna A. Moran, Meghan Bergeron, Julia E. Foster, Naval Daver, Courtney D. DiNardo Concurrent FLT3 Inhibitor and IDH Inhibitor Therapy in Patients with Acute Myeloid Leukemia (AML).  View on PubMed
  9. Naval Daver, Jessica K. Altman, Joseph Maly, Mark Levis, Ellen Ritchie, Mark Litzow, James K. McCloskey, Catherine C. Smith, Gary J. Schiller, Terrence Bradley, Ramon V. Tiu, Wan-Jen Hong, Bo Tong, Qin Qin, Kimberley Dilley, Alexander E. Perl Efficacy and Safety of Venetoclax in Combination with Gilteritinib for Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia in the Expansion Cohort of a Phase 1b Study.  View on PubMed
  10. Kelly L. Schoenbeck, Sirisha Tummala, Rebecca L. Olin, Neha G. Goyal, Anand Dhruva, Lloyd E. Damon, Aaron C. Logan, Catherine C. Smith, Neil P. Shah Excellent Outcomes Achieved with Medical Management of Chronic Phase CML Patients with Non-Hematologic TKI Intolerance.  View on PubMed
  11. James AJ, Smith CC, Litzow M, Perl AE, Altman JK, Shepard D, Kadokura T, Souda K, Patton M, Lu Z, Liu C, Moy S, Levis MJ, Bahceci E Pharmacokinetic Profile of Gilteritinib: A Novel FLT-3 Tyrosine Kinase Inhibitor.  View on PubMed
  12. Smith CC FLT3 Inhibition in Acute Myeloid Leukemia.  View on PubMed
  13. Smith CC, Levis MJ, Frankfurt O, Pagel JM, Roboz GJ, Stone RM, Wang ES, Severson PL, West BL, Le MH, Kayser S, Lam B, Hsu HH, Zhang C, Bollag G, Perl AE A phase 1/2 study of the oral FLT3 inhibitor pexidartinib in relapsed/refractory FLT3-ITD-mutant acute myeloid leukemia.  View on PubMed
  14. Tarver TC, Hill JE, Rahmat L, Perl AE, Bahceci E, Mori K, Smith CC Gilteritinib is a clinically active FLT3 inhibitor with broad activity against FLT3 kinase domain mutations.  View on PubMed
  15. Smith CC The growing landscape of FLT3 inhibition in AML.  View on PubMed
  16. Benjamin Demaree, Cyrille Delley, Cheryl Peretz, Harish Vasudevan, David Ruff, Aik Ooi, Catherine C. Smith, Adam Abate Combined Single-Cell DNA Genotyping and Protein Quantification (DAb-seq) in Acute Myeloid Leukemias Reveals Distinct Immunophenotypic Subsets Among Pathogenic Clones.  View on PubMed
  17. Kelly L. Schoenbeck, Giselle Salmasi, Miguel Carlos Cerejo, Patricia A. Cornett, Lloyd E. Damon, Aaron C. Logan, Rebecca L. Olin, Andrew D. Leavitt, Catherine C. Smith Direct Oral Anticoagulant Use and Outcomes in Patients with High and Intermediate Risk BCR-ABL-Negative Myeloproliferative Neoplasms.  View on PubMed
  18. Varun Mittal, Mimi Lo, Lloyd E. Damon, Karin L. Gaensler, Thomas G. Martin, Rebecca L. Olin, Catherine C. Smith, Aaron C. Logan Efficacy of Venetoclax Combination Therapy with Hypomethylating Agents in Patients with Relapsed Acute Myeloid Leukemia after Allogeneic Hematopoietic Cell Transplantation.  View on PubMed
  19. Catherine C. Smith, Mark J. Levis, Alexander E. Perl, Giovanni Martinelli, Andreas Neubauer, Ellin Berman, Pau Montesinos, Maria R. Baer, Richard A. Larson, Wen-Chien Chou, Hisayuki Yokoyama, Christian Recher, Sung-Soo Yoon, Jason E. Hill, Matt Rosales, Erkut Bahceci Emerging Mutations at Relapse in Patients with FLT3-Mutated Relapsed/Refractory Acute Myeloid Leukemia Who Received Gilteritinib Therapy in the Phase 3 Admiral Trial.  View on PubMed
  20. Cheryl A Cohler Peretz, Lisa H F McGary, Tanya F Kumar, J Hunter Jackson, Jose Jacob, Robert Durruthy-Durruthy, Chunxiao Zhang, Mark J. Levis, Alexander E. Perl, Anskar Yu Hung Leung, Catherine C. Smith Single Cell Sequencing Reveals Evolution of Tumor Heterogeneity of Acute Myeloid Leukemia on Quizartinib.  View on PubMed

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