A review of new agents evaluated against pediatric acute lymphoblastic leukemia by the Pediatric Preclinical Testing Program

Abstract

Acute lymphoblastic leukemia (ALL) in children exemplifies how multi-agent chemotherapy has improved the outcome for patients. Refinements in treatment protocols and improvements in supportive care for this most common pediatric malignancy have led to a cure rate that now approaches 90%. However, certain pediatric ALL subgroups remain relatively intractable to treatment and many patients who relapse face a similarly dismal outcome. Moreover, survivors of pediatric ALL suffer the long-term sequelae of their intensive treatment throughout their lives. Therefore, the development of drugs to treat relapsed/refractory pediatric ALL, as well as those that more specifically target leukemia cells, remains a high priority. As pediatric malignancies represent a minority of the overall cancer burden, it is not surprising that they are generally underrepresented in drug development efforts. The identification of novel therapies relies largely on the reappropriation of drugs developed for adult malignancies. However, despite the large number of experimental agents available, clinical evaluation of novel drugs for pediatric ALL is hindered by limited patient numbers and the availability of effective established drugs. The Pediatric Preclinical Testing Program (PPTP) was established in 2005 to provide a mechanism by which novel therapeutics could be evaluated against xenograft and cell line models of the most common childhood malignancies, including ALL, to prioritize those with the greatest activity for clinical evaluation. In this article, we review the results of >50 novel agents and combinations tested against the PPTP ALL xenografts, highlighting comparisons between PPTP results and clinical data where possible.

Bioluminescence Imaging Enhances Analysis of Drug Responses in a Patient-Derived Xenograft Model of Pediatric ALL

“…The definition of a CR would then become similar to that of an MCR, which requires PB levels <1% huCD45 + cells for the last 3 weeks of the 42-day monitoring period. This additional stringency will likely discount the majority of novel agents as, using previous scores of MCR for comparison, only 4/57 drugs tested against the PPTP ALL PDX panel have achieved an MCR in >50% of PDXs (14). However this may be improved with more biomarker-driven testing, as 16/57 drugs induced at least one MCR (14).…”

“…This additional stringency will likely discount the majority of novel agents as, using previous scores of MCR for comparison, only 4/57 drugs tested against the PPTP ALL PDX panel have achieved an MCR in >50% of PDXs (14). However this may be improved with more biomarker-driven testing, as 16/57 drugs induced at least one MCR (14). It is noteworthy that the ALL-57-GL 0.5x VXL group achieved a clinical CR despite the presence of considerable extramedullary disease, however clinically the prognosis of BM relapse is significantly poorer than that of extramedullary relapse (53, 54), supporting the use of the BM-based threshold in this study.…”

“…These PDXs accurately recapitulate fundamental characteristics of the original disease including immunophenotype, chromosomal translocations, gene mutations, gene expression profiles, DNA methylation patterns and drug sensitivity (9–13). Pediatric ALL PDXs used as part of the NCI-funded Pediatric Preclinical Testing Program (PPTP) have shown concordance between preclinical results and corresponding available clinical data for established and novel drugs (14). …”

Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia

“…This approach will complement in vivo PDX models, which have obvious limitations in compound coverage and flexibility. 15 Drug sensitivity testing revealed individual drug response phenotypes in acute myeloid leukemia (AML) 16 and identified new strategies to bypass resistance to tyrosine kinase inhibitors (TKIs) in patients with deleterious BCR-ABL mutations. 17 Conversely, characteristic tyrosine kinase mutations could be predicted on the basis of drug activity.…”

Dysregulation of BCL-2 family proteins by leukemia fusion genes

“…Mechanistically, ABT-737 increases the pool of unbound BH3-only proteins, which in steady state are otherwise bound to and sequestered by BCL-2 and BCL-X L (17). Although ABT-737 treatment increased survival in some imatinib-treated Phϩ ALL xenografts, ABT-263 (navitoclax, identical activity to ABT-737) and ABT-199 (selectively inhibits BCL-2) were ineffective in another Phϩ ALL xenograft model (51,52 The schematics depicting each fusion were produced using a program for visualization of gene rearrangements from RNA sequencing data (Clinker https://github.com/Oshlack/Clinker. Please note that the JBC is not responsible for the long-term archiving and maintenance of this site or any other third party hosted site.).…”