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

Fatih M. Uckun, Sanjive Qazi

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

DOI: 10.4236/jct.2014.51015                

Abstract

The identification of SYK as a master regulator of apoptosis controlling the activation of the PI3-K/AKT, NFκB, and STAT3 pathways—three major anti-apoptotic signaling pathways in B-lineage leukemia/lymphoma cells—prompts the hypothesis that rationally designed inhibitors targeting SYK may overcome the resistance of malignant B-lineage lymphoid cells to apoptosis and thereby provide the foundation for more effective multi-modality treatment regimens for poor prognosis B-precursor acute lymphoblastic leukemia (BPL). In recent preclinical proof-of-concept studies, a liposomal nanoparticle (LNP) formulation of a SYK substrate-binding site inhibitor, known as C61, has been developed as a nanomedicine candidate against poor prognosis and relapsed BPL. This nanoscale formulation of C61 exhibited a uniquely favorable pharmacokinetics and safety profile in mice, induced apoptosis in radiation-resistant primary leukemic cells taken directly from BPL patients as well as in vivo clonogenic BPL xenograft cells, destroyed the leukemic stem cell fraction of BPL blasts, and exhibited potent in vivo anti-leukemic activity in xenograft models of aggressive BPL. Further development of C61-LNP may provide the foundation for new and effective treatment strategies against therapy-refractory BPL.

Keywords

STAT3; SYK; Kinase; Phosphorylation; Apoptosis; Leukemia; Nanomedicine

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	P. S. Gaynon, R. E. Harris, A. J. Altman, B. C. Bostrom, J. C. Brenneman, R. Hawks, et al., “Bone Marrow Transplantation versus Prolonged Intensive Chemotherapy for Children with Acute Lymphoblastic Leukemia and an Initial Bone Marrow Relapse within 12 Months of the Completion of Primary Therapy: Children’s Oncology Group Study CCG-1941,” Journal of Clinical Oncology, Vol. 24, No. 19, 2006, pp. 3150-3156. http://dx.doi.org/10.1200/JCO.2005.04.5856
[2]	H. G. Einsiedel, A. von Stackelberg, R. Hartmann, R. Fengler, M. Schrappe, G. Janka-Schaub, et al., “LongTerm Outcome in Children with Relapsed ALL by RiskStratified Salvage Therapy: Results of Trial Acute Lymphoblastic Leukemia-Relapse Study of the Berlin-Frankfurt-Münster Group 87,” Journal of Clinical Oncology, Vol. 23, No. 31, 2005, pp. 7942-7950. http://dx.doi.org/10.1200/JCO.2005.01.1031
[3]	F. Locatelli, M. Schrappe, M. E. Bernardo and S. Rutella, “How I Treat Relapsed Childhood Acute Lymphoblastic Leukemia,” Blood, Vol. 120, No. 14, 2012, pp. 2807-2816. http://dx.doi.org/10.1182/ blood-2012-02-265884
[4]	D. R. Freyer, M. Devidas, M. La, W. L. Carroll, P. S. Gaynon, S. P. Hunger, et al., “Postrelapse Survival in Childhood Acute Lymphoblastic Leukemia Is Independent of Initial Treatment Intensity: A Report from the Children’s Oncology Group,” Blood, Vol. 117, No. 11, 2011, pp. 3010-3015. http://dx.doi.org/10.1182/blood-2010-07-294678
[5]	F. M. Uckun, J. H. Kersey, R. Haake, D. Weisdorf, M. E. Nesbit and N. K. Ramsay, “Pretransplantation Burden of Leukemic Progenitor Cells as a Predictor of Relapse after Bone Marrow Transplantation for Acute Lymphoblastic Leukemia,” New England Journal of Medicine, Vol. 329, No. 18, 1993, pp. 1296-1301. http://dx.doi.org/10.1056/NEJM199310283291802
[6]	V. J. Weston, B. Austen, W. Wei, E. Marston, A. Alvi, S. Lawson, et al., “Apoptotic Resistance to Ionizing Radiation in Pediatric B-Precursor Acute Lymphoblastic Leukemia Frequently Involves Increased NF Kappa B Survival Pathway Signaling,” Blood, Vol. 104, No. 5, 2004, pp. 1465-1473. http://dx.doi.org/10.1182/blood-2003-11-4039
[7]	E. Marston, V. Weston, J. Jesson, E. Maina, C. McConville, A. Agathanggelou, et al., “Stratification of Pediatric ALL by in Vitro Cellular Responses to DNA Double-Strand Breaks Provides Insight into the Molecular Mechanisms Underlying Clinical Response,” Blood, Vol. 113, No. 1, 2009, pp. 117-126. http://dx.doi.org/10.1182/blood-2008-03-142950
[8]	G. H. Reaman and F. O. Smith, “Childhood Leukemia: A Practical Handbook,” Springer Verlag, Heidelberg-Berlin, 2011. http://dx.doi.org/10.1007/978-3-642-13781-5
[9]	F. M. Uckun and S. Qazi, “Spleen Tyrosine Kinase as a Molecular Target for Treatment of Leukemias and Lymphomas,” Expert Review of Anticancer Therapy, Vol. 10, No. 9, 2010, pp. 1407-1418. http://dx.doi.org/10.1586/era.10.112
[10]	O. D’Cruz and F. M. Uckun, “Protein Kinase Inhibitors against Malignant Lymphoma,” Expert Opinion on Pharmacotherapy, Vol. 14, No. 6, 2013, pp. 707-721. http://dx.doi.org/10.1517/14656566. 2013.780031
[11]	F. M. Uckun, S. Qazi, H. Ma, L. Tuel-Ahlgren and Z. Ozer, “STAT3 Is a Substrate of SYK Tyrosine Kinase in B-Lineage Leukemia/Lymphoma Cells Exposed to Oxidative Stress,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 7, 2010, pp. 2902-2907. http://dx.doi.org/10.1073/pnas.0909086107
[12]	T. Wossning, S. Herzog, F. Kohler, S. Meixlsperger, Y. Kulathu, G. Mittler, et al., “Deregulated Syk Inhibits Differentiation and Induces Growth Factor-Independent Proliferation of Pre-B Cells,” Journal of Experimental Medicine, Vol. 13, No. 13, 2006, pp. 2829-2840. http://dx.doi.org/10.1084/jem. 20060967
[13]	F. M. Uckun, R. O. Ek, S. T. Jan, C. L. Chen and S. Qazi, “Targeting SYK Kinase-Dependent Anti-Apoptotic Resistance Pathway in B-lineage Acute Lymphoblastic Leukemia (ALL) Cells with a Potent SYK Inhibitory Pentapeptide Mimic,” British Journal of Hematology, Vol. 149, No.4, 2010, pp. 508-517. http://dx.doi.org/10.1111/j.1365-2141.2010.08106.x
[14]	D. C. Otero, V. Poli, M. David and R. C. Rickert, “Cutting Edge: Inherent and Acquired Resistance to Radiation-Induced Apoptosis in B-Cells: A Pivotal Role for STAT3,” Journal of Immunology, Vol. 177, No. 10, 2006, pp. 6593-6597.
[15]	S. Haga, K. Terui, H. Q. Zhang, S. Enosawa, W. Ogawa, H. Inoue, et al., “Stat3 Protects against Fas-Induced Liver Injury by Redox-Dependent and -Independent Mechanisms,” Journal of Clinical Investigation, Vol. 112, No. 7, 2003, pp. 989-998.
[16]	K. Terui, S. Enosawa, S. Haga, H. Q. Zhang, H. Kuroda, K. Kouchi, et al., “Stat3 Confers Resistance against Hypoxia/Reoxygenation-Induced Oxidative Injury in Hepatocytes through Upregulation of Mn-SOD,” Journal of Hepatology, Vol. 41, No. 6, 2004, pp. 957-965. http://dx.doi.org/10.1016/j.jhep. 2004.08.019
[17]	F. M. Uckun, S. Qazi, I. Cely, K. Sahin, A. Shahidzadeh, I. Ozercan, et al., “Nanoscale Liposomal Formulation of a SYK P-Site Inhibitor against B-Precursor Leukemia,” Blood, Vol. 121, No. 21, 2013, pp. 4348-4354. http://dx.doi.org/10.1182/blood-2012-11-470633
[18]	K. Cho, X. Wang, S. Nie, Z. G. Chen and D. M. Shin, “Therapeutic Nanoparticles for Drug Delivery in Cancer,” Clinical Cancer Research, Vol. 14, No. 5, 2008, pp. 1310-1316. http://dx.doi.org/10.1158/ 1078-0432.CCR-07-1441
[19]	S. Karve, M. E. Werner, R. Sukumar, N. D. Cummings, J. A. Copp, E. C. Wang, et al., “Revival of the Abandoned Therapeutic Wortmannin by Nanoparticle Drug Delivery,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 21, 2012, 2012, pp. 8230-8235.
[20]	S. H. Yiv and F. M. Uckun, “Lipid Spheres as Attractive Nanoscale Drug Delivery Platforms for Cancer Therapy,” Journal of Nanomedicine & Nanotechnology, Vol. 3, 2012, p. 128.