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. Alexander E Perl, Jessica K Altman, Naoko Hosono, Pau Montesinos, Nikolai Podoltsev, Giovanni Martinelli, Catherine C Smith, Mark J Levis, Christoph Röllig, Marco Groß-Langenhoff, Nahla Hasabou, Qiaoyang Lu, Ramon V Tiu. AML-091: Clinical Outcomes in Patients with Relapsed/Refractory Acute Myeloid Leukemia Treated with Gilteritinib Who Received Prior Midostaurin or Sorafenib. Clinical Lymphoma Myeloma & Leukemia. 2021 Sep 1; 21:s280.  View on PubMed
  2. Jessica K. Altman, Naval Daver, Joseph Maly, Mark Levis, Ellen Ritchie, Mark Litzow, James McCloskey, Catherine C. Smith, Gary Schiller, Terrence Bradley, Ramon V. Tiu, Kiran Naqvi, Satya Siddani, Jing Wang, Paul Lee, Alexander E. Perl. AML-162: Efficacy and Safety of Venetoclax in Combination with Gilteritinib for Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia: Updated Analyses of a Phase 1b Study. Clinical Lymphoma Myeloma & Leukemia. 2021 Sep 1; 21:s285.  View on PubMed
  3. 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. Correction to: Pharmacokinetic Profile of Gilteritinib: A Novel FLT-3 Tyrosine Kinase Inhibitor. Clin Pharmacokinet. 2021 Sep; 60(9):1251.  View on PubMed
  4. Alexander E Perl, Jessica K Altman, Naoko Hosono, Pau Montesinos, Nikolai Podoltsev, Giovanni Martinelli, Catherine C Smith, Mark J Levis, Christoph Röllig, Marco Groß-Langenhoff, Nahla Hasabou, Qiaoyang Lu, Ramon V Tiu. Poster: AML-091: Clinical Outcomes in Patients with Relapsed/Refractory Acute Myeloid Leukemia Treated with Gilteritinib Who Received Prior Midostaurin or Sorafenib. Clinical Lymphoma Myeloma & Leukemia. 2021 Sep 1; 21:s210.  View on PubMed
  5. Jessica K. Altman, Naval Daver, Joseph Maly, Mark Levis, Ellen Ritchie, Mark Litzow, James McCloskey, Catherine C. Smith, Gary Schiller, Terrence Bradley, Ramon V. Tiu, Kiran Naqvi, Satya Siddani, Jing Wang, Paul Lee, Alexander E. Perl. Poster: AML-162: Efficacy and Safety of Venetoclax in Combination with Gilteritinib for Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia: Updated Analyses of a Phase 1b Study. Clinical Lymphoma Myeloma & Leukemia. 2021 Sep 1; 21:s212.  View on PubMed
  6. 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. Haematologica. 2021 Aug 01; 106(8):2242-2245.  View on PubMed
  7. Smith CC, Viny AD, Massi E, Kandoth C, Socci ND, Rapaport F, Najm M, Medina-Martinez JS, Papaemmanuil E, Tarver TC, Hsu HH, Le MH, West B, Bollag G, Taylor BS, Levine RL, Shah NP. Recurrent Mutations in Cyclin D3 Confer Clinical Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia. Clin Cancer Res. 2021 Jul 15; 27(14):4003-4011.  View on PubMed
  8. Mark J. Levis, Catherine Choy Smith, Alexander E. Perl, Gary J. Schiller, Amir Tahmasb Fathi, Gail J. Roboz, Eunice S. Wang, Jessica K. Altman, Makoto Ando, Takeaki Suzuki, Ruth Ann Subach, Gary Maier, Timothy Madden, Mary Johansen, Kin Cheung, Michael R. Kurman. Phase 1 first-in-human study of irreversible FLT3 inhibitor FF-10101-01 in relapsed or refractory acute myeloid leukemia. Journal of Clinical Oncology. 2021 May 20; 39(15_suppl):7008-7008.  View on PubMed
  9. 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. Nat Commun. 2021 03 11; 12(1):1583.  View on PubMed
  10. 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. Blood Adv. 2021 03 09; 5(5):1437-1441.  View on PubMed
  11. Kennedy VE, Smith CC. FLT3 Mutations in Acute Myeloid Leukemia: Key Concepts and Emerging Controversies. Front Oncol. 2020; 10:612880.  View on PubMed
  12. 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, Oxford COVID Vaccine Trial Group . 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. Lancet. 2021 12 19; 396(10267):1979-1993.  View on PubMed
  13. 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. Blood. 2020 Nov 5; 136(Supplement 1):22-23.  View on PubMed
  14. 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. Blood. 2020 Nov 5; 136(Supplement 1):2-3.  View on PubMed
  15. 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). Blood. 2020 Nov 5; 136(Supplement 1):11-12.  View on PubMed
  16. 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. Blood. 2020 Nov 5; 136(Supplement 1):20-22.  View on PubMed
  17. 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. Blood. 2020 Nov 5; 136(Supplement 1):41-42.  View on PubMed
  18. 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. Clin Pharmacokinet. 2020 10; 59(10):1273-1290.  View on PubMed
  19. Smith CC. FLT3 Inhibition in Acute Myeloid Leukemia. Clin Lymphoma Myeloma Leuk. 2020 09; 20 Suppl 1:S5-S6.  View on PubMed
  20. 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. Blood Adv. 2020 04 28; 4(8):1711-1721.  View on PubMed

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