Persistence of targetable lesions, predicted therapy sensitivity and proteomes through disease evolution in pediatric acute lymphoblastic leukemia

Abstract

Childhood acute lymphoblastic leukemia (ALL) genome landscapes indicate that relapses often arise from subclonal outgrowths. However, the impact of clonal evolution on the actionable proteome and response to targeted therapy is not known. Here, we present a comprehensive retrospective analysis of paired ALL diagnosis and relapsed specimen. Targeted next generation sequencing and proteome analysis indicated persistence of genome variants and stable proteomes through disease progression. Although variant-targeted therapies showed poor selectivity against viably-frozen tumor samples, paired samples showed high correlation of drug response. Proteome analysis prioritized PARP1 as a new pan-ALL target candidate; diagnostic and relapsed ALL samples demonstrated robust sensitivity to treatment with two PARP1/2 inhibitors. Together, these findings support initiating prospective precision oncology approaches at ALL diagnosis and emphasize the need to incorporate proteome analysis to prospectively determine tumor sensitivities, which are likely to be retained at disease relapse.

ASAP─Automated Sonication-Free Acid-Assisted Proteomes─from Cells and FFPE Tissues

“…Gene ontology enrichment analysis was performed using g:Profiler with an FDR of 5%. A list of pediatric cancer-associated proteins was derived from the sequencing panel used for the genome and transcriptome analyses of pediatric leukemias and solid tumors − as detailed in Lorentzian et al (preprint) . The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the data set identifier PXD036910.…”

Proteomics and personalized patient-derived xenograft models identify treatment opportunities for a progressive malignancy within a clinically actionable timeframe and change care

“…1F). Among these, we quantified 154 of a set of 349 cancer-associated proteins that we had previously assembled with a focus on drivers and therapeutic targets in pediatric malignancies (28), confirming comprehensive coverage of the most relevant drivers and pathways (Fig. 1F).…”

“…This study sets up the basis to implement proteomics into molecular tumor profiling of patients under PROFYLE and other pediatric precision medicine initiatives. Previous retrospective cohort studies have demonstrated that proteome analysis can identify drug targets and contribute to rational treatment choices in pediatric cancers (28,44). Pediatric precision medicine initiatives such as ZERO and INFORM have showcased the application of functional precision oncology during diagnosis for various cancer types, thereby potentially offering more suitable treatment options.…”