Pre-clinical evaluation of second generation PIM inhibitors for the treatment of T-cell acute lymphoblastic leukemia and lymphoma

Smedt, Renate De; Peirs, Sofie; Morscio, Julie; Matthijssens, Filip; Roels, Juliette; Reunes, Lindy; Lintermans, Béatrice; Goossens, Steven; Lammens, Tim; Roy, Nadine Van; Touzart, Aurore; Jenni, Silvia; Tsai, Yi-Chien; Lovisa, Federica; Mussolin, Lara; Serafin, Valentina; Nieuwerburgh, Filip Van; Deforce, Dieter; Uyttebroeck, Anne; Tousseyn, Thomas; Burkhardt, Birgit; Klapper, Wolfram; Moerloose, Barbara De; Benoît, Yves; Macintyre, Elizabeth; Bourquin, Jean‐Pierre; Basso, Giuseppe; Accordi, Benedetta; Bornhäuser, Beat; Meijerink, Jules P.P.; Vandenberghe, Peter; Vlierberghe, Pieter Van

doi:10.3324/haematol.2018.199257

Cited by 23 publications

(24 citation statements)

References 15 publications

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“…This is in agreement with the higher occurrence of activating mutations in the IL7R signaling pathway in these T-ALL subtypes, including JAK1/3 and STAT5B mutations (18,21,22,78). PIM1 inhibition has proven efficacy in T-ALL using in vitro and in vivo models, with an increased effect observed for ETP-ALL blasts (74,77). Both phospho-STAT5 and PIM1 expression levels can be used as a predictive biomarker for response to JAK inhibitors (74).…”

Section: Pim1 Inhibitorssupporting

confidence: 79%

“…When exploring alternative treatment options for aberrant JAK-STAT signaling, PIM1 was identified as a direct STAT5 transcriptional target gene that is also upregulated by physiologic IL7-induced signaling (71,74,75). Expression of the prosurvival PIM1 kinase is mainly observed in precortical T-ALL, with the highest expression in the TLX and ETP-ALL subtypes (71,74,76,77). This is in agreement with the higher occurrence of activating mutations in the IL7R signaling pathway in these T-ALL subtypes, including JAK1/3 and STAT5B mutations (18,21,22,78).…”

Section: Pim1 Inhibitorsmentioning

confidence: 99%

“…PIM1 inhibition paradoxically results in enhanced MAPK-ERK signaling and may explain the observed synergy of combined PIM1 and MEK inhibitor treatment (74,79). In addition, synergistic effects of PIM1 inhibitors in combination with venetoclax or dexamethasone have been observed (77,80), indicating that PIM1 could be a valuable therapeutic target to counteract unfavorable hallmarks of immature/ ETP-ALL cases such as high BCL2 expression and steroid resistance.…”

Section: Pim1 Inhibitorsmentioning

confidence: 99%

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T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies

Cordó

Zwet

Canté-Barrett

et al. 2021

Blood Cancer Discovery

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T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy characterized by aberrant proliferation of immature thymocytes. Despite an overall survival of 80% in the pediatric setting, 20% of patients with TALL ultimately die from relapsed or refractory disease. Therefore, there is an urgent need for novel therapies. Molecular genetic analyses and sequencing studies have led to the identification of recurrent TALL genetic drivers. This review summarizes the main genetic drivers and targetable lesions of TALL and gives a comprehensive overview of the novel treatments for patients with TALL that are currently under clinical investigation or that are emerging from preclinical research. Significance: TALL is driven by oncogenic transcription factors that act along with secondary acquired mutations. These lesions, together with active signaling pathways, may be targeted by therapeutic agents. Bridging research and clinical practice can accelerate the testing of novel treatments in clinical trials, offering an opportunity for patients with poor outcome.

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Section: Pim1 Inhibitorssupporting

confidence: 79%

Section: Pim1 Inhibitorsmentioning

confidence: 99%

Section: Pim1 Inhibitorsmentioning

confidence: 99%

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T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies

Cordó

Zwet

Canté-Barrett

et al. 2021

Blood Cancer Discovery

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“…PIM1 is activated in a significant fraction of human T‐ALL and T‐LBL patient samples, by rare TCR‐driven translocations or aberrant activation of the JAK‐STAT signalling pathway. Therefore, second‐generation pan‐PIM inhibitors represent a new class of substances that might be evaluated in clinical trials for PIM1 expressing T‐LBL patients (De Smedt et al , ).…”

Section: Future Opportunities In T‐lblmentioning

confidence: 99%

Lymphoblastic lymphoma in children and adolescents: review of current challenges and future opportunities

Burkhardt

Hermiston

2019

Br J Haematol

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Lymphoblastic lymphoma (LBL) is the second most common type of Non-Hodgkin Lymphoma (NHL) in childhood and adolescence, accounting for 25-35% of all cases. The majority, 70-80%, is of T-lymphoblastic origin while 20-25% arise from B lymphoblasts. With current therapy, the event-free and overall survivals for paediatric LBL patients now exceeds 80%. Therapy, especially in T-LBL with large mediastinal tumours, is challenging, with both significant morbidity and late sequela. An additional challenge is the dismal prognosis of patients with refractory or relapsed disease. This review article will focus on the growing knowledge of the pathogenesis and biology of LBL, recent advances and challenges in the therapy of LBL, and ongoing and future efforts and opportunities in optimizing therapy and developing novel targeted treatment approaches.

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“…The use of JAK and PIM1 inhibitors in combination might warrant further study as increased levels of PIM1 were also reported in T-ALL patients harbouring IL7R, JAK3, and JAK1 mutations, not only in HOXA-mutated cases. 90,94 BET inhibitors In a study by Booth et al 87 investigating the co-operation of Ezh2, Runx1, and FLT3 alterations in T-ALL, BET inhibitors effectively inhibited leukaemic cell growth in vitro and reduced tumour burden in Ezh2 -/-Runx1 -/-Flt3-ITD mice. In this mouse model, PRC2 complex inactivation occurs resulting in the loss of the repressive H3K27me3 mark leading to subsequent increases in H3K27 acetylation.…”

Section: Jak Inhibitors Alone and In Combinationmentioning

confidence: 99%

The effect of co-occurring lesions on leukaemogenesis and drug response in T-ALL and ETP-ALL

et al. 2019

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Despite advances in the management of acute lymphoblastic leukaemia (ALL), current regimens fail to significantly transform outcomes for patients with high-risk subtypes. Advances in genomic analyses have identified novel lesions including mutations in genes that encode chromatin modifiers and those that influence cytokine and kinase signalling, rendering many of these alterations potentially targetable by tyrosine kinase and epigenetic inhibitors currently in clinical use. Although specific genomic lesions, gene expression patterns, and immunophenotypic profiles have been associated with specific clinical outcomes in some cancers, the application of precision medicine approaches based on these data has been slow. This approach is complicated by the reality that patients often harbour multiple mutations, and in many cases, the precise functional significance and interaction of these mutations in driving leukaemia and drug responsiveness/resistance remains unknown. Given that signalling pathways driving leukaemic pathogenesis could plausibly result from the coexistence of specific lesions and the resultant perturbation of protein interactions, the use of combined therapeutics that target multiple aberrant pathways, according to an individual's mutational profile, might improve outcomes and lower a patient's risk of relapse. Here we outline the genomic alterations that occur in T cell ALL (T-ALL) and early T cell precursor (ETP)-ALL and review studies highlighting the possible effects of co-occurring lesions on leukaemogenesis and drug response.

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Pre-clinical evaluation of second generation PIM inhibitors for the treatment of T-cell acute lymphoblastic leukemia and lymphoma

Cited by 23 publications

References 15 publications

T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies

T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies

Lymphoblastic lymphoma in children and adolescents: review of current challenges and future opportunities

The effect of co-occurring lesions on leukaemogenesis and drug response in T-ALL and ETP-ALL

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