Therapeutic targeting of mutant p53 in pediatric acute lymphoblastic leukemia

Demir, Salih; Boldrin, Elena; Sun, Qian; Hampp, Stephanie; Tausch, Eugen; Eckert, Cornelia; Ebinger, Martin; Handgretinger, Rupert; Kronnie, Geertruy te; Wiesmüller, Lisa; Stilgenbauer, Stephan; Selivanova, Galina; Debatin, Klaus‐Michael; Meyer, Lüder Hinrich

doi:10.3324/haematol.2018.199364

Cited by 42 publications

(32 citation statements)

References 26 publications

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“…An even more attractive approach to tackle TP53 mutated EGFR mt+ tumors might be the specific targeting of TP53 mutations by TP53 inhibitors. This approach is being discussed extensively in a variety of cancers, such as breast cancer [27] and hematologic malignancies [28]. Recently a trial combining a TP53 inhibitor (APREA 246) in combination with azacitidine in TP53 mutant MDS showed a 100% response rate with 8/9 patients even achieving complete remission with median PFS and median OS not reached.…”

Section: Discussionmentioning

confidence: 99%

TP53 co-mutations in EGFR mutated patients in NSCLC stage IV: A strong predictive factor of ORR, PFS and OS in EGFR mt+ NSCLC

et al. 2020

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Introduction: The impact of TP53 co-mutations in EGFR mutated patients on PFS and OS is controversial. Different classifications of TP53 mutations with respect to functional and potential clinical impact have been published. Therefore, we retrospectively analyzed the impact of TP53 co-mutations on ORR, PFS and OS in a cohort of EGFR mutated NSCLC IV patients (UICC 7) using different classifications of TP53 mutations. Methods: 75 EGFR mutated NSCLC IV patients homogeneously treated with 1st line EGFR TKI were analyzed for TP53 co-mutations. TP53 mutations were classified according to three different types of classifications. The endpoints ORR, PFS and OS were investigated. Results: TP53 co-mutations were found in 29/59 patients (49.2%). TP53 comutations were a statistically significant independent negative predictive factor for ORR, PFS and OS. TP53 co-mutations were associated with inferior mPFS and mOS: mPFS/mOS 12 vs. 18/24 vs. 42 months for non-disruptive/disruptive mutations vs. WT (p < 0.004)/(p < 0.009), 11 vs. 17/23 vs. 42 months for pathogenic vs. nonpathogenic/WT (p < 0.001)/(p < 0.001), and 7 vs. 12 vs. 18/12 vs. 28 vs. 42 months for exon 8 vs. non-exon 8 vs. WT (p < 0.001)/(p < 0.002). Conclusions: TP53 co-mutations are frequent in EGFR mt+ NSCLC and have a strong negative impact on all clinical endpoints of TKI therapy.

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Section: Discussionmentioning

confidence: 99%

TP53 co-mutations in EGFR mutated patients in NSCLC stage IV: A strong predictive factor of ORR, PFS and OS in EGFR mt+ NSCLC

et al. 2020

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“…The presence of TP53 alterations has been associated with a reduced response rate to induction therapy and correlated with a shortened duration of survival, even after successful reinduction therapy [ 35 , 36 ]. Different therapeutic strategies to target mutant p53 have been developed for the high risk TP53 -mutant ALL, such as the use of the small molecule APR-246 which exhibits antileukemia activity in TP53 mut BCP-ALL, targeting non-functional mutant p53 and restoring its tumor suppressive function [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Integrated Genomic Analysis of Chromosomal Alterations and Mutations in B-Cell Acute Lymphoblastic Leukemia Reveals Distinct Genetic Profiles at Relapse

et al. 2020

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The clonal basis of relapse in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is complex and not fully understood. Next-generation sequencing (NGS), array comparative genomic hybridization (aCGH), and multiplex ligation-dependent probe amplification (MLPA) were carried out in matched diagnosis–relapse samples from 13 BCP-ALL patients to identify patterns of genetic evolution that could account for the phenotypic changes associated with disease relapse. The integrative genomic analysis of aCGH, MLPA and NGS revealed that 100% of the BCP-ALL patients showed at least one genetic alteration at diagnosis and relapse. In addition, there was a significant increase in the frequency of chromosomal lesions at the time of relapse (p = 0.019). MLPA and aCGH techniques showed that IKZF1 was the most frequently deleted gene. TP53 was the most frequently mutated gene at relapse. Two TP53 mutations were detected only at relapse, whereas the three others showed an increase in their mutational burden at relapse. Clonal evolution patterns were heterogeneous, involving the acquisition, loss and maintenance of lesions at relapse. Therefore, this study provides additional evidence that BCP-ALL is a genetically dynamic disease with distinct genetic profiles at diagnosis and relapse. Integrative NGS, aCGH and MLPA analysis enables better molecular characterization of the genetic profile in BCP-ALL patients during the evolution from diagnosis to relapse.

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“…Despite being originally considered as undruggable, a small molecule screen nearly 20 years ago identified APR-246 via its ability to induce apoptosis in human tumor cells through restoration of the transactivation function of mutant p53 (76). Since that time, several reports have shown anti-leukemic activity of APR-246 in vitro both in ALL (77) and AML (78, 79). A first-in-human trial in refractory hematologic malignancies concluded that APR-246 could be administered safely and induced p53-dependent biologic effects in tumor cells in vivo (80).…”

Section: Apoptosis Regulatorsmentioning

confidence: 99%

Molecular Approaches to Treating Pediatric Leukemias

2019

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Over the past decades, striking progress has been made in the treatment of pediatric leukemia, approaching 90% overall survival in children with acute lymphoblastic leukemia (ALL) and 75% in children with acute myeloid leukemia (AML). This has mainly been achieved through multiagent chemotherapy including CNS prophylaxis and risk-adapted therapy within collaborative clinical trials. However, prognosis in children with refractory or relapsed leukemia remains poor and has not significantly improved despite great efforts. Hence, more effective and less toxic therapies are urgently needed. Our understanding of disease biology, molecular drivers, drug resistance and, thus, the possibility to identify children at high-risk for treatment failure has significantly improved in recent years. Moreover, several new drugs targeting key molecular pathways involved in leukemia development, cell growth, and proliferation have been developed and approved. These striking achievements are linked to the great hope to further improve survival in children with refractory and relapsed leukemia. This review gives an overview on current molecularly targeted therapies in children with leukemia, including kinase, and proteasome inhibitors, epigenetic and enzyme targeting, as well as apoptosis regulators among others.

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Therapeutic targeting of mutant p53 in pediatric acute lymphoblastic leukemia

Cited by 42 publications

References 26 publications

TP53 co-mutations in EGFR mutated patients in NSCLC stage IV: A strong predictive factor of ORR, PFS and OS in EGFR mt+ NSCLC

TP53 co-mutations in EGFR mutated patients in NSCLC stage IV: A strong predictive factor of ORR, PFS and OS in EGFR mt+ NSCLC

Integrated Genomic Analysis of Chromosomal Alterations and Mutations in B-Cell Acute Lymphoblastic Leukemia Reveals Distinct Genetic Profiles at Relapse

Molecular Approaches to Treating Pediatric Leukemias

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