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

Frismantas, Viktoras; Dobay, Maria Pamela; Rinaldi, Anna Maria; Tchinda, Joëlle; Dunn, Samuel H.; Kunz, Joachim; Richter-Pechańska, Paulina; Marovca, Blerim; Pail, Orrin; Jenni, Silvia; Díaz-Flores, Ernesto; Chang, Bill H.; Brown, Timothy J.; Collins, Robert H.; Uhrig, Sebastian; Balasubramanian, Gnana Prakash; Bandapalli, Obul Reddy; Higi, Salome; Eugster, Sabrina; Voegeli, P.; Delorenzi, Mauro; Cario, Gunnar; Loh, Mignon L.; Schrappe, Martin; Stanulla, Martin; Kulozik, Andreas E.; Muckenthaler, Martina U.; Saha, Vaskar; Irving, Julie; Meisel, Roland; Radimerski, Thomas; Stackelberg, Arend von; Eckert, Cornelia; Tyner, Jeffrey W.; Horváth, Péter; Bornhäuser, Beat; Bourquin, Jean‐Pierre

doi:10.1182/blood-2016-09-738070

Cited by 195 publications

(226 citation statements)

References 58 publications

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“…In T‐ALL, primary and PDX cells were reported to be generally stable at the genomic level (Wang et al , ), although the PDX material more closely resembled the relapsed leukemias rather than the pattern observed in initial disease, which suggested that the PDX maneuver selects for subclones that may later give rise to the relapse (Clappier et al , ). Extensive genomic studies of BCP‐ALL showed that PDXs mirror the clonal composition of the original leukemia samples, including from MRD samples, with the exception of losses and gains of alternations in RAS pathway genes, which is also frequently observed in relapsed ALL (Fischer et al , ; Frismantas et al , ). Moreover, PDX models of ALL served for identification of a rare subpopulation that resembled relapse‐inducing cells whose gene expression profile was similar to primary cells isolated from patients at MRD (Ebinger et al , ).…”

Section: Introductionmentioning

confidence: 99%

PDX models recapitulate the genetic and epigenetic landscape of pediatric T‐cell leukemia

et al. 2018

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We compared 24 primary pediatric T‐cell acute lymphoblastic leukemias (T‐ALL) collected at the time of initial diagnosis and relapse from 12 patients and 24 matched patient‐derived xenografts (PDXs). DNA methylation profile was preserved in PDX mice in 97.5% of the promoters (ρ = 0.99). Similarly, the genome‐wide chromatin accessibility (ATAC‐Seq) was preserved remarkably well (ρ = 0.96). Interestingly, both the ATAC regions, which showed a significant decrease in accessibility in PDXs and the regions hypermethylated in PDXs, were associated with immune response, which might reflect the immune deficiency of the mice and potentially the incomplete interaction between murine cytokines and human receptors. The longitudinal approach of this study allowed an observation that samples collected from patients who developed a type 1 relapse (clonal mutations maintained at relapse) preserved their genomic composition; whereas in patients who developed a type 2 relapse (subset of clonal mutations lost at relapse), the preservation of the leukemia's composition was more variable. In sum, this study underlines the remarkable genomic stability, and for the first time documents the preservation of the epigenomic landscape in T‐ALL‐derived PDX models.

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Section: Introductionmentioning

confidence: 99%

PDX models recapitulate the genetic and epigenetic landscape of pediatric T‐cell leukemia

et al. 2018

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“…Supporting Information Figure S4A‐D shows the dose‐response curves of all four PDXs with IC 50 values summarized in Supporting Information Figure S4E. The IC 50 observed for ALL‐93 was much higher in coculture (3.9 µM) compared with monoculture (58.7 nM), consistent with previous reports where MSCs provided survival signals and contributed to chemoresistance . However, no notable differences were observed between coculture and monoculture conditions in the other three PDXs.…”

Section: Resultsmentioning

confidence: 99%

Optimization of a clofarabine‐based drug combination regimen for the preclinical evaluation of pediatric acute lymphoblastic leukemia

Xie

Span

Maarseveen

et al. 2019

Pediatric Blood & Cancer

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Background The aim of this study was to improve the predictive power of patient‐derived xenografts (PDXs, also known as mouse avatars) to more accurately reflect outcomes of clofarabine‐based treatment in pediatric acute lymphoblastic leukemia (ALL) patients. Procedure Pharmacokinetic (PK) studies were conducted using clofarabine at 3.5 to 15 mg/kg in mice. PDXs were established from relapsed/refractory ALL patients who exhibited good or poor responses to clofarabine. PDX engraftment and response to clofarabine (either as a single agent or in combinations) were assessed based on stringent objective response measures modeled after the clinical setting. Results In naïve immune‐deficient NSG mice, we determined that a clofarabine dose of 3.5 mg/kg resulted in systemic exposures equivalent to those achieved in pediatric ALL patients treated with clofarabine‐based regimens. This dose was markedly lower than the doses of clofarabine used in previously reported preclinical studies (typically 30‐60 mg/kg) and, when scheduled consistent with the clinical regimen (daily × 5), resulted in 34‐fold lower clofarabine exposures. Using a well‐tolerated clofarabine/etoposide/cyclophosphamide combination regimen, we then found that the responses of PDXs better reflected the clinical responses of the patients from whom the PDXs were derived. Conclusions This study has identified an in vivo clofarabine treatment regimen that reflects the clinical responses of relapsed/refractory pediatric ALL patients. This regimen could be used prospectively to identify patients who might benefit from clofarabine‐based treatment. Our findings are an important step toward individualizing prospective patient selection for the use of clofarabine in relapsed/refractory pediatric ALL patients and highlight the need for detailed PK evaluation in murine PDX models.

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“…Recent work indicates that resistant/relapsed ALL cells are particularly vulnerable to SMAC mimetics and cell death is orchestrated through routes distinct from conventional chemotherapeutic agents [55]. Finally, ex vivo profiling of resistant B ALL samples showed that a subset of B ALL samples were quite sensitive to Bcl-2 selective BH3 mimetic inhibitor venetoclax [56]. This has been validated in xenograft models particularly MLL rearranged leukemias although other BH3 mimetics may have broader activity [57].…”

Section: Targeting Underlying Mechanisms Of Relapsementioning

confidence: 99%

New targeted therapies for relapsed pediatric acute lymphoblastic leukemia

Pierro

Hogan

Bhatla

et al. 2017

Expert Review of Anticancer Therapy

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Introduction The improvement in outcomes for children with acute lymphoblastic leukemia (ALL) is one of the greatest success stories of modern oncology however the prognosis for patients who relapse remains dismal. Recent discoveries by high resolution genomic technologies have characterized the biology of relapsed leukemia, most notably pathways leading to the drug resistant phenotype. These observations open the possibility of targeting such pathways to prevent and/or treat relapse. Likewise, early experiences with new immunotherapeutic approaches have shown great promise. Areas Covered We performed a literature search on PubMed and recent meeting abstracts using the keywords below. We focus on the biology and clonal evolution of relapsed disease and highlight potential new targets of therapy. We further summarize the results of early trials of the three most prominent immunotherapy agents currently under investigation. Expert Commentary Discovery of targetable pathways that lead to drug resistance and recent breakthroughs in immunotherapy show great promise towards treating this aggressive disease. The best way to treat relapse, however, is to prevent it which makes incorporation of these new approaches into frontline therapy the best approach. Challenges remain to balance efficacy with toxicity and to prevent the emergence of resistant subclones which is why combining these newer agents with conventional chemotherapy will likely become standard of care.

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

Abstract: Key Points Ex vivo drug profiling captures disease-relevant features and relevant sensitivity to therapeutic agents in ALL. A subset of drug-resistant T-ALL without mutations in ABL1 is highly responsive to dasatinib, which provides a rationale for drug repurposing.

Cited by 195 publications

References 58 publications

PDX models recapitulate the genetic and epigenetic landscape of pediatric T‐cell leukemia

PDX models recapitulate the genetic and epigenetic landscape of pediatric T‐cell leukemia

Optimization of a clofarabine‐based drug combination regimen for the preclinical evaluation of pediatric acute lymphoblastic leukemia

New targeted therapies for relapsed pediatric acute lymphoblastic leukemia

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