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Frontiers in Immunology 2023Hypermethylated in Cancer 1 (HIC1) was originally confirmed as a tumor suppressor and has been found to be hypermethylated in human cancers. Although growing evidence...
BACKGROUND
Hypermethylated in Cancer 1 (HIC1) was originally confirmed as a tumor suppressor and has been found to be hypermethylated in human cancers. Although growing evidence has supported the critical roles of HIC1 in cancer initiation and development, its roles in tumor immune microenvironment and immunotherapy are still unclear, and no comprehensive pan-cancer analysis of HIC1 has been conducted.
METHODS
HIC1 expression in pan-cancer, and differential HIC1 expression between tumor and normal samples were investigated. Immunohistochemistry (IHC) was employed to validate HIC1 expression in different cancers by our clinical cohorts, including lung cancer, sarcoma (SARC), breast cancer, and kidney renal clear cell carcinoma (KIRC). The prognostic value of HIC1 was illustrated by Kaplan-Meier curves and univariate Cox analysis, followed by the genetic alteration analysis of HIC1 in pan-cancer. Gene Set Enrichment Analysis (GSEA) was conducted to illustrate the signaling pathways and biological functions of HIC1. The correlations between HIC1 and tumor mutation burden (TMB), microsatellite instability (MSI), and the immunotherapy efficacy of PD-1/PD-L1 inhibitors were analyzed by Spearman correlation analysis. Drug sensitivity analysis of HIC1 was performed by extracting data from the CellMiner™ database.
RESULTS
HIC1 expression was abnormally expressed in most cancers, and remarkable associations between HIC1 expression and prognostic outcomes of patients in pan-cancer were detected. HIC1 was significantly correlated with T cells, macrophages, and mast cell infiltration in different cancers. Moreover, GSEA revealed that HIC1 was significantly involved in immune-related biological functions and signaling pathways. There was a close relationship of HIC1 with TMB and MSI in different cancers. Furthermore, the most exciting finding was that HIC1 expression was significantly correlated with the response to PD-1/PD-L1 inhibitors in cancer treatment. We also found that HIC1 was significantly correlated with the sensitivity of several anti-cancer drugs, such as axitinib, batracylin, and nelarabine. Finally, our clinical cohorts further validated the expression pattern of HIC1 in cancers.
CONCLUSIONS
Our investigation provided an integrative understanding of the clinicopathological significance and functional roles of HIC1 in pan-cancer. Our findings suggested that HIC1 can function as a potential biomarker for predicting the prognosis, immunotherapy efficacy, and drug sensitivity with immunological activity in cancers.
Topics: Humans; Ferroptosis; Immune Checkpoint Inhibitors; Programmed Cell Death 1 Receptor; Prognosis; Carcinoma, Renal Cell; Kidney Neoplasms; Tumor Microenvironment; Kruppel-Like Transcription Factors
PubMed: 37388742
DOI: 10.3389/fimmu.2023.1182030 -
OncoTargets and Therapy Feb 2009Nelarabine is the prodrug of 9-beta-arabinofuranosylguanine (ara-G) and is therapeutically classified as a purine nucleoside analog. Nelarabine is converted to ara-G by...
Nelarabine is the prodrug of 9-beta-arabinofuranosylguanine (ara-G) and is therapeutically classified as a purine nucleoside analog. Nelarabine is converted to ara-G by adenosine deaminase and transported into cells by a nucleoside transporter. Ara-G is subsequently phosphorylated to ara-G triphosphate (ara-GTP), thereby initiating the therapeutic effect by inhibiting DNA synthesis. Nelarabine has been extensively studied in regards to its pharmacokinetics, and the data have demonstrated that ara-GTP preferentially accumulates in malignant T-cells. Clinical responses to nelarabine have been demonstrated in various T-cell malignancies and appear to correlate with a relatively high intracellular concentration of ara-GTP compared to nonresponders. Therefore, this unique drug feature of nelarabine accounts for clinical utilization in treating adult and pediatric patients with relapsed or refractory T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma. Neuropathy is the most predominant adverse effect associated with nelarabine and the incidence correlates with the dose administered. Myelosuppression has been observed, with thrombocytopenia and neutropenia as the most common hematologic complications. This article reviews the pharmacology, mechanism of action, and pharmacokinetic properties of nelarabine, as well as nelarabine's clinical efficacy in T-ALL, T-LBL, and other hematologic malignancies. The toxicity profile, dosage, and administration, and areas of ongoing and future research, are also presented.
PubMed: 20616909
DOI: 10.2147/ott.s4770 -
Journal of Clinical Oncology : Official... Aug 2012Children's Oncology Group study AALL00P2 was designed to assess the feasibility and safety of adding nelarabine to a BFM 86-based chemotherapy regimen in children with...
PURPOSE
Children's Oncology Group study AALL00P2 was designed to assess the feasibility and safety of adding nelarabine to a BFM 86-based chemotherapy regimen in children with newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL).
PATIENTS AND METHODS
In stage one of the study, eight patients with a slow early response (SER) by prednisone poor response (PPR; ≥ 1,000 peripheral blood blasts on day 8 of prednisone prephase) received chemotherapy plus six courses of nelarabine 400 mg/m(2) once per day; four patients with SER by high minimal residual disease (MRD; ≥ 1% at day 36 of induction) received chemotherapy plus five courses of nelarabine; 16 patients with a rapid early response (RER) received chemotherapy without nelarabine. In stage two, all patients received six 5-day courses of nelarabine at 650 mg/m(2) once per day (10 SER patients [one by MRD, nine by PPR]) or 400 mg/m(2) once per day (38 RER patients; 12 SER patients [three by MRD, nine by PPR]).
RESULTS
The only significant difference in toxicities was decreased neutropenic infections in patients treated with nelarabine (42% with v 81% without nelarabine). Five-year event-free survival (EFS) rates were 73% for 11 stage one SER patients and 67% for 22 stage two SER patients treated with nelarabine versus 69% for 16 stage one RER patients treated without nelarabine and 74% for 38 stage two RER patients treated with nelarabine. Five-year EFS for all patients receiving nelarabine (n = 70) was 73% versus 69% for those treated without nelarabine (n = 16).
CONCLUSION
Addition of nelarabine to a BFM 86-based chemotherapy regimen was well tolerated and produced encouraging results in pediatric patients with T-ALL, particularly those with a SER, who have historically fared poorly.
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleosides; Child; Child, Preschool; Disease-Free Survival; Female; Humans; Infant; Male; Peripheral Nervous System Diseases; Pilot Projects; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 22734022
DOI: 10.1200/JCO.2011.40.8724 -
Journal of Hematology & Oncology Jun 2013New genetic markers for adult acute lymphoblastic leukemia (ALL) have been found to have prognostic impact, such as the lymphoid transcription factor gene IKZF1... (Review)
Review
New genetic markers for adult acute lymphoblastic leukemia (ALL) have been found to have prognostic impact, such as the lymphoid transcription factor gene IKZF1 alterations, which are associated with a high rate of leukemic relapse in B-ALL. Although complete remission rates by induction chemotherapy in ALL are now high, the long-term survival is still disappointing. Improvements in the survival outcome of ALL have been observed in young adults as a result of the use of pediatric inspired regimens and the broadening of the number of patients who are eligible for allogeneic SCT. Development of new and less toxic agents also provide promise to improve the outcome in adult ALL, such as tyrosine kinase inhibitors in Ph-positive ALL, rituximab in CD20-positive disease, blinatumomab in precursor B-ALL and nelarabine in T-lineage ALL. Challenges for the future are to implement genomic profiling into the clinical setting to guide risk stratification and providing novel targets for tailored therapies.
Topics: Biomarkers, Tumor; Disease-Free Survival; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Treatment Outcome
PubMed: 23773228
DOI: 10.1186/1756-8722-6-40 -
Genomics Jul 2021The RGS (regulator of G protein signaling) gene family, which includes negative regulators of G protein-coupled receptors, comprises important drug targets for malignant...
The RGS (regulator of G protein signaling) gene family, which includes negative regulators of G protein-coupled receptors, comprises important drug targets for malignant tumors. It is thus of great significance to explore the value of RGS family genes for diagnostic and prognostic prediction in ovarian cancer. The RNA-seq, immunophenotype, and stem cell index data of pan-cancer, The Cancer Genome Atlas (TCGA) data, and GTEx data of ovarian cancer were downloaded from the UCSC Xena database. In the pan-cancer database, the expression level of RGS1, RGS18, RGS19, and RGS13 was positively correlated with stromal and immune cell scores. Cancer patients with high RGS18 expression were more sensitive to cyclophosphamide and nelarabine, whereas those with high RGS19 expression were more sensitive to cladribine and nelarabine. The relationship between RGS family gene expression and overall survival (OS) and progression-free survival (PFS) of ovarian cancer patients was analyzed using the KM-plotter database, RGS17, RGS16, RGS1, and RGS8 could be used as diagnostic biomarkers of the immune subtype of ovarian cancer, and RGS10 and RGS16 could be used as biomarkers to predict the clinical stage of this disease. Further, Lasso cox analysis identified a five-gene risk score (RGS11, RGS10, RGS13, RGS4, and RGS3). Multivariate COX analysis showed that the risk score was an independent prognostic factor for patients with ovarian cancer. Immunohistochemistry and the HPA protein database confirmed that the five-gene signature is overexpressed in ovarian cancer. GSEA showed that it is mainly involved in the ECM-receptor interaction, TGF-beta signaling pathway, Wnt signaling pathway, and chemokine signaling pathway, which promote the occurrence and development of ovarian cancer. The prediction model of ovarian cancer constructed using RGS family genes is of great significance for clinical decision making and the personalized treatment of patients with ovarian cancer.
Topics: Carcinoma, Ovarian Epithelial; Humans; Ovarian Neoplasms; Prognosis; RGS Proteins; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 33845140
DOI: 10.1016/j.ygeno.2021.04.012 -
Clinical Lymphoma, Myeloma & Leukemia Oct 2022While outcomes for children with T-cell acute lymphoblastic leukemia (T-ALL) and T-lymphoblastic lymphoma (T-LL) have improved significantly with contemporary therapy,... (Review)
Review
While outcomes for children with T-cell acute lymphoblastic leukemia (T-ALL) and T-lymphoblastic lymphoma (T-LL) have improved significantly with contemporary therapy, outcomes for patients with relapsed or refractory (r/r) disease remain dismal. Improved risk stratification and the incorporation of novel therapeutics have the potential to improve outcomes further in T-ALL/T-LL by limiting relapse risk and improving salvage rates for those with r/r disease. In this review we will discuss the challenges and new opportunities for improved risk stratification in T-ALL and T-LL. We will further discuss the recent incorporation of the novel therapeutics nelarabine and bortezomib into front-line therapy for children with T-ALL and T-LL. Finally, we will address new classes of targeted small molecule inhibitors, immunotherapeutics, and chimeric antigen receptor T-cell therapies under investigation in r/r T-ALL and T-LL.
Topics: Bortezomib; Child; Humans; Immunotherapy, Adoptive; Lymphoma, Non-Hodgkin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Chimeric Antigen; T-Lymphocytes
PubMed: 35941070
DOI: 10.1016/j.clml.2022.07.010 -
Biology Sep 2020In the prediction of the synergy of drug combinations, systems pharmacology models expand the scope of experiment screening and overcome the limitations of current...
In the prediction of the synergy of drug combinations, systems pharmacology models expand the scope of experiment screening and overcome the limitations of current computational models posed by their lack of mechanical interpretation and integration of gene essentiality. We therefore investigated the synergy of drug combinations for cancer therapies utilizing records in NCI ALMANAC, and we employed logistic regression to test the statistical significance of gene and pathway features in that interaction. We trained our predictive models using 43 NCI-60 cell lines, 165 KEGG pathways, and 114 drug pairs. Scores of drug-combination synergies showed a stronger correlation with pathway than gene features in overall trend analysis and a significant association with both genes and pathways in genome-wide association analyses. However, we observed little overlap of significant gene expressions and essentialities and no significant evidence that associated target and non-target genes and their pathways. We were able to validate four drug-combination pathways between two drug combinations, Nelarabine-Exemestane and Docetaxel-Vermurafenib, and two signaling pathways, PI3K-AKT and AMPK, in 16 cell lines. In conclusion, pathways significantly outperformed genes in predicting drug-combination synergy, and because they have very different mechanisms, gene expression and essentiality should be considered in combination rather than individually to improve this prediction.
PubMed: 32906805
DOI: 10.3390/biology9090278 -
MedRxiv : the Preprint Server For... Nov 2023Gamma delta T-cell receptor-positive acute lymphoblastic leukemia (γδ T-ALL) is a high-risk but poorly characterized disease.
PURPOSE
Gamma delta T-cell receptor-positive acute lymphoblastic leukemia (γδ T-ALL) is a high-risk but poorly characterized disease.
METHODS
We studied clinical features of 200 pediatric γδ T-ALL, and compared the prognosis of 93 cases to 1,067 protocol-matched non-γδ T-ALL. Genomic features were defined by transcriptome and genome sequencing. Experimental modeling was used to examine the mechanistic impacts of genomic alterations. Therapeutic vulnerabilities were identified by high throughput drug screening of cell lines and xenografts.
RESULTS
γδ T-ALL in children under three was extremely high-risk with 5-year event-free survival (33% v. 70% [age 3-<10] and 73% [age ≥10], =9.5 x 10 ) and 5-year overall survival (49% v. 78% [age 3-<10] and 81% [age ≥10], =0.002), differences not observed in non-γδ T-ALL. γδ T-ALL in this age group was enriched for genomic alterations activating activation and inactivating inactivation ( ). Mechanistically, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer-promoter looping resulting in deregulation of gene expression associated with T-cell differentiation. Drug screening showed resistance to prednisolone, consistent with clinical slow treatment response, but identified a vulnerability in DNA repair pathways arising from STAG2 inactivation, which was efficaciously targeted by Poly(ADP-ribose) polymerase (PARP) inhibition, with synergism with HDAC inhibitors. Ex-vivo drug screening on PDX cells validated the efficacy of PARP inhibitors as well as other potential targets including nelarabine.
CONCLUSION
γδ T-ALL in children under the age of three is extremely high-risk and enriched for ALL. STAG2 loss perturbs chromatin conformation and differentiation, and ALL is sensitive to PARP inhibition. These data provide a diagnostic and therapeutic framework for pediatric γδ T-ALL.
SUPPORT
The authors are supported by the American and Lebanese Syrian Associated Charities of St Jude Children's Research Hospital, NCI grants R35 CA197695, P50 CA021765 (C.G.M.), the Henry Schueler 41&9 Foundation (C.G.M.), and a St. Baldrick's Foundation Robert J. Arceci Innovation Award (C.G.M.), Gabriella Miller Kids First X01HD100702 (D.T.T and C.G.M.) and R03CA256550 (D.T.T. and C.G.M.), F32 5F32CA254140 (L.M.), and a Garwood Postdoctoral Fellowship of the Hematological Malignancies Program of the St Jude Children's Research Hospital Comprehensive Cancer Center (S.K.). This project was supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180820, UG1CA189859, U24CA114766, U10CA180899, U10CA180866 and U24CA196173.
DISCLAIMER
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding agencies were not directly involved in the design of the study, gathering, analysis and interpretation of the data, writing of the manuscript, or decision to submit the manuscript for publication.
PubMed: 37986997
DOI: 10.1101/2023.11.06.23298028 -
British Journal of Haematology Jul 2016
Topics: Antineoplastic Combined Chemotherapy Protocols; Arabinonucleosides; Cyclophosphamide; Etoposide; Female; Humans; Lymphoma; Male; Middle Aged; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Salvage Therapy
PubMed: 26403537
DOI: 10.1111/bjh.13771 -
Bulletin Du Cancer Aug 2011Cytogenetic, molecular and phenotyping features of malignant hematologic diseases succeeded in improving their management by a more accurate stratification of patients... (Review)
Review
Cytogenetic, molecular and phenotyping features of malignant hematologic diseases succeeded in improving their management by a more accurate stratification of patients according to several groups of risk and by providing a rational for targeted therapy. Three major types of treatment (excluding cellular therapy) are currently available in onco-hematology: conventional chemotherapy, small molecules for targeted therapy and monoclonal antibodies. Conventional chemotherapy with optimization of doses and multidrug-based regimens allowed to substantially improve survival of patients and keeps a place of choice in treatment of these diseases. Targeted treatments came from the cytogenetic and molecular characterization of hemopathies. Thus, the kinase Bcr-Abl, as a result of the translocation t(9;22)(q34;q11), has been successfully targeted by tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia. Molecular abnormalities like internal-tandem duplication/point activating mutations in FLT3 in some acute myeloblastic leukemia or epigenetic dysregulations in some blood malignancies can also be targeted by small molecules. Hematopoietic malignant cells are phenotypically characterized by expression of cluster of differentiation (CD) on their surface. These CD are detected by flow cytometry using specific antibodies. Monoclonal antibodies targeting different CD have been developed for treatment. Rituximab, an anti-CD20 antibody, was the first monoclonal antibody successfully developed for treatment of malignant hematologic diseases. Since rituximab, many other monoclonal antibodies are being developed. Trends in malignant hematologic diseases presented here will include treatments, which have at least entered phase I/II clinical trials in adult or childhood leukemia. They include some novel drugs of conventional chemotherapy like second-generation nucleoside analogues. We will give an overview of the small molecules targeting the different cellular pathways and we will highlight those appearing as the most promising like novel TKIs. The large field of monoclonal antibodies will be also approached focusing on antibodies developed in leukemias.
Topics: Adenine Nucleotides; Antibodies, Monoclonal; Antineoplastic Agents; Arabinonucleosides; Chemistry, Pharmaceutical; Clofarabine; Hematologic Neoplasms; Humans; Molecular Targeted Therapy; Purine Nucleosides; Pyrimidinones
PubMed: 21865110
DOI: 10.1684/bdc.2011.1412