ORCID Profile
0000-0001-5518-6605
Current Organisations
Uppsala University
,
Centenary Institute
,
Harvard Medical School
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Publisher: Cold Spring Harbor Laboratory
Date: 24-08-2021
DOI: 10.1101/2021.08.23.457344
Abstract: The development of resistance to treatments of melanoma is commonly associated with upregulation of the MAPK pathway and development of an undifferentiated state. Prior studies have suggested that melanoma with these resistance characteristics may be susceptible to innate death mechanisms such as pyroptosis triggered by activation of inflammasomes. In the present studies we have taken cell lines from patients before and after development of resistance to BRAF V600 inhibitors and exposed the resistant melanoma to temozolomide (a commonly used chemotherapy) with and without chloroquine to inhibit autophagy. It was found that melanoma with an inflammatory undifferentiated state appeared susceptible to this combination when tested in vitro and in vivo against xenografts in NSG mice. Translation of the latter results into patients would promise durable responses in patients treated by the combination. The inflammasome and death mechanism involved appeared to vary between melanoma and involved either AIM2, NLRP3 or NLRC4 inflammasomes and gasdermin D or E. These preliminary studies have raised questions as to the selectivity for different inflammasomes in different melanoma and their selective targeting by chemotherapy. They also question whether the inflammatory state of melanoma may be used as biomarkers to select patients for inflammasome targeted therapy.
Publisher: MDPI AG
Date: 04-2021
Abstract: Dipeptidyl peptidase (DPP) 9, DPP8, DPP4 and fibroblast activation protein (FAP) are the four enzymatically active members of the S9b protease family. Associations of DPP9 with human liver cancer, exonic single nucleotide polymorphisms (SNPs) in DPP9 and loss of function (LoF) variants have not been explored. Human genomic databases, including The Cancer Genome Atlas (TCGA), were interrogated to identify DPP9 LoF variants and associated cancers. Survival and gene signature analyses were performed on hepatocellular carcinoma (HCC) data. We found that DPP9 and DPP8 are intolerant to LoF variants. DPP9 exonic LoF variants were most often associated with uterine carcinoma and lung carcinoma. All four DPP4-like genes were overexpressed in liver tumors and their joint high expression was associated with poor survival in HCC. Increased DPP9 expression was associated with obesity in HCC patients. High expression of genes that positively correlated with overexpression of DPP4, DPP8, and DPP9 were associated with very poor survival in HCC. Enriched pathways analysis of these positively correlated genes featured Toll-like receptor and SUMOylation pathways. This comprehensive data mining suggests that DPP9 is important for survival and that the DPP4 protease family, particularly DPP9, is important in the pathogenesis of human HCC.
Publisher: Wiley
Date: 20-02-2020
DOI: 10.1111/PCMR.12870
Publisher: Frontiers Media SA
Date: 16-06-2021
DOI: 10.3389/FGENE.2021.680633
Abstract: Epigenetic dysregulation has been implicated in a variety of pathological processes including carcinogenesis. A major group of enzymes that influence epigenetic modifications are lysine demethylases (KDMs) also known as “erasers” which remove methyl groups on lysine (K) amino acids of histones. Numerous studies have implicated aberrant lysine demethylase activity in a variety of cancers, including melanoma. This review will focus on the structure, classification and functions of KDMs in normal biology and the current knowledge of how KDMs are deregulated in cancer pathogenesis, emphasizing our interest in melanoma. We highlight the current knowledge gaps of KDMs in melanoma pathobiology and describe opportunities to increases our understanding of their importance in this disease. We summarize the progress of several pre-clinical compounds that inhibit KDMs and represent promising candidates for further investigation in oncology.
Publisher: Wiley
Date: 21-02-2019
DOI: 10.1002/CAM4.1978
Publisher: The Korean Society of Menopause
Date: 2016
Publisher: American Association for Cancer Research (AACR)
Date: 07-2018
DOI: 10.1158/1538-7445.AM2018-5833
Abstract: Background Acquired drug resistance in BRAF mutant melanoma is the main cause for disease relapse. We previously described a slow cycling induced drug tolerant state upon continuous BRAF/MEK treatment preceding permanent resistance with generic changes in histone methylation. Rationale Genetic alterations linked to acquired BRAF inhibitor resistance are absent in about 40% of relapsed melanoma patients suggesting the involvement of epigenetic alterations in the development of acquired drug resistance. We investigated epigenetic remodeling in BRAF mutant melanoma upon BRAF/MEK inhibition. Methods An in-vitro model of time lapse dependent transition to acquired drug resistance using mutant BRAF melanoma was used to investigate epigenetic changes following chronic drug exposure. Histone methylation patters were investigated using ChIP-seq, followed by target gene promoter ChIP-PCR and functional verification. Findings were confirmed by gene silencing, combined treatment regimes in vivo, in PDX tumors and clinical data sets. Results A state dependent response to chronic drug treatment was observed. Long term treatment of more than 45 days enables the cells to escape the slow cycling state which results in proliferating cellular clusters (drug-tolerant persister colonies) with stem-like characteristics that regain global H3K4me3. Persister colonies are then giving rise to fast proliferating BRAF/MEK inhibitor resistant cells. H3K4me3 ChIP-seq of colonies compared to parental cells revealed differential marking at promotor regions of several target genes involved in MAPKi resistance, including ARAF, BRAF, and CRAF. H3K4me3 remodeling corresponded to increased gene expression and susceptibility to pan-RAF inhibitors, suggesting an H3K4me3 mediated increase of ARAF and CRAF as a mechanism of BRAF/MEK inhibitor resistance. Two enzymes, OGT and TET1 that are both linked to H3K4me3 regulation in embryonic stem cells are highly upregulated in persister colonies and tumor tissue of PDXs from BRAF mutant melanoma patients under MEK1/2 inhibition. A shift in OGT nuclear localization and O-linked glycosylation patterns was observed in colonies compared to parental cells suggestive of altered transcriptional and protein activity. OGT ChIP-PCR of colonies compared to parental cells confirmed a set of genes with exclusively H3K4me3 marking in colonies. shRNA mediated knockdown of OGT and TET1 blocked H3K4me3 increase in IDTC colonies, prevented colony formation and delayed tumor relapse in a BRAF mutant xenograft mouse model. High TET1 mRNA expression is linked to significantly shorter survival in TGCA data. Conclusion OGT and TET1 mediated epigenetic remodeling through H3K4me3 with upregulation of MAPKi resistant genes is responsible for the emergence of permanent resistance. Both enzymes are promising targets to combat treatment failure and prolong overall survival. Citation Format: Dinoop Ravindran Menon, Heinz Hammerlindl, Abdullah Al Emran, Joachim Torrano, Sabrina Hammerlindl, Gao Zhang, Rajasekharan Somasundaram, Richard A. Sturm, Nikolas K. Haass, Keith Flaherty, Meenhard Herlyn, Helmut Schaider. Escape form adaptive drug tolerance through OGT and TET1 mediated H3K4me3 remodeling in MAPKi resistant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018 2018 Apr 14-18 Chicago, IL. Philadelphia (PA): AACR Cancer Res 2018 (13 Suppl):Abstract nr 5833.
Publisher: Springer Science and Business Media LLC
Date: 08-03-2019
Publisher: MDPI AG
Date: 28-07-2020
Abstract: Background: Survival from melanoma is strongly related to patient sex, with females having a survival rate almost twice that of males. Many explanations have been proposed but have not withstood critical scrutiny. Prior analysis of different cancers with a sex bias has identified six X-linked genes that escape X chromosome inactivation in females and are, therefore, potentially involved in sex differences in survival. Four of the genes are well-known epigenetic regulators that are known to influence the expression of hundreds of other genes and signaling pathways in cancer. Methods: Survival and interaction analysis were performed on the skin cutaneous melanoma (SKCM) cohort in The Cancer Genome Atlas (TCGA), comparing high vs. low expression of KDM6A, ATRX, KDM5C, and DDX3X. The Leeds melanoma cohort (LMC) on 678 patients with primary melanoma was used as a validation cohort. Results: Analysis of TCGA data revealed that two of these genes—KDM6A and ATRX—were associated with improved survival from melanoma. Tumoral KDM6A was expressed at higher levels in females and was associated with inferred lymphoid infiltration into melanoma. Gene set analysis of high KDM6A showed strong associations with immune responses and downregulation of genes associated with Myc and other oncogenic pathways. The LMC analysis confirmed the prognostic significance of KDM6A and its interaction with EZH2 but also revealed the expression of KDM5C and DDX3X to be prognostically significant. The analysis also confirmed a partial correlation of KDM6A with immune tumor infiltrates. Conclusion: When considered together, the results from these two series are consistent with the involvement of X-linked epigenetic regulators in the improved survival of females from melanoma. The identification of gene signatures associated with their expression presents insights into the development of new treatment initiatives but provides a basis for exploration in future studies.
Publisher: EManuscript Technologies
Date: 02-2011
Publisher: Elsevier BV
Date: 09-2021
DOI: 10.1016/J.JID.2020.12.038
Abstract: Dysregulation of epigenetic modifiers is a frequent event in melanoma and underlies many aspects of melanoma biology, including resistance to targeted therapy and immunotherapies. Here, we report that dual targeting of BET and CDK9 proteins have synergistic effects against melanoma cells in vitro and in vivo. The BET inhibitor (IBET151) and CDK9 inhibitor (CDKI73) synergistically killed melanoma cells in vitro independent of their BRAF or NRAS mutation status. The combination of drugs markedly inhibited the growth of human melanoma C002M cells in vitro in three-dimensional spheroids and in vivo in NOD-SCID gamma mice compared with vehicle control and the in idual drugs (P < 0.05). Cell death was associated with mitochondrial depolarization, caspase-dependent apoptosis with cleavage of PARP1, and downregulation of anti-apoptotic proteins BCL2, BCLXL, and MCL1. Gene set enrichment analysis revealed downregulation of hallmark gene sets associated with E2F, G2M checkpoint, and c-MYC. Survival analysis showed worse prognosis with high G2M, E2F, or c-MYC gene signatures, suggesting biomarkers of response of BET and CDK9 inhibitors in melanoma. This combination of epigenetic inhibitors targets multiple downstream genes, leading to cell death of melanoma cells in vitro and in vivo, and warrants further investigation for treatment of melanoma in patients not responding to current therapies.
Publisher: Springer Science and Business Media LLC
Date: 23-01-2016
Publisher: Elsevier BV
Date: 04-2022
Publisher: Elsevier BV
Date: 04-2019
Abstract: Methylation of DNA at CpG sites is the most common and stable of epigenetic changes in cancer. Hypermethylation acts to limit immune checkpoint blockade immunotherapy by inhibiting endogenous interferon responses needed for recognition of cancer cells. By contrast, global hypomethylation results in the expression of programmed death ligand 1 (PD-L1) and inhibitory cytokines, accompanied by epithelial-mesenchymal changes that can contribute to immunosuppression. The drivers of these contrasting methylation states are not well understood. DNA methylation also plays a key role in cytotoxic T cell 'exhaustion' associated with tumor progression. We present an updated exploratory analysis of how DNA methylation may define patient subgroups and can be targeted to develop tailored treatment combinations to help improve patient outcomes.
Publisher: Future Medicine Ltd
Date: 05-2019
Abstract: Aim: To investigate the integrated epigenetic regulation of acquired drug resistance in cancer. Materials & methods: Our gene expression data of five induced drug-tolerant cell models, one resistant cell line and one publicly available drug-resistant dataset were integrated to identify common differentially expressed genes and pathways. ChIP-seq and DNA methylation by HM450K beadchip were used to study the epigenetic profile of differential expressed genes. Results & conclusion: Integrated transcriptomic analysis identified a common ‘viral mimicry’ related gene signature in induced drug-tolerant cells and the resistant state. Analysis of the epigenetic regulation revealed a common set of down-regulated genes, which are marked and regulated by a concomitant loss of H3K4me3, gain of H3K9me3 and increment of regional DNA methylation levels associated with tumor suppressor genes and apoptotic signaling.
Publisher: American Association for Cancer Research (AACR)
Date: 14-01-2016
DOI: 10.1158/1538-7445.CHROMEPI15-B34
Abstract: Background: Resistance to chemotherapy and targeted therapies is a major problem for cancer treatment. Acquired drug resistance is not only dependent on somatic mutations or drug efflux suggestive of alternative mechanisms like epigenetic changes and chromatin remodeling. Recent studies also suggest drug holidays after initial treatment with a drug re-sensitizing cancer cells to the same drug. We recently have identified early stress induced multi-drug resistant cancer cells termed induced drug tolerant cells (IDTCs). Methods: Lung, breast, colon, liver and melanoma cancer cell lines (A549, SKBR3, HT-29, HEPG2, and WM1366) were exposed to chemotherapeutic drugs like Doxorubicin, Docetaxel,molecular inhibitors like Dabrafanib or Trametinib, or nutrient starvation (low glucose-1g/L) at different concentrations for twelve to twenty consecutive days for acquiring an IDTC state. Drug holiday was employed by withdrawing drug treatment for a period of seven days and maintained in normal growth medium. CD271 expression, which is a marker of IDTCs, was determined by immunofluorescence and FACS. Histone modifications were probed by immunofluorescence and common survival pathways were observed by western blot analysis. Genome wide expression analysis were performed by microarray with IDTCs of different cancer types compared to parental control Results: Transcriptional active histone marks like H3K4me3 and repressive marks like- H3K9Me3 and H3K27me3 were altered (up-regulation of H3K9Me3 and down-regulation of H3K4Me3 and H3K27Me3) in IDTCs compared to parental cancer cells. These data were consistent in all of the five cancer types indicating that this effect is neither a consequence from a specific therapy nor for a particular cancer rather a common mechanism of initial drug resistance. Similar histone modification patterns were observed under conditions of nutrient starvation, if a drug holiday was provided, dynamic switching of histone modification was observed resembling the histone modifications of the parental population. Moreover microarray data suggest that, specific enzymes responsible for H3K4Me3, H3K27Me3 and H3K27Me3 were observed to show an altered expression profile in IDTCs. Such it can be concluded that multiple players maintain a particular histone modification and there is a dynamic switching of histone methylase and demethylase stabilizing a specific histone modification depending on the context. Along with that, different pro-survival pathways like ERK, AKT, MTOR and AMPK were upregulated in all five cancer types. Conclusion: Global histone modifications render cancer cells to transform into IDTCs characterized by a distinct morphology, expression of IDTC markers like CD271, multidrug resistance and activation of pro-survival signaling. Histone modifications, chromatin remodelling, and DNA methylation act in cohort to maintain the euchromatin and heterochromatin state of IDTCs. We aim to further elucidate target genes of active and inactive histone modifiers in IDTCs crucial for the transition of early- to acquired permanent drug resistance. Citation Format: Abdullah Al Emran, Dinoop Ravindran Menon, Peter Soyer, Brian Gabrielli, Rick Sturm, Meenhard Herlyn, Helmut Schaider. Global histone modifications define early stress induced drug tolerance in cancer. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer Sep 24-27, 2015 Atlanta, GA. Philadelphia (PA): AACR Cancer Res 2016 (2 Suppl):Abstract nr B34.
Publisher: Research Square Platform LLC
Date: 22-11-2021
DOI: 10.21203/RS.3.RS-1099054/V1
Abstract: The recent pandemic caused by the novel coronavirus SARS-CoV-2 has impacted global health by increasing mortality and unexpected infection rate. Extensive clinical research is undergoing to repurposing the old drug against this virus. So, this is an emerging need to develop therapy against the virus. Plant-derived natural products have proven to be potent therapeutics for several infections and diseases. Centella asiatica , is a native plant of the Indian subcontinent, has been vastly using as folk medicine against diseases including infectious diseases. So, using bioinformatics approach we identified and checked the phytochemicals of the plant as inhibitors against the main protease (Mpro), the key regulatory enzyme of the SARS-CoV-2 lifecycle. Computer-aided drug designing methods were performed to reveal the best nine drug-like phytochemicals those theoretically have the higher binding affinity of inhibiting Mpro. This outcome may direct to the development of potent therapeutics against the SARS-CoV-2 and demands experimental validation.
Publisher: Informa UK Limited
Date: 10-04-2012
DOI: 10.3109/01480545.2012.658920
Abstract: Pioglitazone, a member of the thiazolidinediones, is a potent, highly selective agonist for peroxisome proliferator-activated receptor gamma and is an excellent insulin sensitizer used in treating type 2 diabetes mellitus. The present study investigated the effect of pioglitazone on glucose, total cholesterol, triglyceride, low-density lipoprotein (LDL) cholesterol and high density lipoprotein (HDL) cholesterol, total proteins, albumin (ALB), alanine transaminase (ALT), and aspartate transaminase (AST) levels in 20 healthy Bengali male volunteers in a randomized, placebo-controlled study. Blood s les were collected before and 0.5-24.0 hours after a single oral dose of a 30 mg pioglitazone tablet. Plasma pioglitazone level was determined using a validated method of reverse-phase binary high-performance liquid chromatography. Blood lipid profile and levels of glucose, ALT, and AST were estimated using enzyme assay kits, plasma protein level was estimated by the biuret method, and plasma ALB level was determined colorimetrically. No significant change in blood glucose, total proteins, total cholesterol, triglyceride, HDL, and LDL levels was observed over the 24-hour assessment period, indicating no plasma biochemical alterations. There were no significant differences between baseline and 24-hour values of ALB, ALT, and AST levels, indicating a lack of liver toxicity. Our results indicate that a single dose of 30 mg of pioglitazone has no hypoglycemic or hypolipidemic effect or liver toxicity within 24 hours of treatment among healthy Bengali males.
Publisher: Wiley
Date: 24-04-2020
DOI: 10.1002/IJC.33000
Publisher: Springer Science and Business Media LLC
Date: 19-01-2021
Publisher: MDPI AG
Date: 10-01-2022
Abstract: One of the limitations of immunotherapy is the development of a state referred to as T cell exhaustion (TEx) whereby T cells express inhibitory receptors (IRs) and lose production of effectors involved in killing of their targets. In the present studies we have used the repeated stimulation model with anti CD3 and anti CD28 to understand the factors involved in TEx development and treatments that may reduce changes of TEx. The results show that addition of nicotinamide (NAM) involved in energy supply to cells prevented the development of inhibitory receptors (IRs). This was particularly evident for the IRs CD39, TIM3, and to a lesser extent LAG3 and PD1 expression. NAM also prevented the inhibition of IL-2 and TNFα expression in TEx and induced differentiation of CD4+ and CD8 T cells to effector memory and terminal effector T cells. The present results showed that effects of NAM were linked to regulation of reactive oxygen species (ROS) consistent with previous studies implicating ROS in upregulation of TOX transcription factors that induce TEx. These effects of NAM in reducing changes of TEx and in increasing the differentiation of T cells to effector states appears to have important implications for the use of NAM supplements in immunotherapy against cancers and viral infections and require further exploration in vivo.
Publisher: Frontiers Media SA
Date: 10-03-2020
Publisher: Elsevier BV
Date: 12-2020
Publisher: American Association for Cancer Research (AACR)
Date: 28-02-2018
DOI: 10.1158/1078-0432.CCR-16-2118
Abstract: Purpose: Identify and characterize novel combinations of sorafenib with anti-inflammatory painkillers to target difficult-to-treat RAS-mutant cancer. Experimental Design: The cytotoxicity of acetylsalicylic acid (aspirin) in combination with the multikinase inhibitor sorafenib (Nexavar) was assessed in RAS-mutant cell lines in vitro. The underlying mechanism for the increased cytotoxicity was investigated using selective inhibitors and shRNA-mediated gene knockdown. In vitro results were confirmed in RAS-mutant xenograft mouse models in vivo. Results: The addition of aspirin but not isobutylphenylpropanoic acid (ibruprofen) or celecoxib (Celebrex) significantly increased the in vitro cytotoxicity of sorafenib. Mechanistically, combined exposure resulted in increased BRAF/CRAF dimerization and the simultaneous hyperactivation of the AMPK and ERK pathways. Combining sorafenib with other AMPK activators, such as metformin or A769662, was not sufficient to decrease cell viability due to sole activation of the AMPK pathway. The cytotoxicity of sorafenib and aspirin was blocked by inhibition of the AMPK or ERK pathways through shRNA or via pharmacologic inhibitors of RAF (LY3009120), MEK (trametinib), or AMPK (compound C). The combination was found to be specific for RAS/RAF–mutant cells and had no significant effect in RAS/RAF–wild-type keratinocytes or melanoma cells. In vivo treatment of human xenografts in NSG mice with sorafenib and aspirin significantly reduced tumor volume compared with each single-agent treatment. Conclusions: Combination sorafenib and aspirin exerts cytotoxicity against RAS/RAF–mutant cells by simultaneously affecting two independent pathways and represents a promising novel strategy for the treatment of RAS-mutant cancers. Clin Cancer Res 24(5) 1090–102. ©2017 AACR.
Publisher: Informa UK Limited
Date: 08-2014
DOI: 10.2147/DDDT.S67861
Publisher: American Chemical Society (ACS)
Date: 12-01-2023
Publisher: Elsevier BV
Date: 05-2022
DOI: 10.1016/J.JID.2021.09.030
Abstract: The development of resistance to treatments of melanoma is commonly associated with an upregulation of the MAPK pathway and the development of an undifferentiated state. Previous studies have suggested that melanoma with these resistance characteristics may be susceptible to innate death mechanisms such as pyroptosis triggered by the activation of inflammasomes. In this study, we have taken cell lines from patients before and after the development of resistance to BRAF V600 inhibitors and exposed the resistant melanoma to temozolomide (a commonly used chemotherapy) with and without chloroquine to inhibit autophagy. It was found that melanoma with an inflammatory undifferentiated state appeared susceptible to this combination when tested in vitro and in vivo against xenografts in nonobese diabetic scid gamma mice. Translation of the latter results into patients would promise durable responses in patients treated by the combination. The inflammasome and death mechanism involved appeared to vary between melanoma and involved either AIM2 or NLRP3 inflammasomes and gasdermin D or E. These preliminary studies have raised questions as to the selectivity for different inflammasomes in different melanoma and their selective targeting by chemotherapy. They also question whether the inflammatory state of melanoma may be used as biomarkers to select patients for inflammasome-targeted therapy.
Publisher: University of Queensland Library
Date: 2018
Publisher: Spandidos Publications
Date: 30-03-2020
Publisher: Impact Journals, LLC
Date: 24-12-2017
No related grants have been discovered for Abdullah Al Emran.