While most children with B cell acute lymphoblastic leukemia (B-ALL) are cured with modern multi-agent chemotherapy regimens, approximately 15% of children have recurrent or therapy-resistant disease. Relapsed ALL remains a leading cause of pediatric cancer mortality, highlighting a need for improved biologic understanding that can inform new therapeutic approaches. Many subtypes of high-risk childhood ALL harbor genetic alterations that activate signal transduction networks, which may be targeted with small molecule kinase inhibitors. Indeed, recent studies have demonstrated constitutive activation of spleen tyrosine kinase (SYK) signaling in various genetic subtypes of B-ALL, as well as in vitro preclinical activity of the SYK/FLT3/JAK inhibitor fostamatinib. However, SYK activation in B-ALL, its potential dependence upon pre-B cell receptor signaling and possible association with cytogenetic subtypes is not well understood. We hypothesize that basal SYK activation occurs in clinically high-risk childhood B-ALL and may correlate with specific leukemia-associated molecular lesions.
In this project, we are investigating the anti-leukemia activity of the SYK inhibitor entospletinib in preclinical models of childhood B-ALL via the following aims:
(1) Assess basal SYK signaling activation in childhood B-ALL specimens.
(2) Quantify treatment efficacy, pharmacokinetics (PK) and pharmacodynamic (PD) effects of entospletinib in childhood B-ALL patient-derived xenograft (PDX) models.
Our preliminary results show that constitutive activation of SYK signaling occurs frequently in childhood Ph-like and infant KMT2A-R childhood B-ALL. Entospletinib treatment of B-ALL PDX models potently inhibited SYK pathway signaling proteins and significantly inhibited leukemia proliferation in vivo. Additional testing of entospletinib (likely in combination with chemotherapy) in B-ALL is warranted.