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2.
J Clin Invest ; 132(22)2022 11 15.
Article in English | MEDLINE | ID: mdl-36377657

ABSTRACT

Pediatric high-grade gliomas (pHGGs) are aggressive diseases with poor outcomes. The diverse molecular heterogeneity in these rare tumors and inadequate tumor models have limited the development of effective therapies. In this issue of the JCI, Haase et al. produced a genetically engineered mouse model of H3.3-G34R-mutant pHGG to help identify vulnerabilities in DNA repair pathways. The authors designed a therapy that combined radiation with DNA damage response inhibitors to induce an adaptive immune response and extend survival. These findings suggest that combinations of small-molecule therapies with immunotherapies could drive a more durable response and improve mortality for patients with pHGG.


Subject(s)
Brain Neoplasms , Glioma , Mice , Animals , Brain Neoplasms/genetics , Brain Neoplasms/therapy , Brain Neoplasms/metabolism , Glioma/genetics , Glioma/therapy , Glioma/metabolism , Immune System/metabolism , Mutation
4.
Clin Cancer Res ; 22(3): 621-32, 2016 Feb 01.
Article in English | MEDLINE | ID: mdl-26080839

ABSTRACT

PURPOSE: The aim of our study is to evaluate the preclinical therapeutic activity and mechanism of action of BEZ235, a dual PI3K/mTOR inhibitor, in combination with dexamethasone in acute lymphoblastic leukemia (ALL). EXPERIMENTAL DESIGN: The cytotoxic effects of BEZ235 and dexamethasone as single agents and in combination were assessed in a panel of ALL cell lines and xenograft models. The underlying mechanism of BEZ235 and dexamethasone was evaluated using immunoblotting, TaqMan RT-PCR, siRNA, immunohistochemistry, and immunoprecipitation. RESULTS: Inhibition of the PI3K/AKT/mTOR pathway with the dual PI3K/mTOR inhibitor BEZ235 enhanced dexamethasone-induced anti-leukemic activity in in vitro (continuous cell lines and primary ALL cultures) and systemic in vivo models of T-ALL (including a patient-derived xenograft). Through inhibition of AKT1, BEZ235 was able to alleviate AKT1-mediated suppression of dexamethasone-induced apoptotic pathways leading to increased expression of the proapoptotic BCL-2 protein BIM. Downregulation of MCL-1 by BEZ235 further contributed to the modulation of dexamethasone resistance by increasing the amount of BIM available to induce apoptosis, especially in PTEN-null T-ALL where inhibition of AKT only partially overcame AKT-induced BIM suppression. CONCLUSIONS: Our data support the further investigation of agents targeting the PI3K/mTOR pathway to modulate glucocorticoid resistance in T-ALL.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis Regulatory Proteins/genetics , Drug Resistance, Neoplasm , Gene Expression Regulation, Neoplastic/drug effects , Imidazoles/pharmacology , Membrane Proteins/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins/genetics , Quinolines/pharmacology , Animals , Apoptosis/drug effects , Apoptosis Regulatory Proteins/metabolism , Bcl-2-Like Protein 11 , Cell Line, Tumor , Cell Survival/drug effects , Dexamethasone/pharmacology , Disease Models, Animal , Drug Synergism , Female , Glucocorticoids/pharmacology , Humans , Membrane Proteins/metabolism , Myeloid Cell Leukemia Sequence 1 Protein/genetics , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Phosphoinositide-3 Kinase Inhibitors , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/mortality , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , TOR Serine-Threonine Kinases/antagonists & inhibitors , Tumor Burden/drug effects , Xenograft Model Antitumor Assays
5.
Clin Cancer Res ; 21(5): 1139-50, 2015 Mar 01.
Article in English | MEDLINE | ID: mdl-25733708

ABSTRACT

PURPOSE: To determine the pharmacokinetics and the antitumor activity in pediatric cancer models of MM-398, a nanoliposomal irinotecan (nal-IRI). EXPERIMENTAL DESIGN: Mouse plasma and tissue pharmacokinetics of nal-IRI and the current clinical formulation of irinotecan were characterized. In vivo activity of irinotecan and nal-IRI was compared in xenograft models (3 each in nu/nu mice) of Ewing's sarcoma family of tumors (EFT), neuroblastoma (NB), and rhabdomyosarcoma (RMS). SLFN11 expression was assessed by Affymetrix HuEx arrays, Taqman RT-PCR, and immunoblotting. RESULTS: Plasma and tumor concentrations of irinotecan and SN-38 (active metabolite) were approximately 10-fold higher for nal-IRI than for irinotecan. Two doses of NAL-IRI (10 mg/kg/dose) achieved complete responses maintained for >100 days in 24 of 27 EFT-xenografted mice. Event-free survival for mice with RMS and NB was significantly shorter than for EFT. High SLFN11 expression has been reported to correlate with sensitivity to DNA damaging agents; median SLFN11 mRNA expression was >100-fold greater in both EFT cell lines and primary tumors compared with NB or RMS cell lines or primary tumors. Cytotoxicity of SN-38 inversely correlated with SLFN11 mRNA expression in 20 EFT cell lines. CONCLUSIONS: In pediatric solid tumor xenografts, nal-IRI demonstrated higher systemic and tumor exposures to SN-38 and improved antitumor activity compared with the current clinical formulation of irinotecan. Clinical studies of nal-IRI in pediatric solid tumors (especially EFT) and correlative studies to determine if SLFN11 expression can serve as a biomarker to predict nal-IRI clinical activity are warranted.


Subject(s)
Antineoplastic Agents/administration & dosage , Camptothecin/analogs & derivatives , Gene Expression , Liposomes , Nuclear Proteins/genetics , Sarcoma, Ewing/genetics , Sarcoma, Ewing/pathology , Sucrose/analogs & derivatives , Animals , Antineoplastic Agents/pharmacokinetics , Camptothecin/administration & dosage , Camptothecin/pharmacokinetics , Cell Line, Tumor , Disease Models, Animal , Drug Combinations , Female , Humans , Irinotecan , Macrophages/immunology , Macrophages/pathology , Mice , Sarcoma, Ewing/drug therapy , Sarcoma, Ewing/mortality , Sucrose/administration & dosage , Sucrose/pharmacokinetics , Tissue Distribution , Tumor Burden/drug effects , Xenograft Model Antitumor Assays
6.
Exp Biol Med (Maywood) ; 239(10): 1390-402, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24951472

ABSTRACT

ABT-737 is a BH3-mimetic that has a wide spectrum of single-agent activity against acute lymphoblastic leukemia (ALL) cell lines and xenografts. Previously, we reported that in response to ABT-737, ABT-737-resistant ALL cell lines showed an apparent increase in Mcl-1 (an anti-apoptotic Bcl-2 family protein that is not effectively inhibited by ABT-737) while ABT-737-sensitive ALL cell lines showed decreased Mcl-1 levels. Here we explored the mechanism of Mcl-1 cleavage by ABT-737 and the effect of adjacent phosphorylation sites on Mcl-1 cleavage and apoptosis induced by ABT-737 in a human B-lineage ALL cell line. Caspase cleavage sites in Mcl-1 and the effect of mutation in Mcl-1 phosphorylation sites were determined by transducing Mcl-1 variants tagged with the V5 epitope into human ALL cells. Cytotoxicity was by fluorescence-based DIMSCAN, and changes in protein by immunoblotting. ABT-737 induced a caspase-dependent cleavage of Mcl-1. Of the two Mcl-1 caspase cleavage sites (D127 and D157), D157 was the site of ABT-737-induced cleavage in ALL cells. Cells with exogenously expressed Mcl-1 Δ157 fragment showed greater caspase-3 and caspase-9 activation when they were treated with ABT-737 compared with cells expressing wild-type or D157A mutant Mcl-1. Cells with mutated phosphorylation sites on Mcl-1 (S159A and T163A) were less susceptible to Mcl-1 cleavage and apoptosis induced by ABT-737. Our data showed that Mcl-1 is post-translationally regulated in response to ABT-737 treatment, primarily via a caspase-dependent cleavage that generates a pro-apoptotic Mcl-1 fragment.


Subject(s)
Apoptosis , B-Lymphocytes/drug effects , B-Lymphocytes/physiology , Biphenyl Compounds/toxicity , Caspases/metabolism , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Nitrophenols/toxicity , Sulfonamides/toxicity , Cell Line, Tumor , Cytological Techniques , Humans , Hydrolysis , Immunoblotting , Phosphorylation , Piperazines/toxicity
7.
Leuk Res ; 36(3): 342-9, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22137317

ABSTRACT

Activation of the mTOR pathway subsequent to phosphatase and tensin homolog (PTEN) mutation may be associated with glucocorticoid (GC) resistance in acute lymphoblastic leukemia (ALL). The combination activity of rapamycin and dexamethasone in cell lines and xenograft models of ALL was determined. Compared with either drug alone, dexamethasone+rapamycin showed significantly greater apoptosis and cell cycle arrest in some cell lines, and was more frequently seen in T-lineage cell lines with PTEN mutation. The combination significantly extended the event-free survival of mice carrying PTEN mutated xenografts. Our data suggest that PI3K/mTOR pathway inhibitors could benefit patients with PTEN mutated T-ALL.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Animals , Blotting, Western , Cell Line, Tumor , Dexamethasone/administration & dosage , Drug Synergism , Enzyme-Linked Immunosorbent Assay , Female , Flow Cytometry , Humans , In Vitro Techniques , Membrane Potential, Mitochondrial/drug effects , Mice , Mice, Inbred NOD , Mice, SCID , Mutation/genetics , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Sirolimus/administration & dosage , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism
8.
Br J Haematol ; 145(3): 389-93, 2009 May.
Article in English | MEDLINE | ID: mdl-19298590

ABSTRACT

Due to the development of neurological toxicity and resistance to methotrexate (MTX), other antifolates have been evaluated for its potential replacement in the treatment of childhood acute lymphoblastic leukaemia (ALL). Aminopterin (AMT) has been suggested to provide clinical advantages over MTX and other antifolates. AMT activity, compared with MTX, was evaluated in ALL and lymphoma preclinical models. The minimum survival fraction at the range of concentrations tested was lower with AMT than with MTX in 3 out of 15 cell lines. Both AMT and MTX significantly extended the event-free survival of mice bearing 3 out of 4 xenografts with equivalent activity.


Subject(s)
Aminopterin/therapeutic use , Folic Acid Antagonists/therapeutic use , Lymphoma/drug therapy , Methotrexate/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Aminopterin/adverse effects , Animals , Cell Line, Tumor , Dose-Response Relationship, Drug , Female , Folic Acid Antagonists/adverse effects , Humans , Inhibitory Concentration 50 , Methotrexate/adverse effects , Mice , Mice, SCID , Recurrence , Regression Analysis , Xenograft Model Antitumor Assays
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