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Targeting mitochondrial respiration selectively sensitizes pediatric acute lymphoblastic leukemia cell lines and patient samples to standard chemotherapy.

ABSTRACT: The clinical management of pediatric acute lymphoblastic leukemia (ALL) is still changeling and identification of agents that can sensitize standard chemotherapy is needed for its better management. In this work, we demonstrate that tigecycline, a FDA-approved antibiotic, is an attractive candidate for ALL treatment. Tigecycline inhibits growth and induces apoptosis of multiple ALL cell lines. Compared to normal hematopoietic cells, tigecycline is more active against primary lymphocytes and CD34 progenitors from ALL patients through decreasing survival and clonogenic growth. Notably, tigecycline significantly augments the efficacy of chemotherapeutic drugs, such as doxorubicin and vincristine, in ALL cell lines, primary samples and xenograft mouse model. Tigecycline acts on ALL via inhibiting mitochondrial respiration, leading to energy crisis and oxidative stress and damage. We show that the enhanced mitochondrial biogenesis and increased oxygen consumption rate in ALL versus normal hematopoietic cells are important for their different sensitivity to tigecycline. We further show that ATP production and growth rate are largely affected in mitochondrial respiration-deficient ?0 ALL cells. Our work provides pre-clinical evidence for repurposing tigecycline for ALL treatment and highlights the therapeutic value of targeting mitochondrial metabolism in sensitizing ALL to chemotherapy.

SUBMITTER: Fu X

PROVIDER: S-EPMC5752682 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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Targeting mitochondrial respiration selectively sensitizes pediatric acute lymphoblastic leukemia cell lines and patient samples to standard chemotherapy.

Fu Xuedong X Liu Wei W Huang Qian Q Wang Yanjun Y Li Huijuan H Xiong Ying Y

American journal of cancer research 20171201 12

The clinical management of pediatric acute lymphoblastic leukemia (ALL) is still changeling and identification of agents that can sensitize standard chemotherapy is needed for its better management. In this work, we demonstrate that tigecycline, a FDA-approved antibiotic, is an attractive candidate for ALL treatment. Tigecycline inhibits growth and induces apoptosis of multiple ALL cell lines. Compared to normal hematopoietic cells, tigecycline is more active against primary lymphocytes and CD34 ...[more]

PMID: 29312795

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Project description:During the last few decades, pediatric acute lymphoblastic leukemia (ALL) cure rates have improved significantly with rates exceeding 90%. Parallel to this remarkable improvement, there has been mounting interest in the long-term health of the survivors. Consequently, modified treatment protocols have been developed and resulted in the reduction of many adverse long-term consequences. Nevertheless, these are still substantial concerns that warrant further mitigation efforts. In the current review, pediatric-ALL survivors' late adverse events, including secondary malignant neoplasms (SMNs), cardiac toxicity, neurotoxicity, bone toxicity, hepatic dysfunction, visual changes, obesity, impact on fertility, and neurocognitive effects have been evaluated. Throughout this review, we attempted to answer a fundamental question: can the recent molecular findings mitigate pediatric-ALL chemotherapy's long-term sequelae on adult survivors? For SMNs, few genetic predisposition factors have been identified including TP53 and POT1 variants. Other treatment-related risk factors have been identified such as anthracyclines' possible association with breast cancer in female survivors. Cardiotoxicity is another significant and common adverse event with some germline variants been found, albeit with conflicting evidence, to increase the risk of cardiac toxicity. For peripheral neurotoxicity, vincristine is the primary neurotoxic agent in ALL regimens. Some germline genetic variants were found to be associated with the vincristine neurotoxic effect's vulnerability. However, these were mainly detected with acute neuropathy. Moreover, the high steroid doses and prolonged use increase bone toxicity and obesity risk with some pharmacogenetic biomarkers were associated with increased steroid sensitivity. Therefore, the role of these biomarkers in tailoring steroid choice and dose is a promising research area. Future directions in pediatric ALL treatment should consider the various opportunities provided by genomic medicine. Understanding the molecular bases underlying toxicities will classify patients into risk groups and implement a closer follow-up to those at higher risk. Pharmacogenetic-guided dosing and selecting between alternative agents have proven their efficacy in the short-term management of childhood ALL. It is the right time to think about a similar approach for the life-long consequences on survivors.

Project description:ImportanceTisagenlecleucel, a chimeric antigen receptor T-cell therapy for relapsed or refractory pediatric acute lymphoblastic leukemia, has been approved for use in multiple jurisdictions. The public list price is US $475 000, or more than CaD $600 000. Assessing the cost-effectiveness of tisagenlecleucel is necessary to inform policy makers on the economic value of this treatment.ObjectiveTo assess the value for money of tisagenlecleucel compared with current standard care for tisagenlecleucel-eligible pediatric patients with acute lymphoblastic leukemia under unknown long-term effectiveness.Design, setting, and participantsA cost-utility analysis of tisagenlecleucel compared with current standard care using a Canadian population-based registry of pediatric patients with acute lymphoblastic leukemia was performed. Results from 3 pooled single-arm tisagenlecleucel clinical trials and a provincial pediatric cancer registry were combined to create treatment and control arms, respectively. The population-based control arm consisted of patients meeting clinical trial inclusion and exclusion criteria, starting at second relapse. Multistate and individual-level simulation modeling were combined to predict patient lifetime health trajectories by treatment strategy. Tisagenlecleucel efficacy was modeled across long-term cure rates, from 10% to 40%, to account for limited information on its long-term effectiveness. Uncertainty was tested with 1-way and probabilistic sensitivity analysis. Data were collected in September 2017, and analysis began in December 2017.ExposuresTisagenlecleucel compared with current standard care for tisagenlecleucel-eligible patients.Main outcomes and measuresRelative health care costs, survival gains, and quality-adjusted life-years (QALYs) between tisagenlecleucel and current standard care.ResultsThe treatment and control arms were modeled on 192 and 118 patients, respectively. The mean (SD) age of control individuals was 10 (4.25) years, and the mean (SD) age of the pooled clinical trial sample was 11 (6) years. The control individuals had 78 boys (66%), and the pooled clinical trial sample had 102 boys (53%). Treatment with tisagenlecleucel was associated with an additional 2.14 to 9.85 life years or 1.68 to 6.61 QALYs, compared with current care. The average additional cost of tisagenlecleucel was CaD $470 013 (US $357 031). Accounting for the total discounted cost over the patient lifetime resulted in an incremental cost of CaD $71 000 (US $53 933) to CaD $281 000 (US $213 453) per QALY gain.Conclusions and relevanceTo our knowledge, this study offers the first cost-effectiveness analysis of tisagenlecleucel compared with current standard care for pediatric patients with acute lymphoblastic leukemia using a constructed population-based control arm. At a willingness-to-pay threshold of $150 000/QALY, tisagenlecleucel had a 32% likelihood of being cost-effective. Tisagenlecleucel cost-effectiveness would fall below $50 000/QALY with a long-term cure rate of over 0.40 or a price discount of 49% at its currently known effectiveness.

Project description:BackgroundThe treatment of acute lymphoblastic leukemia (ALL) and osteosarcoma (OSC) is very effective: the vast majority of patients recover and survive for decades. However, they still need to face serious adverse effects of chemotherapy. One of these is cardiotoxicity which may lead to progressive heart failure in the long term. Cardiotoxicity is contributed mainly to the use of anthracyclines and might have genetic risk factors. Our goal was to test the association between left ventricular function and genetic variations of candidate genes.MethodsEchocardiography data from medical records of 622 pediatric ALL and 39 OSC patients were collected from the period 1989-2015. Fractional shortening (FS) and ejection fraction (EF) were determined, 70 single nucleotide polymorphisms (SNPs) in 26 genes were genotyped. Multivariate logistic regression and multi-adjusted general linear model were performed to investigate the influence of genetic polymorphisms on the left ventricular parameters. Bayesian network based Bayesian multilevel analysis of relevance (BN-BMLA) method was applied to test for the potential interaction of the studied cofactors and SNPs.ResultsOur results indicate that variations in ABCC2, CYP3A5, NQO1, SLC22A6 and SLC28A3 genes might influence the left ventricular parameters. CYP3A5 rs4646450 TT was 17% among ALL cases with FS lower than 28, and 3% in ALL patients without pathological FS (p = 5.60E-03; OR = 6.94 (1.76-27.39)). SLC28A3 rs7853758 AA was 12% in ALL cases population, while only 1% among controls (p = 6.50E-03; OR = 11.56 (1.98-67.45)). Patients with ABCC2 rs3740066 GG genotype had lower FS during the acute phase of therapy and 5-10 years after treatment (p = 7.38E-03, p = 7.11E-04, respectively). NQO1 rs1043470 rare T allele was associated with lower left ventricular function in the acute phase and 5-10 years after the diagnosis (p = 4.28E-03 and 5.82E-03, respectively), and SLC22A6 gene rs6591722 AA genotype was associated with lower mean FS (p = 1.71E-03), 5-10 years after the diagnosis.ConclusionsGenetic variants in transporters and metabolic enzymes might modulate the individual risk to cardiac toxicity after chemotherapy.

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Targeting mitochondrial respiration selectively sensitizes pediatric acute lymphoblastic leukemia cell lines and patient samples to standard chemotherapy.

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Targeting mitochondrial respiration selectively sensitizes pediatric acute lymphoblastic leukemia cell lines and patient samples to standard chemotherapy.

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