Publication Date:
2019-11-13
Description:
Introduction: While children diagnosed with acute lymphoblastic leukemia (ALL) experience close to a 90% likelihood of cure, the outcome for certain high-risk pediatric ALL subtypes as well as adult ALL remains poor. Several standard-of-care drugs used in multi-agent treatment protocols for ALL (including vincristine, daunorubicin and methotrexate) are substrates for the ATP-dependent drug efflux pump P-glycoprotein (P-gp), encoded by the ABCB1 gene, although there are limited reports of ABCB1 gene expression being associated with poor outcome in ALL (Carrillo et al, Hematol. 22:286-91, 2017). A previously identified high-risk subtype of T-ALL (early T-cell precursor ALL, ETP-ALL) characterized by poor early response to conventional induction treatment, expresses significantly higher levels of the ABCB1 gene compared with typical T-ALL (1.97-fold; false discovery rate=0.0026; P=0.00029; Zhang et al, Nature 481:157-63, 2012). E7130 is a novel anti-microtubule drug that is a less potent substrate for P-gp compared with other anti-microtubule drugs such as vincristine, and it has shown significant preclinical activity against patient-derived xenograft (PDX) models of adult malignancies. Therefore, it was of interest for the Pediatric Preclinical Testing Consortium (PPTC) to test the in vivo activity of E7130 against its PDX models of pediatric ETP-ALL. Methods: ABCB1 mRNA expression in ALL PDXs was quantified by RNAseq (https://pedcbioportal.org) and qRT-PCR. P-gp protein expression was assessed by immunoblotting, while its activity was measured by the Rhodamine-123 efflux assay in the absence or presence of the P-gp inhibitor tariquidar. E7130 and vincristine were evaluated in vivo against 6 ETP-ALL PDXs. Each PDX was inoculated into 6-8 immune-deficient (NSG) mice per treatment group (2-5 x 106 cells/mouse). Engraftment and drug responses were evaluated by enumerating the proportion of human CD45+ cells in the peripheral blood (%huCD45+) at weekly intervals. E7130 was tested at 2 dose levels (0.09 and 0.135 mg/kg IV), while vincristine was evaluated at 1 mg/kg IP. Both drugs were administered weekly x 3. Events were defined as the %huCD45+ ≥25%. Drug efficacy was assessed by event-free survival of treated (T) and control (C) groups by T-C, T/C and stringent objective response criteria (Houghton et al, Pediatr Blood Cancer 49:928-40, 2007). Results: RNAseq analysis of the 6 ETP-ALL PDXs in the PPTC panel of 90 pediatric ALL PDXs revealed 3 with high ABCB1 expression (FPKM 7.1-13.6; ETP-2, -3 and -6) and 3 with low expression (FPKM 0-0.15; ETP-1, -4 and -5), which was confirmed by qRT-PCR and immunoblotting. Moreover, high levels of tariquidar-sensitive Rhodamine-123 efflux activity were confirmed in the 2 high ABCB1 expressing PDXs tested (ETP-2 and -3). E7130 was generally well tolerated in NSG mice, with maximum average weight loss of 2.7-17.6% in the groups treated with the highest dose compared with 3.2-12.7% in the vincristine treated groups. E7130 (0.09 mg/kg) significantly (P
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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