Mechanism of Action

DAURISMO is a Hedgehog pathway inhibitor that has been shown to chemosensitize leukemic stem cells (LSCs) in preclinical studies2,3
The Hedgehog pathway is involved in LSC proliferation4
  • The Hedgehog (Hh) pathway regulates self-renewal and the differentiation of cells. It is highly active during embryogenesis, where it guides organ and tissue development4,5
  • Preclinical research has suggested that inappropriate activation of the Hedgehog pathway is associated with a variety of cancers, including AML4
DAURISMO blocks a key signaling pathway implicated in LSC maintenance2,3
Preclinical and in vitro data may not necessarily correlate with clinical outcomes.
  • DAURISMO (glasdegib) inhibits the Smoothened (SMO) receptor, a key mediator of Hedgehog pathway signaling in LSCs2,3,6
In preclinical studies, DAURISMO has been shown to limit LSC self-renewal and block LSC quiescence3
  • When LSCs go from a less active state (quiescence) to active division, they may become more sensitive to chemotherapy2,3,5,7-9
  • In preclinical studies, DAURISMO + LDAC inhibited tumor growth and reduced the percentage of AML blasts in the marrow to a greater extent than DAURISMO or LDAC alone2*
*Blast cells were defined as CD45+/CD33+.
Preclinical evidence may not necessarily correlate with clinical outcomes.
 
References
  1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia V.3.2020. © National Comprehensive Cancer Network, Inc. 2019. All rights reserved. Accessed January 13, 2020. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
  2. DAURISMO Prescribing Information. New York, NY: Pfizer Inc.
  3. Fukushima N, Minami Y, Kakiuchi S, et al. Small-molecule Hedgehog inhibitor attenuates the leukemia-initiation potential of acute myeloid leukemia cells. Cancer Sci. 2016;107(10):1422-1429.
  4. Aberger F, Hutterer E, Sternberg C, del Burgo PJ, Hartmann TN. Acute myeloid leukemia – strategies and challenges for targeting oncogenic Hedgehog/GLI signaling. Cell Commun Signal. 2017;15(1):8.
  5. Irvine DA, Copland M. Targeting hedgehog in hematologic malignancy. Blood. 2012;119(10):2196-2204.
  6. Queiroz KC, Ruela-de-Sousa RR, Fuhler GM, et al. Hedgehog signaling maintains chemoresistance in myeloid leukemic cells. Oncogene. 2010;29(48):6314-6322.
  7. Pollyea DA, Jordan CT. Therapeutic targeting of acute myeloid leukemia stem cells. Blood. 2017;129(12):1627-1635.
  8. Lane SW, Scadden DT, Gilliland DG. The leukemic stem cell niche: current concepts and therapeutic opportunities. Blood. 2009;114(6):1150-1157.
  9. Tabe Y, Konopleva M. Role of microenvironment in resistance to therapy in AML. Curr Hematol Malig Rep. 2015;10(2):96-103.