Publications by authors named "Xiao-Nan Li"

115 Publications

CRISPR editing of the GLI1 first intron abrogates GLI1 expression and differentially alters lineage commitment.

Stem Cells 2021 May 22;39(5):564-580. Epub 2021 Feb 22.

Developmental Biology Program, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.

GLI1 is one of three GLI family transcription factors that mediate Sonic Hedgehog signaling, which plays a role in development and cell differentiation. GLI1 forms a positive feedback loop with GLI2 and likely with itself. To determine the impact of GLI1 and its intronic regulatory locus on this transcriptional loop and human stem cell differentiation, we deleted the region containing six GLI binding sites in the human GLI1 intron using CRISPR/Cas9 editing to produce H1 human embryonic stem cell (hESC) GLI1-edited clones. Editing out this intronic region, without removing the entire GLI1 gene, allowed us to study the effects of this highly complex region, which binds transcription factors in a variety of cells. The roles of GLI1 in human ESC differentiation were investigated by comparing RNA sequencing, quantitative-real time PCR (q-rtPCR), and functional assays. Editing this region resulted in GLI1 transcriptional knockdown, delayed neural commitment, and inhibition of endodermal and mesodermal differentiation during spontaneous and directed differentiation experiments. We found a delay in the onset of early osteogenic markers, a reduction in the hematopoietic potential to form granulocyte units, and a decrease in cancer-related gene expression. Furthermore, inhibition of GLI1 via antagonist GANT-61 had similar in vitro effects. These results indicate that the GLI1 intronic region is critical for the feedback loop and that GLI1 has lineage-specific effects on hESC differentiation. Our work is the first study to document the extent of GLI1 abrogation on early stages of human development and to show that GLI1 transcription can be altered in a therapeutically useful way.
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http://dx.doi.org/10.1002/stem.3341DOI Listing
May 2021

REST promotes ETS1-dependent vascular growth in medulloblastoma.

Mol Oncol 2021 May 7;15(5):1486-1506. Epub 2021 Feb 7.

Department of Pediatrics, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.

Expression of the RE1-silencing transcription factor (REST), a master regulator of neurogenesis, is elevated in medulloblastoma (MB) tumors. A cell-intrinsic function for REST in MB tumorigenesis is known. However, a role for REST in the regulation of MB tumor microenvironment has not been investigated. Here, we implicate REST in remodeling of the MB vasculature and describe underlying mechanisms. Using REST mice, we demonstrate that elevated REST expression in cerebellar granule cell progenitors, the cells of origin of sonic hedgehog (SHH) MBs, increased vascular growth. This was recapitulated in MB xenograft models and validated by transcriptomic analyses of human MB samples. REST upregulation was associated with enhanced secretion of proangiogenic factors. Surprisingly, a REST-dependent increase in the expression of the proangiogenic transcription factor E26 oncogene homolog 1, and its target gene encoding the vascular endothelial growth factor receptor-1, was observed in MB cells, which coincided with their localization at the tumor vasculature. These observations were confirmed by RNA-Seq and microarray analyses of MB cells and SHH-MB tumors. Thus, our data suggest that REST elevation promotes vascular growth by autocrine and paracrine mechanisms.
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http://dx.doi.org/10.1002/1878-0261.12903DOI Listing
May 2021

Corrigendum to "Impact of SCID mouse gender on tumorigenicity, xenograft growth and drug-response in a large panel of orthotopic PDX models of pediatric brain tumors" [Cancer Lett. 493 (2020) 197-206].

Cancer Lett 2021 Mar 23;500:294. Epub 2020 Dec 23.

Pre-clinical Neuro-oncology Research Program, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, 77030, USA; Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, 77030, USA. Electronic address:

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http://dx.doi.org/10.1016/j.canlet.2020.12.007DOI Listing
March 2021

LiBis: an ultrasensitive alignment augmentation for low-input bisulfite sequencing.

Brief Bioinform 2020 Dec 15. Epub 2020 Dec 15.

Texas A&M University College of Medicine.

The cell-free DNA (cfDNA) methylation profile in liquid biopsy has been utilized to diagnose early-stage disease and estimate therapy response. However, typical clinical procedures are capable of purifying only very small amounts of cfDNA. Whole-genome bisulfite sequencing (WGBS) is the gold standard for measuring DNA methylation; however, WGBS using small amounts of fragmented DNA introduces a critical challenge for data analysis, namely a low-mapping ratio. The resulting low sequencing depth and low coverage of CpG sites genome-wide is a bottleneck for the clinical application of cfDNA-based WGBS assays. We developed LiBis (Low-input Bisulfite Sequencing), a novel method for low-input WGBS data alignment. By dynamically clipping initially unmapped reads and remapping clipped fragments, we judiciously rescued those reads and uniquely aligned them to the genome. By substantially increasing the mapping ratio by up to 88%, LiBis dramatically improved the number of informative CpGs and the precision in quantifying the methylation status of individual CpG sites. LiBis significantly improved the cost efficiency of low-input WGBS experiments by dynamically removing contamination introduced by random priming. The high sensitivity and cost effectiveness afforded by LiBis for low-input samples will allow the discovery of genetic and epigenetic features suitable for downstream analysis and biomarker identification using liquid biopsy.
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http://dx.doi.org/10.1093/bib/bbaa332DOI Listing
December 2020

Correction to: C11orf95-RELA reprograms 3D epigenome in supratentorial ependymoma.

Acta Neuropathol 2020 Dec;140(6):961-962

The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.

In the original publication, Fig. 1 was incorrectly published with same two histograms at the bottom.
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http://dx.doi.org/10.1007/s00401-020-02240-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852849PMC
December 2020

Reliable tumor detection by whole-genome methylation sequencing of cell-free DNA in cerebrospinal fluid of pediatric medulloblastoma.

Sci Adv 2020 Oct 16;6(42). Epub 2020 Oct 16.

Center for Epigenetics and Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA.

Medulloblastoma (MB), the most common form of pediatric brain malignancy, has a low frequency of oncogenic mutations but pronouncedly abnormal DNA methylation changes. Epigenetic analysis of circulating cell-free tumor DNA (ctDNA) by liquid biopsy offers an approach for real-time monitoring of tumor status without tumor dissection. In this study, we identified 6598 differentially methylated CpGs in both MB tumors and the ctDNA isolated from matched cerebrospinal fluid (CSF) compared with normal cerebellum, which could be used to detect MB tumor occurrence and determine its subtype. Furthermore, DNA methylation changes in serial CSF samples could be used to monitor the treatment response and tumor recurrence. Integrating our data with large public datasets, we identified reliable MB DNA methylation signatures in ctDNA that have potential diagnostic and prognostic values. Our study sets the stage for exploiting epigenetic markers in CSF to improve the clinical management of patients with MB.
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http://dx.doi.org/10.1126/sciadv.abb5427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567591PMC
October 2020

[An assessment of white matter development in preterm infants with bronchopulmonary dysplasia using diffusion tensor imaging].

Zhongguo Dang Dai Er Ke Za Zhi 2020 Oct;22(10):1079-1084

Department of Neonatology, Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.

Objective: To assess white matter development in preterm infants with bronchopulmonary dysplasia (BPD) using fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values of diffusion tensor imaging (DTI).

Methods: Ninety-six infants with a gestational age of ≤32 weeks and a birth weight of <1 500 g who were admitted to the neonatal intensive care unit within 24 hours after birth from August 2016 to April 2019 and underwent head MRI and DTI before discharge were enrolled. According to the discharge diagnosis, they were divided into BPD group with 48 infants and non-BPD group with 48 infants. The two groups were compared in terms of FA and ADC values of the same regions of interest on DTI image.

Results: There were no significant differences in the incidence rates of periventricular/intraventricular hemorrhage, periventricular leukomalacia, and punctate white matter lesions between the two groups (P>0.05). Compared with the non-BPD group, the BPD group had significantly lower FA values and significantly higher ADC values of the posterior limb of the internal capsule, the splenium of the corpus callosum, the occipital white matter, the cerebellum, and the cerebral peduncle (P<0.05). Compared with the non-BPD group, the BPD group had a significantly higher frequency of apnea, a significantly higher proportion of infants with pneumonia or mechanical ventilation, and a significantly longer duration of assisted ventilation (P<0.05).

Conclusions: BPD may has potential adverse effects to white matter development in preterm infants, leading to delayed white matter development. Therefore, it is necessary to pay attention to the neurological function of these infants.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568998PMC
October 2020

Functional Precision Medicine Identifies New Therapeutic Candidates for Medulloblastoma.

Cancer Res 2020 12 12;80(23):5393-5407. Epub 2020 Oct 12.

Rady Children's Institute for Genomic Medicine, San Diego, California.

Medulloblastoma is among the most common malignant brain tumors in children. Recent studies have identified at least four subgroups of the disease that differ in terms of molecular characteristics and patient outcomes. Despite this heterogeneity, most patients with medulloblastoma receive similar therapies, including surgery, radiation, and intensive chemotherapy. Although these treatments prolong survival, many patients still die from the disease and survivors suffer severe long-term side effects from therapy. We hypothesize that each patient with medulloblastoma is sensitive to different therapies and that tailoring therapy based on the molecular and cellular characteristics of patients' tumors will improve outcomes. To test this, we assembled a panel of orthotopic patient-derived xenografts (PDX) and subjected them to DNA sequencing, gene expression profiling, and high-throughput drug screening. Analysis of DNA sequencing revealed that most medulloblastomas do not have actionable mutations that point to effective therapies. In contrast, gene expression and drug response data provided valuable information about potential therapies for every tumor. For example, drug screening demonstrated that actinomycin D, which is used for treatment of sarcoma but rarely for medulloblastoma, was active against PDXs representing Group 3 medulloblastoma, the most aggressive form of the disease. Functional analysis of tumor cells was successfully used in a clinical setting to identify more treatment options than sequencing alone. These studies suggest that it should be possible to move away from a one-size-fits-all approach and begin to treat each patient with therapies that are effective against their specific tumor. SIGNIFICANCE: These findings show that high-throughput drug screening identifies therapies for medulloblastoma that cannot be predicted by genomic or transcriptomic analysis.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718387PMC
December 2020

Tanshinone IIA prevents LPS-induced inflammatory responses in mice via inactivation of succinate dehydrogenase in macrophages.

Acta Pharmacol Sin 2020 Oct 7. Epub 2020 Oct 7.

School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.

Metabolic reprogramming is associated with NLRP3 inflammasome activation in activated macrophages, contributing to inflammatory responses. Tanshinone IIA (Tan-IIA) is a major constituent from Salvia miltiorrhiza Bunge, which exhibits anti-inflammatory activity. In this study, we investigated the effects of Tan-IIA on inflammation in macrophages in focus on its regulation of metabolism and redox state. In lipopolysaccharides (LPS)-stimulated mouse bone marrow-derived macrophages (BMDMs), Tan-IIA (10 μM) significantly decreased succinate-boosted IL-1β and IL-6 production, accompanied by upregulation of IL-1RA and IL-10 release via inhibiting succinate dehydrogenase (SDH). Tan-IIA concentration dependently inhibited SDH activity with an estimated IC of 4.47 μM in LPS-activated BMDMs. Tan-IIA decreased succinate accumulation, suppressed mitochondrial reactive oxygen species production, thus preventing hypoxia-inducible factor-1α (HIF-1α) induction. Consequently, Tan-IIA reduced glycolysis and protected the activity of Sirtuin2 (Sirt2), an NAD-dependent protein deacetylase, by raising the ratio of NAD/NADH in activated macrophages. The acetylation of α-tubulin was required for the assembly of NLRP3 inflammasome; Tan-IIA increased the binding of Sirt2 to α-tubulin, and thus reduced the acetylation of α-tubulin, thus impairing this process. Sirt2 knockdown or application of Sirt2 inhibitor AGK-2 (10 μM) neutralized the effects of Tan-IIA, suggesting that Tan-IIA inactivated NLRP3 inflammasome in a manner dependent on Sirt2 regulation. The anti-inflammatory effects of Tan-IIA were observed in mice subjected to LPS challenge: pre-administration of Tan-IIA (20 mg/kg, ip) significantly attenuated LPS-induced acute inflammatory responses, characterized by elevated IL-1β but reduced IL-10 levels in serum. The peritoneal macrophages isolated from the mice displayed similar metabolic regulation. In conclusion, Tan-IIA reduces HIF-1α induction via SDH inactivation, and preserves Sirt2 activity via downregulation of glycolysis, contributing to suppression of NLRP3 inflammasome activation. This study provides a new insight into the anti-inflammatory action of Tan-IIA from the respect of metabolic and redox regulation.
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http://dx.doi.org/10.1038/s41401-020-00535-xDOI Listing
October 2020

C11orf95-RELA reprograms 3D epigenome in supratentorial ependymoma.

Acta Neuropathol 2020 12 9;140(6):951-960. Epub 2020 Sep 9.

The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.

Supratentorial ependymoma (ST-EPN) is a type of malignant brain tumor mainly seen in children. Since 2014, it has been known that an intrachromosomal fusion C11orf95-RELA is an oncogenic driver in ST-EPN [Parker et al. Nature 506:451-455 (2014); Pietsch et al. Acta Neuropathol 127:609-611 (2014)] but the molecular mechanisms of oncogenesis are unclear. Here we show that the C11orf95 component of the fusion protein dictates DNA binding activity while the RELA component is required for driving the expression of ependymoma-associated genes. Epigenomic characterizations using ChIP-seq and HiChIP approaches reveal that C11orf95-RELA modulates chromatin states and mediates chromatin interactions, leading to transcriptional reprogramming in ependymoma cells. Our findings provide important characterization of the molecular underpinning of C11orf95-RELA fusion and shed light on potential therapeutic targets for C11orf95-RELA subtype ependymoma.
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http://dx.doi.org/10.1007/s00401-020-02225-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666583PMC
December 2020

Impact of SCID mouse gender on tumorigenicity, xenograft growth and drug-response in a large panel of orthotopic PDX models of pediatric brain tumors.

Cancer Lett 2020 11 3;493:197-206. Epub 2020 Sep 3.

Pre-clinical Neuro-oncology Research Program, Houston, TX, 77030, USA; Texas Children's Cancer Center, Houston, TX, 77030, USA. Electronic address:

Brain tumor is the leading cause of cancer related death in children. Clinically relevant animals are critical for new therapy development. To address the potential impact of animal gender on tumorigenicity rate, xenograft growth and in vivo drug responses, we retrospectively analyzed 99 of our established patient derived orthotopic xenograft mouse models (orthotopic PDX or PDOX). From 27 patient tumors, including 5 glioblastomas (GBMs), 11 medulloblastomas (MBs), 4 ependymomas (EPNs), 4 atypical teratoid/rhabdoid tumors (ATRTs) and 3 diffuse intrinsic pontine gliomas (DIPGs), that were directly implanted into matching locations in the brains of approximately equal numbers of male and female animals (n = 310) in age-matched (within 2-week age-difference) SCID mice, the tumor formation rate was 50.6 ± 21.5% in male and 52.7 ± 23.5% in female mice with animal survival times of 192.6 ± 31.7 days in male and 173.9 ± 34.5 days in female mice (P = 0.46) regardless of pathological diagnosis. Once established, PDOX tumors were serially subtransplanted for up to VII passage. Analysis of 1,595 mice from 59 PDOX models (18 GBMs, 18 MBs, 5 ATRTs, 6 EPNs, 7 DIPGs and 5 PENTs) during passage II and VII revealed similar tumor take rates of the 6 different tumor types between male (85.4 ± 15.5%) and female mice (84.7 ± 15.2%) (P = 0.74), and animal survival times were 96.7 ± 23.3 days in male mice and 99.7 ± 20 days in female (P = 0.25). A total of 284 mice from 7 GBM, 2 MB, 1 ATRT, 1 EPN, 2 DIPG and 1 PNET were treated with a series of standard and investigational drugs/compounds. The overall survival times were 106.9 ± 25.7 days in male mice, and 110.9 ± 31.8 days in female mice (P = 0.41), similar results were observed when different types/models were analyzed separately. In conclusion, our data demonstrated that the gender of SCID mice did not have a major impact on animal model development nor drug responses in vivo, and SCID mice of both genders are appropriate for use.
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http://dx.doi.org/10.1016/j.canlet.2020.08.035DOI Listing
November 2020

Patient-Derived Orthotopic Xenograft (PDOX) Mouse Models of Primary and Recurrent Meningioma.

Cancers (Basel) 2020 Jun 5;12(6). Epub 2020 Jun 5.

Jan and Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.

Background: Meningiomas constitute one-third of all primary brain tumors. Although typically benign, about 20% of these tumors recur despite surgery and radiation, and may ultimately prove fatal. There are currently no effective chemotherapies for meningioma. We, therefore, set out to develop patient-derived orthotopic xenograft (PDOX) mouse models of human meningioma using tumor.

Method: Of nine patients, four had World Health Organization (WHO) grade I tumors, five had WHO grade II tumors, and in this second group two patients also had recurrent (WHO grade III) meningioma. We also classified the tumors according to our recently developed molecular classification system (Types A, B, and C, with C being the most aggressive). We transplanted all 11 surgical samples into the skull base of immunodeficient (SCID) mice. Only the primary and recurrent tumor cells from one patient-both molecular Type C, despite being WHO grades II and III, respectively-led to the formation of meningioma in the resulting mouse models. We characterized the xenografts by histopathology and RNA-seq and compared them with the original tumors. We performed an in vitro drug screen using 60 anti-cancer drugs followed by in vivo validation.

Results: The PDOX models established from the primary and recurrent tumors from patient K29 (K29P-PDOX and K29R-PDOX, respectively) replicated the histopathology and key gene expression profiles of the original samples. Although these xenografts could not be subtransplanted, the cryopreserved primary tumor cells were able to reliably generate PDOX tumors. Drug screening in K29P and K29R tumor cell lines revealed eight compounds that were active on both tumors, including three histone deacetylase (HDAC) inhibitors. We tested the HDAC inhibitor Panobinostat in K29R-PDOX mice, and it significantly prolonged mouse survival ( < 0.05) by inducing histone H3 acetylation and apoptosis.

Conclusion: Meningiomas are not very amenable to PDOX modeling, for reasons that remain unclear. Yet at least some of the most malignant tumors can be modeled, and cryopreserved primary tumor cells can create large panels of tumors that can be used for preclinical drug testing.
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http://dx.doi.org/10.3390/cancers12061478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352400PMC
June 2020

Tumor necrosis factor overcomes immune evasion in p53-mutant medulloblastoma.

Nat Neurosci 2020 07 18;23(7):842-853. Epub 2020 May 18.

Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.

Many immunotherapies act by enhancing the ability of cytotoxic T cells to kill tumor cells. Killing depends on T cell recognition of antigens presented by class I major histocompatibility complex (MHC-I) proteins on tumor cells. In this study, we showed that medulloblastomas lacking the p53 tumor suppressor do not express surface MHC-I and are therefore resistant to immune rejection. Mechanistically, this is because p53 regulates expression of the peptide transporter Tap1 and the aminopeptidase Erap1, which are required for MHC-I trafficking to the cell surface. In vitro, tumor necrosis factor (TNF) or lymphotoxin-β receptor agonist can rescue expression of Erap1, Tap1 and MHC-I on p53-mutant tumor cells. In vivo, low doses of TNF prolong survival and synergize with immune checkpoint inhibitors to promote tumor rejection. These studies identified p53 as a key regulator of immune evasion and suggest that TNF could be used to enhance sensitivity of tumors to immunotherapy.
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http://dx.doi.org/10.1038/s41593-020-0628-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456619PMC
July 2020

A novel viologen-based coordination polymer with multi-stimuli responsive chromic properties: photochromism, thermochromism, chemochromism and electrochromism.

Dalton Trans 2020 Mar 25;49(10):3228-3233. Epub 2020 Feb 25.

Institute of Polyoxometalate Chemistry, Department of Chemistry, Northeast Normal University, Changchun, Jilin 130024, PR China.

Increasing interest in chromic materials is due to the growing demand. However, most chromic materials exhibit color changes in response to only one stimulus, but there are multiple stimuli in nature. Therefore, the construction of multistimuli responsive chromic materials still faces great challenges. Herein, a new multi-stimuli responsive coordination polymer [Zn(2,3-PDC)CV·(HO)]·HO (1) (2,3-PDC = 2,3-pyridine dicarboxylic acid, CV = N,N'-4,4'-bipyridiniodipropionate) has been successfully synthesized, which exhibits photochromism under 300 W xenon lamp irradiation accompanied by an obvious color change from colorless to light blue. Meanwhile, compound 1 displays excellent thermochromic properties with a color change from colorless to light yellow when heated at 106 °C. The product of thermochromism is named 1T and the loss of free water improves the photoresponsive properties of 1T. Moreover, the compound can show differentiable detection of amines because of the electron-deficient nature of the viologen. Finally, 1 shows excellent electrochromic properties and turns from colorless to purple at E = -3 V. In conclusion, compound 1 exhibits multi-chromic behaviors in response to light, heat, amines and electricity, which are prominent in viologen based coordination polymers.
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http://dx.doi.org/10.1039/c9dt04699bDOI Listing
March 2020

A phase I/II study of veliparib (ABT-888) with radiation and temozolomide in newly diagnosed diffuse pontine glioma: a Pediatric Brain Tumor Consortium study.

Neuro Oncol 2020 06;22(6):875-885

Cincinnati Children's Hospital, Cincinnati, Ohio.

Background: A Pediatric Brain Tumor Consortium (PBTC) phase I/II trial of veliparib and radiation followed by veliparib and temozolomide (TMZ) was conducted in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). The objectives were to: (i) estimate the recommended phase II dose (RP2D) of veliparib with concurrent radiation; (ii) evaluate the pharmacokinetic parameters of veliparib during radiation; (iii) evaluate feasibility of intrapatient TMZ dose escalation; (iv) describe toxicities of protocol therapy; and (v) estimate the overall survival distribution compared with historical series.

Methods: Veliparib was given Monday through Friday b.i.d. during radiation followed by a 4-week rest. Patients then received veliparib at 25 mg/m2 b.i.d. and TMZ 135 mg/m2 daily for 5 days every 28 days. Intrapatient dose escalation of TMZ was investigated for patients experiencing minimal toxicity.

Results: Sixty-six patients (65 eligible) were enrolled. The RP2D of veliparib was 65 mg/m2 b.i.d. with radiation. Dose-limiting toxicities during radiation with veliparib therapy included: grade 2 intratumoral hemorrhage (n = 1), grade 3 maculopapular rash (n = 2), and grade 3 nervous system disorder (generalized neurologic deterioration) (n = 1). Intrapatient TMZ dose escalation during maintenance was not tolerated. Following a planned interim analysis, it was concluded that this treatment did not show a survival benefit compared with PBTC historical controls, and accrual was stopped for futility. The 1- and 2-year overall survival rates were 37.2% (SE 7%) and 5.3% (SE 3%), respectively.

Conclusion: Addition of veliparib to radiation followed by TMZ and veliparib was tolerated but did not improve survival for patients with newly diagnosed DIPG.

Trial Registration: NCT01514201.
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http://dx.doi.org/10.1093/neuonc/noaa016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283021PMC
June 2020

Astrocytic trans-Differentiation Completes a Multicellular Paracrine Feedback Loop Required for Medulloblastoma Tumor Growth.

Cell 2020 02 23;180(3):502-520.e19. Epub 2020 Jan 23.

Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA. Electronic address:

The tumor microenvironment (TME) is critical for tumor progression. However, the establishment and function of the TME remain obscure because of its complex cellular composition. Using a mouse genetic system called mosaic analysis with double markers (MADMs), we delineated TME evolution at single-cell resolution in sonic hedgehog (SHH)-activated medulloblastomas that originate from unipotent granule neuron progenitors in the brain. First, we found that astrocytes within the TME (TuAstrocytes) were trans-differentiated from tumor granule neuron precursors (GNPs), which normally never differentiate into astrocytes. Second, we identified that TME-derived IGF1 promotes tumor progression. Third, we uncovered that insulin-like growth factor 1 (IGF1) is produced by tumor-associated microglia in response to interleukin-4 (IL-4) stimulation. Finally, we found that IL-4 is secreted by TuAstrocytes. Collectively, our studies reveal an evolutionary process that produces a multi-lateral network within the TME of medulloblastoma: a fraction of tumor cells trans-differentiate into TuAstrocytes, which, in turn, produce IL-4 that stimulates microglia to produce IGF1 to promote tumor progression.
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http://dx.doi.org/10.1016/j.cell.2019.12.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259679PMC
February 2020

Mislocalized cytoplasmic p27 activates PAK1-mediated metastasis and is a prognostic factor in osteosarcoma.

Mol Oncol 2020 04 14;14(4):846-864. Epub 2020 Feb 14.

Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.

The development of pulmonary metastasis is the leading cause of death in osteosarcoma (OS), which is the most common malignant bone tumor in children. We have previously reported that the tumor suppressor p27 (KIP1, CDKN1B) is frequently mislocalized to the cytoplasm of OS. However, its prognostic significance and metastatic mechanism are still elusive. Here, we show that cytoplasmic p27 significantly correlated with a higher metastatic status and poorer survival of OS patients (n = 136, P < 0.05), highlighting the clinical significance of p27 mislocalization in OS. Mechanistically, cytoplasmic p27 is co-immunoprecipitated with p21-activated kinase 1 (PAK1), which resulted in higher PAK1 phosphorylations, actin polymerization, and cell motility in p27-mislocalized OS cells. Silencing PAK1 expression in different p27-mislocalized OS cell lines decreased the migratory and adhesion abilities in vitro, as well as the development of pulmonary metastases in vivo. Similar PAK1-dependent motility was also observed in other p27-mislocalized cancer cell lines. In summary, our study suggests that cytoplasmic p27-mediated PAK1 activation is crucial for OS metastasis. A biomarker-guided targeted therapeutic approach for metastatic OS and other cancers harboring p27 mislocalization can be developed, where cytoplasmic p27 is used for risk stratification and PAK1 can be exploited as a potential therapeutic target.
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http://dx.doi.org/10.1002/1878-0261.12624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138393PMC
April 2020

Polyoxometalate-viologen photochromic hybrids for rapid solar ultraviolet light detection, photoluminescence-based UV probing and inkless and erasable printing.

Dalton Trans 2020 Jan 9;49(1):89-94. Epub 2019 Dec 9.

Institute of Polyoxometalate Chemistry, Department of Chemistry, Northeast Normal University, Changchun, Jilin 130024, PR China.

In this work, a new crystalline polyoxometalate-viologen hybrid, (Pbpy)(MeNH)[PWZnO] (1: Pbpy = 1,1'-[1,4-phenylenebis-(methylene)]bis(4,4'-bipyridinium)), has been synthesized. It showed efficient ultraviolet light detection ability with an obvious colour change from pale yellow to blue and fast response with ultraviolet intensity as low as 0.006 mW cm in narrow-band UV regions. The POM-viologen-based film of 1 has also been readily prepared on quartz substrates using a drop casting method and could exhibit different levels of colour changes under sunlight irradiation at different local times on a sunny day, indicating its potential to be used as a portable device for solar ultraviolet light detection. Ultraviolet light detection is not only reflected in colour changes, but also accompanies the photoluminescence phenomenon. The fluorescence intensity decreased with the increase of UV intensity, and when irradiated with an ultraviolet xenon lamp (8 mW cm) for about 5 min, the fluorescence intensity was almost completely quenched. The compound has the potential to achieve fluorescence based UV probing. The powdered sample of compound 1 could also be deposited in paper simply by coating it with a solution of ethanol. The paper can be used as an inkless and erasable print medium, which was found to remain clear for 11 d in the dark under an ambient atmosphere and was also reusable when erased.
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http://dx.doi.org/10.1039/c9dt04116hDOI Listing
January 2020

The molecular landscape of ETMR at diagnosis and relapse.

Nature 2019 12 4;576(7786):274-280. Epub 2019 Dec 4.

Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.

Embryonal tumours with multilayered rosettes (ETMRs) are aggressive paediatric embryonal brain tumours with a universally poor prognosis. Here we collected 193 primary ETMRs and 23 matched relapse samples to investigate the genomic landscape of this distinct tumour type. We found that patients with tumours in which the proposed driver C19MC was not amplified frequently had germline mutations in DICER1 or other microRNA-related aberrations such as somatic amplification of miR-17-92 (also known as MIR17HG). Whole-genome sequencing revealed that tumours had an overall low recurrence of single-nucleotide variants (SNVs), but showed prevalent genomic instability caused by widespread occurrence of R-loop structures. We show that R-loop-associated chromosomal instability can be induced by the loss of DICER1 function. Comparison of primary tumours and matched relapse samples showed a strong conservation of structural variants, but low conservation of SNVs. Moreover, many newly acquired SNVs are associated with a mutational signature related to cisplatin treatment. Finally, we show that targeting R-loops with topoisomerase and PARP inhibitors might be an effective treatment strategy for this deadly disease.
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http://dx.doi.org/10.1038/s41586-019-1815-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6908757PMC
December 2019

[Risk factors for poor prognosis of neonatal bacterial meningitis].

Zhongguo Dang Dai Er Ke Za Zhi 2019 Nov;21(11):1064-1068

Department of Neonatology, Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.

Objective: To investigate the risk factors for poor prognosis of neonatal bacterial meningitis.

Methods: A retrospective analysis was performed for the clinical data of 152 children with neonatal bacterial meningitis. According to their prognosis, they were divided into a good prognosis group with 122 children and a poor prognosis group with 30 children. The two groups were compared in terms of general status, initial symptoms, and laboratory findings, and the risk factors for poor prognosis were analyzed.

Results: Compared with the good prognosis group, the poor prognosis group had a significantly higher proportion of children with a very low birth weight, a peripheral blood white blood cell count (WBC) of <5×10/L or >20×10/L, a C-reactive protein level of >50 mg/L, a cerebrospinal fluid (CSF) WBC of >500×10/L, a CSF glucose level of <1 mmol/L, or a CSF protein level of >2 g/L, as well as significantly higher positive rates of blood culture and/or CSF culture, Gram-positive bacteria, and Streptococcus agalactiae (P<0.05). The multivariate logistic regression analysis showed that a CSF glucose level of <1 mmol/L and a CSF protein level of >2 g/L were independent risk factors for poor prognosis of neonatal bacterial meningitis.

Conclusions: A CSF glucose level of <1 mmol/L and a CSF protein level of >2 g/L are risk factors for poor prognosis of neonatal bacterial meningitis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7389301PMC
November 2019

Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design.

Cell Rep 2019 11;29(6):1675-1689.e9

Preclinical Neurooncology Research Program, Texas Children's Cancer Research Center, Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer.
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http://dx.doi.org/10.1016/j.celrep.2019.09.071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880934PMC
November 2019

Resolving medulloblastoma cellular architecture by single-cell genomics.

Nature 2019 08 24;572(7767):74-79. Epub 2019 Jul 24.

Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Research Discovery Institute, La Jolla, CA, USA.

Medulloblastoma is a malignant childhood cerebellar tumour type that comprises distinct molecular subgroups. Whereas genomic characteristics of these subgroups are well defined, the extent to which cellular diversity underlies their divergent biology and clinical behaviour remains largely unexplored. Here we used single-cell transcriptomics to investigate intra- and intertumoral heterogeneity in 25 medulloblastomas spanning all molecular subgroups. WNT, SHH and Group 3 tumours comprised subgroup-specific undifferentiated and differentiated neuronal-like malignant populations, whereas Group 4 tumours consisted exclusively of differentiated neuronal-like neoplastic cells. SHH tumours closely resembled granule neurons of varying differentiation states that correlated with patient age. Group 3 and Group 4 tumours exhibited a developmental trajectory from primitive progenitor-like to more mature neuronal-like cells, the relative proportions of which distinguished these subgroups. Cross-species transcriptomics defined distinct glutamatergic populations as putative cells-of-origin for SHH and Group 4 subtypes. Collectively, these data provide insights into the cellular and developmental states underlying subtype-specific medulloblastoma biology.
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http://dx.doi.org/10.1038/s41586-019-1434-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754173PMC
August 2019

A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor.

Cancer Cell 2019 07;36(1):51-67.e7

Children's Brain Tumor Research Centre, Queen's Medical Centre University of Nottingham, Nottingham NG72UH, UK.

Embryonal tumors with multilayered rosettes (ETMRs) are highly lethal infant brain cancers with characteristic amplification of Chr19q13.41 miRNA cluster (C19MC) and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogenic mechanisms and discovered a C19MC-LIN28A-MYCN circuit fueled by multiple complex regulatory loops including an MYCN core transcriptional network and super-enhancers resulting from long-range MYCN DNA interactions and C19MC gene fusions. Our data show that this powerful oncogenic circuit, which entraps an early neural lineage network, is potently abrogated by bromodomain inhibitor JQ1, leading to ETMR cell death.
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http://dx.doi.org/10.1016/j.ccell.2019.06.002DOI Listing
July 2019

Reunderstanding the photoinduced charge transfer process of ammonium polyoxomolybdate.

Dalton Trans 2019 Jul;48(28):10683-10688

Institute of Polyoxometalate Chemistry, Department of Chemistry, Northeast Normal University, Changchun, Jilin 130024, PR China.

Photoinduced charge transfer (PCT) reactions account for the rich photochromic and photocatalytic properties of polyoxometalates (POMs). Yamase proposed a hypothesis that photoinduced O→Mo(vi) charge transfer reactions of ammonium polyoxomolybdate correlate with a proton transfer process from the ammonium cation to the polyoxomolybdate anion. Many subsequent experimental studies adopted this hypothesis to explain the photochromic phenomena of ammonium polyoxomolybdate. This research attempts to verify the appropriateness of this hypothesis experimentally. Firstly, studies on two adducts of 4-phenylpyridine (4pp) and carboxylic acids revealed that only protonation of 4pp can enable charge transfer from the carboxyl group to 4pp to achieve photochromism. Then, a new ammonium polyoxomolybdate [H(4pp)]4Mo8O26·2(4pp) was synthesized using the protonated 4pp as an indicator for proton transfer. IR analysis and the above control experiment revealed that proton transfer did not occur in the photochromic process of [H(4pp)]4Mo8O26·2(4pp), which proves that the PCT of ammonium polyoxomolybdate does not necessarily need proton transfer from the ammonium cation to the polyoxomolybdate anion.
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http://dx.doi.org/10.1039/c9dt02106jDOI Listing
July 2019

A novel photochromic metal-organic framework with good anion and amine sensing.

Dalton Trans 2019 May;48(19):6558-6563

Institute of polyoxometalate Chemistry, Department of Chemistry, Northeast Normal University, Changchun, Jilin 130024, PR China.

A novel metal-organic hybrid photochromic compound [Zn (CV) (L2)]·2H2O (1) (CV = N,N'-4,4'-bipyridiniodipropionate, H2L2 = isophthalic acid) has been synthesized solvothermally. Compound 1 features a two-dimensional (2D) framework structure, exhibiting photochromic properties under sunlight and UV irradiation with an obvious color change from colorless to dark blue. Meanwhile, the luminescence properties of 1 were investigated, and the results suggested that 1 has good properties of detecting dichromate ions. Furthermore, compound 1 shows different color changes when exposed to different alkyl-amines, and 1 can also be deposited into paper to use as portable test strips. This work can be applied to practical applications as a multifunctional detector against light and chemicals.
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http://dx.doi.org/10.1039/c8dt05032eDOI Listing
May 2019

Transcriptional repressor REST drives lineage stage-specific chromatin compaction at and increases AKT activation in a mouse model of medulloblastoma.

Sci Signal 2019 01 22;12(565). Epub 2019 Jan 22.

Department of Pediatrics, University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.

In medulloblastomas (MBs), the expression and activity of RE1-silencing transcription factor (REST) is increased in tumors driven by the sonic hedgehog (SHH) pathway, specifically the SHH-α (children 3 to 16 years) and SHH-β (infants) subgroups. Neuronal maturation is greater in SHH-β than SHH-α tumors, but both correlate with poor overall patient survival. We studied the contribution of REST to MB using a transgenic mouse model ( ) wherein conditional -controlled transgene expression in lineage-committed cerebellar granule neuron progenitors (CGNPs) accelerated tumorigenesis and increased penetrance and infiltrative disease. This model revealed a neuronal maturation context-specific antagonistic interplay between the transcriptional repressor REST and the activator GLI1 at Expression of , which encodes β-arrestin1 (a GLI1 inhibitor), was substantially reduced in proliferating and, to a lesser extent, lineage-committed cells compared with wild-type proliferating CGNPs. Lineage-committed cells also had decreased GLI1 activity and increased histone H3K9 methylation at the locus, which correlated with premature silencing of These cells also had decreased expression of , which encodes a negative regulator of the kinase AKT. Expression of and were less, and was somewhat greater, in patient SHH-β than SHH-α MBs, whereas that of was similarly lower in both subtypes than in others. Inhibition of histone modifiers or AKT reduced proliferation and induced apoptosis, respectively, in cultured REST-high MB cells. Our findings linking REST to differentiation-specific chromatin remodeling, silencing, and AKT activation in MB tissues reveal potential subgroup-specific therapeutic targets for MB patients.
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http://dx.doi.org/10.1126/scisignal.aan8680DOI Listing
January 2019

Resveratrol protects against oxidative stress by activating the Keap-1/Nrf2 antioxidant defense system in obese-asthmatic rats.

Exp Ther Med 2018 Dec 17;16(6):4339-4348. Epub 2018 Sep 17.

Department of Pediatrics, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China.

The aim of the present study was to investigate the potential mechanism underlying the anti-obesity-asthmatic effects of resveratrol (RSV) in a rat model of obese-asthma. Rat models of obesity and asthma were established using a high-fat diet and the administration of ovalbumin, respectively. Rats were divided into 7 different groups: A normal control, a normal obese, a normal asthma, a normal obese + asthma, a RSV obese, a RSV asthma and a RSV obese + asthma group. Body weight, Lee index, body fat and lung histopathological changes were evaluated. Serum lipid levels were evaluated using calorimetric methods. Levels of reactive oxygen species (ROS) were examined using enzyme-linked immunosorbent assays. Cellular antioxidant enzyme activities were measured using commercial kits. Levels of kelch-like ECH associated protein 1 (Keap-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) was examined using western blot analysis. The results indicated that obese and asthma rat models were successfully established. It was also demonstrated that RSV decreased fasting blood glucose in obese, asthmatic and obese-asthmatic rats. RSV altered serum lipid levels; it significantly increased high density lipoprotein cholesterol levels and significantly decreased serum triglyceride, serum total cholesterol and very low density lipoprotein levels, compared with untreated obese, asthmatic and obese-asthmatic rats (P<0.05). ROS levels were significantly decreased in the RSV treatment group compared with obese, asthmatic and obese-asthmatic rats (P<0.05). RSV treatment significantly increased catalase, glutathione, glutathione peroxidase and total superoxide dismutase levels compared with untreated obese, asthmatic and obese-asthmatic rats (P<0.05). Furthermore, RSV treatment significantly downregulated Keap-1 and upregulated Nrf2 levels in the heart, lung and kidney tissues of rats compared with untreated controls. Therefore, the results demonstrate that RSV protects against oxidative stress by activating the Keap-1/Nrf2 antioxidant defense system in obese-asthmatic rat models.
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http://dx.doi.org/10.3892/etm.2018.6747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6257826PMC
December 2018

Systems biology-based drug repositioning identifies digoxin as a potential therapy for groups 3 and 4 medulloblastoma.

Sci Transl Med 2018 10;10(464)

Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute and Cancer Center, Weill Cornell Medicine, Houston, TX 77030, USA.

Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Although outcomes have improved in recent decades, new treatments are still needed to improve survival and reduce treatment-related complications. The MB subtypes groups 3 and 4 represent a particular challenge due to their intragroup heterogeneity, which limits the options for "rational" targeted therapies. Here, we report a systems biology approach to drug repositioning that integrates a nonparametric, bootstrapping-based simulated annealing algorithm and a 3D drug functional network to characterize dysregulated driver signaling networks, thereby identifying potential drug candidates. From more than 1300 drug candidates studied, we identified five members of the cardiac glycoside family as potentially inhibiting the growth of groups 3 and 4 MB and subsequently confirmed this in vitro. Systemic in vivo treatment of orthotopic patient-derived xenograft (PDX) models of groups 3 and 4 MB with digoxin, a member of the cardiac glycoside family approved for the treatment of heart failure, prolonged animal survival at plasma concentrations known to be tolerated in humans. These results demonstrate the power of a systematic drug repositioning method in identifying a potential treatment for MB. Our strategy could potentially be used to accelerate the repositioning of treatments for other human cancers that lack clearly defined rational targets.
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http://dx.doi.org/10.1126/scitranslmed.aat0150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6644046PMC
October 2018

Developmental phosphoproteomics identifies the kinase CK2 as a driver of Hedgehog signaling and a therapeutic target in medulloblastoma.

Sci Signal 2018 09 11;11(547). Epub 2018 Sep 11.

Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.

A major limitation of targeted cancer therapy is the rapid emergence of drug resistance, which often arises through mutations at or downstream of the drug target or through intrinsic resistance of subpopulations of tumor cells. Medulloblastoma (MB), the most common pediatric brain tumor, is no exception, and MBs that are driven by sonic hedgehog (SHH) signaling are particularly aggressive and drug-resistant. To find new drug targets and therapeutics for MB that may be less susceptible to common resistance mechanisms, we used a developmental phosphoproteomics approach in murine granule neuron precursors (GNPs), the developmental cell of origin of MB. The protein kinase CK2 emerged as a driver of hundreds of phosphorylation events during the proliferative, MB-like stage of GNP growth, including the phosphorylation of three of the eight proteins commonly amplified in MB. CK2 was critical to the stabilization and activity of the transcription factor GLI2, a late downstream effector in SHH signaling. CK2 inhibitors decreased the viability of primary SHH-type MB patient cells in culture and blocked the growth of murine MB tumors that were resistant to currently available Hh inhibitors, thereby extending the survival of tumor-bearing mice. Because of structural interactions, one CK2 inhibitor (CX-4945) inhibited both wild-type and mutant CK2, indicating that this drug may avoid at least one common mode of acquired resistance. These findings suggest that CK2 inhibitors may be effective for treating patients with MB and show how phosphoproteomics may be used to gain insight into developmental biology and pathology.
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http://dx.doi.org/10.1126/scisignal.aau5147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475502PMC
September 2018

Inhibition of Mutated Isocitrate Dehydrogenase 1 in Cancer.

Med Chem 2018 ;14(7):715-724

Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, United States.

Background: R132H mutation of isocitrate dehydrogenase 1 (IDH1) is found in ~75% of low-grade gliomas and secondary glioblastomas as well as in several other types of cancer. More chemotypes of inhibitors of IDH1(R132H) are therefore needed.

Objective: The study aimed to develop a new class of IDH1(R132H) inhibitors as potent antitumor agents.

Method: A biochemical assay was developed to find inhibitors of IDH1(R132H) mutant enzyme. Chemical synthesis and structure-activity relationship studies were used to find compounds with improved potency. Antitumor activities of selected compounds were evaluated.

Results: A series of aromatic sulfonamide compounds was found to be novel, potent inhibitors of IDH1(R132H) with Ki values as low as 0.6 µM. Structure-activity relationships of these compounds are discussed. Enzyme kinetics studies showed that one compound is a competitive inhibitor against the substrate α-KG and a non-competitive inhibitor against the cofactor NADPH. Several inhibitors were found to have no activity against wild-type IDH1, showing a high selectivity. Two potent inhibitors exhibited strong activity against proliferation of BT142 glioma cells with IDH1 R132H mutation, while these compounds did not significantly affect the growth of glioma cells without IDH1 mutation.

Conclusion: This novel series of IDH1(R132H) inhibitors have potential to be further developed for the treatment of glioma with IDH1 mutation.
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http://dx.doi.org/10.2174/1573406414666180524093659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205205PMC
October 2018