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Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
10:49

Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia

Published on: September 18, 2013

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SYK as a New Therapeutic Target in B-Cell Precursor Acute Lymphoblastic Leukemia

Fatih M Uckun1, Sanjive Qazi2

  • 1Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, USA ; Children's Center for Cancer and Blood Diseases, CHLA, Los Angeles, USA.

Journal of Cancer Therapy
|May 23, 2014
PubMed

Insights

New nanomedicine targets spleen tyrosine kinase (SYK) to overcome apoptosis resistance in B-lineage leukemia. This approach shows promise for treating poor prognosis B-precursor acute lymphoblastic leukemia (BPL).

Area of Science:

  • Oncology
  • Nanomedicine
  • Molecular Biology

Background:

  • Spleen tyrosine kinase (SYK) is identified as a key regulator of apoptosis in B-lineage leukemia/lymphoma cells.
  • SYK controls major anti-apoptotic pathways including PI3-K/AKT, NFκB, and STAT3.
  • Resistance to apoptosis is a major challenge in treating poor prognosis B-precursor acute lymphoblastic leukemia (BPL).

Purpose of the Study:

  • To test the hypothesis that SYK inhibitors can overcome apoptosis resistance in malignant B-lineage lymphoid cells.
  • To evaluate a liposomal nanoparticle (LNP) formulation of a SYK inhibitor (C61) as a nanomedicine for BPL.
  • To establish a foundation for improved multi-modality treatment regimens for BPL.

Main Methods:

  • Development of a liposomal nanoparticle (LNP) formulation of a SYK substrate-binding site inhibitor (C61).
  • Preclinical evaluation of C61-LNP in mouse models and primary patient-derived leukemic cells.
  • Assessment of pharmacokinetics, safety, apoptosis induction, leukemic stem cell targeting, and in vivo anti-leukemic activity.

Main Results:

  • C61-LNP demonstrated a favorable pharmacokinetic and safety profile in mice.
  • The nanomedicine induced apoptosis in radiation-resistant primary BPL cells and in vivo xenograft cells.
  • C61-LNP effectively destroyed the leukemic stem cell fraction and showed potent in vivo anti-leukemic activity.

Conclusions:

  • Targeting SYK with rationally designed inhibitors like C61-LNP offers a potential strategy to overcome apoptosis resistance in BPL.
  • C61-LNP exhibits promising preclinical efficacy against aggressive and therapy-refractory BPL.
  • Further development of C61-LNP may lead to novel and effective treatment strategies for BPL.
Keywords:
ApoptosisKinaseLeukemiaNanomedicinePhosphorylationSTAT3SYK

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