Acute Sensitivity of Ph-like Acute Lymphoblastic Leukemia to the SMAC-Mimetic Birinapant

Abstract

Ph-like acute lymphoblastic leukemia (ALL) is a genetically defined high-risk ALL subtype with a generally poor prognosis. In this study, we evaluated the efficacy of birinapant, a small molecule mimetic of the apoptotic regulator SMAC, against a diverse set of ALL subtypes. Birinapant exhibited potent and selective cytotoxicity against B-cell precursor ALL (BCP-ALL) cells that were cultured ex vivo or in vivo as patient-derived tumor xenografts (PDX). Cytotoxicity was consistently most acute in Ph-like BCP-ALL. Unbiased gene expression analysis of BCP-ALL PDX specimens identified a 68-gene signature associated with birinapant sensitivity, including an enrichment for genes involved in inflammatory response, hematopoiesis and cell death pathways. All Ph-like PDXs analyzed clustered within this 68-gene classifier. Mechanistically, birinapant sensitivity was associated with expression of TNF receptor TNFR1 and was abrogated by interfering with the TNFα/TNFR1 interaction. In combination therapy, birinapant enhanced the in vivo efficacy of induction-type regimen of vincristine, dexamethasone and L-asparaginase against Ph-like ALL xenografts, offering a preclinical rationale to further evaluate this SMAC mimetic for BCP-ALL treatment.

Patient-Derived-Tumor-Xenograft: modeling cancer for basic and translational cancer research

“…They performed a global gene expression profile of ALL-PDTX, 6 responders and 6 nonresponders, to birinapant (SMAC mimetic). Using this approach, they found that the efficacy of birinapant strongly depends on TNFα (or other inflammatory cytokines) expression, which could be used as predictive biomarker for birinapant response in ALL patients [63]. Since the capacity to positively engraft breast cancers into host mice depends on the aggressiveness of the primary tumor, Moon et al were able to show a specific prognostic signature linked to TNBC PDTX engraftment predicting patient survival [64].…”

Cytogenetics, Molecular Genetics and Epigenetics and Their Impact on The Management of Acute Lymphoblastic Leukemia

“…When compared to other pre-B ALL subtypes, Ph-like ALL has the following characteristic features: (1) higher median leukocyte count at presentation, (2) higher median levels of MRD at the end of induction therapy, (3) inferior estimated event-free survival (EFS) at 5 years [58% versus (vs.) 84% in children, 41% vs. 83% in adolescents and 24% vs 63% in young adults], and (4) inferior estimated OS at 5 years [73% vs. 92% in children, 66% vs. 93% in adolescents and 26% vs 75% in young adults [88]. The various genetic abnormalities that are encountered in patients with Ph-like ALL and their targeted therapies are shown in Table 8 [19,[93][94][95][96][97] The investigational targeted therapies in Ph-like ALL are shown in Table 9 [89,98].…”

“…Unfortunately, Ph-like ALL is essentially heterogeneous and a HR subtype of ALL [19,[92][93][94][95]98]. It has characteristic and distinct genetic mutations and rearrangements that are activated by a diverse array of cytokine receptor and tyrosine kinase signaling [87,89,[92][93][94]96].…”

“…Ph-like ALL is associated: with resistance to cytotoxic chemotherapy, very high risk of disease relapse and poor OS [88,90,92,93,95,96,98,99]. The identification of a wide range of genetic alterations that activate certain signaling pathways makes such gene alterations amenable to inhibition by a variety of TKIs [97].…”

“…Birinapant is a small molecule mimetic of the apoptotic regulator SMAC. It targets tumor necrosis factor (TNF)-α-dependent signaling [98]. One study published in 2016 showed that: (1) birinapant exhibited profound anti-leukemic activity as a single agent or in combination with cytotoxic chemotherapy in pediatric patients with Ph-like ALL, and (2) the activity of birinapant was superior in pre-B ALL compared to T-cell ALL [98].…”