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Bcr-Abl Tyrosine Kinase Inhibitors in the Treatment of Pediatric CML.

ABSTRACT: The therapeutic approach to Chronic Myeloid Leukemia (CML) has changed since the advent of the tyrosine kinase inhibitor (TKI) imatinib, which was then followed by the second generation TKIs dasatinib, nilotinib, and, finally, by ponatinib, a third-generation drug. At present, these therapeutic options represent the first-line treatment for adults. Based on clinical experience, imatinb, dasatinib, and nilotinib have been approved for children even though the studies that were concerned with efficacy and safety toward pediatric patients are still awaiting more specific and high-quality data. In this scenario, it is of utmost importance to prospectively validate data extrapolated from adult studies to set a standard therapeutic management for pediatric CML by employing appropriate formulations on the basis of pediatric clinical trials, which allow a careful monitoring of TKI-induced adverse effects especially in growing children exposed to long-term therapy.

SUBMITTER: Carofiglio F

PROVIDER: S-EPMC7352889 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Bcr-Abl Tyrosine Kinase Inhibitors in the Treatment of Pediatric CML.

Carofiglio Francesca F Lopalco Antonio A Lopedota Angela A Cutrignelli Annalisa A Nicolotti Orazio O Denora Nunzio N Stefanachi Angela A Leonetti Francesco F

International journal of molecular sciences 20200623 12

The therapeutic approach to Chronic Myeloid Leukemia (CML) has changed since the advent of the tyrosine kinase inhibitor (TKI) imatinib, which was then followed by the second generation TKIs dasatinib, nilotinib, and, finally, by ponatinib, a third-generation drug. At present, these therapeutic options represent the first-line treatment for adults. Based on clinical experience, imatinb, dasatinib, and nilotinib have been approved for children even though the studies that were concerned with effi ...[more]

PMID: 32586039

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Project description:ImportanceThe US Food and Drug Administration (FDA) highlighted the potential risk of hepatitis B reactivation that was associated with Bcr-Abl tyrosine kinase inhibitor (TKI) treatment and has required updated product labels.ObjectiveTo examine the association between hepatitis B flare and exposure to Bcr-Abl TKIs compared with non-Bcr-Abl TKIs.Design, setting, and participantsThis nested case-control study included patients who entered a hepatitis B carrier cohort in Taiwan after January 1, 2005. Patients who received their first antiviral agents for hepatitis B flare for more than 28 days after the cohort entry date were included as case patients. For each case, a corresponding risk set was formed that included all eligible patients in the study cohort who had the same age (within 1 year), same sex, and were at risk of developing hepatitis B flare at the case date. As many as 10 control patients were randomly selected from the risk set for each case patient. TKIs were evaluated before the hepatitis B flare for case patients and before the corresponding index date for control patients. Data were collected from the Taiwan National Health Insurance research database from January 2000 to 2015. Data analysis was conducted from January to June 2019.ExposureUse of Bcr-AbL TKIs.Main outcomes and measuresConditional logistic regression was used to estimate the rate ratio for the association between hepatitis B flare and exposure to Bcr-Abl TKIs compared with non-Bcr-Abl TKIs.ResultsAmong 698 342 patients who carried incident hepatitis B virus, 66 702 patients with hepatitis B flare that required antiviral treatment (47 492 [71.2%] men; mean [SD] age at index date, 50.2 [13.8] years) were included as case patients, and 666 989 age and sex-matched patients (474 903 [71.2%] men; mean [SD] age, 50.2 [13.8] years) were included as control patients. Analysis revealed that Bcr-Abl TKI use during the previous 90 days was independently associated with a 56% higher risk of hepatitis B flare (adjusted rate ratio [aRR], 1.56; 95% CI, 1.11-2.20), and the aRR increased to 1.66 (95% CI, 1.20-2.28) for Bcr-Abl TKI use during the previous 365 days. Use of Bcr-AbL TKIs during the previous 60 days was associated with a significantly increased risk of flare among women (aRR, 3.20; 95% CI, 1.70-6.03) but not among men (aRR, 1.14; 95% CI, 0.72-1.81).Conclusions and relevanceThese findings suggest that sex-specific strategies may be needed to monitor for hepatitis B reactivation among patients receiving Bcr-Abl TKIs.

Project description:The chimeric oncoprotein Bcr-Abl is the causative agent of virtually all chronic myeloid leukemias (CML) and a subset of acute lymphoblastic leukemias (ALL). As a result of the so-called Philadelphia Chromosome translocation t(9;22), Bcr-Abl manifests as a constitutively active tyrosine kinase which promotes leukemogenesis by activation of cell cycle signaling pathways. Constitutive and oncogenic activation is mediated by an N-terminal coiled-coil oligomerization domain in Bcr (Bcr-CC), presenting a therapeutic target for inhibition of Bcr-Abl activity toward the treatment of Bcr-Abl+ leukemias. Previously, we demonstrated that a rationally designed Bcr-CC mutant, CCmut3, exerts a dominant negative effect upon Bcr-Abl activity by preferential oligomerization with Bcr-CC. Moreover, we have shown conjugation to a leukemia-specific cell-penetrating peptide (CPP-CCmut3) improves intracellular delivery and activity. However, our full-length CPP-CCmut3 construct (81 aa) is encumbered by an intrinsically high degree of conformational variability and susceptibility to proteolytic degradation, relative to traditional small molecule therapeutics. Here, we iterate a new generation of our inhibitor against Bcr-CC mediated Bcr-Abl assembly that is designed to address these constraints through incorporation of all-hydrocarbon staples spanning i, i + 7 positions in helix α2 (CPP-CCmut3-st). We utilize computational modeling and biomolecular simulation to design and characterize single and double staple candidates in silico, evaluating binding energetics and building upon our seminal work modeling single hydrocarbon staples when applied to a truncated Bcr-CC sequence. This strategy enables us to efficiently build, characterize, and screen lead single/double stapled CPP-CCmut3-st candidates for experimental studies and validation in vitro and in vivo. In addition to full-length CPP-CCmut, we model a truncated system characterized by deletion of helix α1 and the flexible-loop linker, which are known to impart high conformational variability. To study the impact of the N-terminal cyclic CPP toward model stability and inhibitor activity, we also model the full-length and truncated systems without CPP, with cyclized CPP, and with linear CPP, for a total of six systems which comprise our library. From this library, we present lead stapled peptide candidates to be synthesized and evaluated experimentally as our next-generation inhibitors against Bcr-Abl.

Project description:In Chronic Myeloid Leukemia (CML), successful treatment requires accurate molecular monitoring to evaluate disease response and provide timely interventions for patients failing to achieve the desired outcomes. We wanted to determine whether measuring BCR-ABL1 mRNA doubling-times (DTs) could distinguish inconsequential rises in the oncogene's expression from resistance to tyrosine kinase inhibitors (TKIs). Thus, we retrospectively examined BCR-ABL1 evolution in 305 chronic-phase CML patients receiving imatinib mesylate (IM) as a first line treatment. Patients were subdivided in two groups: those with a confirmed rise in BCR-ABL1 transcripts without MR3.0 loss and those failing IM. We found that the DTs of the former patients were significantly longer than those of patients developing IM resistance (57.80 vs. 41.45 days, p = 0.0114). Interestingly, the DT values of individuals failing second-generation (2G) TKIs after developing IM resistance were considerably shorter than those observed at the time of IM failure (27.20 vs. 41.45 days; p = 0.0035). We next wanted to establish if decreases in BCR-ABL1 transcripts would identify subjects likely to obtain deep molecular responses. We therefore analyzed the BCR-ABL1 halving-times (HTs) of a different cohort comprising 174 individuals receiving IM in first line and observed that, regardless of the time point selected for our analyses (6, 12, or 18 months), HTs were significantly shorter in subjects achieving superior molecular responses (p = 0.002 at 6 months; p < 0.001 at 12 months; p = 0.0099 at 18 months). Moreover, 50 patients receiving 2G TKIs as first line therapy and obtaining an MR3.0 (after 6 months; p = 0.003) or an MR4.0 (after 12 months; p = 0.019) displayed significantly shorter HTs than individuals lacking these molecular responses. Our findings suggest that BCR-ABL1 DTs and HTs are reliable tools to, respectively, identify subjects in MR3.0 that are failing their assigned TKI or to recognize patients likely to achieve deep molecular responses that should be considered for treatment discontinuation.

Project description:Background In the ongoing battle against BCR-ABL+ leukemia, despite significant advances with tyrosine kinase inhibitors (TKIs), the persistent challenges of drug resistance and the enduring presence of leukemic stem cells (LSCs) remain formidable barriers to achieving a cure. Methods In this study, we demonstrated that Disulfiram (DSF) induces ferroptosis to synergize with TKIs in inhibiting BCR-ABL+ cells, particularly targeting resistant cells and LSCs, using cell models, mouse models, and primary cells from patients. We elucidated the mechanism by which DSF promotes GPX4 degradation to induce ferroptosis through immunofluorescence, co-immunoprecipitation (CO-IP), RNA sequencing, lipid peroxidation assays, and rescue experiments. Results Here, we present compelling evidence elucidating the sensitivity of DSF, an FDA-approved drug for alcohol dependence, towards BCR-ABL+ cells. Our findings underscore DSF's ability to selectively induce a potent cytotoxic effect on BCR-ABL+ cell lines and effectively inhibit primary BCR-ABL+ leukemia cells. Crucially, the combined treatment of DSF with TKIs selectively eradicates TKI-insensitive stem cells and resistant cells. Of particular note is DSF's capacity to disrupt GPX4 stability, elevate the labile iron pool, and intensify lipid peroxidation, ultimately leading to ferroptotic cell death. Our investigation shows that BCR-ABL expression induces alterations in cellular iron metabolism and increases GPX4 expression. Additionally, we demonstrate the indispensability of GPX4 for LSC development and the initiation/maintenance of BCR-ABL+ leukemia. Mechanical analysis further elucidates DSF's ability to circumvent resistance by reducing GPX4 levels through the disruption of its binding with HSPA8, thereby promoting GPX4 ubiquitination and subsequent degradation. Furthermore, the combined treatment of DSF with TKIs effectively targets both BCR-ABL+ blast cells and drug-insensitive LSCs, conferring a significant survival advantage in mouse models. Conclusion In summary, the dual inhibition of GPX4 and BCR-ABL presents a promising therapeutic strategy to synergistically target blast cells and drug-insensitive LSCs in patients, offering potential avenues for advancing leukemia treatment.

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Bcr-Abl Tyrosine Kinase Inhibitors in the Treatment of Pediatric CML.

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Bcr-Abl Tyrosine Kinase Inhibitors in the Treatment of Pediatric CML.

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