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Yves Pommier - One of the best experts on this subject based on the ideXlab platform.

  • The Indenoisoquinoline LMP517: A Novel Antitumor Agent Targeting both TOP1 and TOP2.
    Molecular cancer therapeutics, 2020
    Co-Authors: Laetitia Marzi, Shar-yin N. Huang, Yilun Sun, Amy James, Simone Difilippantonio, Yves Pommier
    Abstract:

    The camptothecin derivatives topoisomerase I (TOP1) inhibitors, irinotecan and topotecan, are FDA approved for the treatment of colorectal, ovarian, lung and breast cancers. Because of the chemical instability of camptothecins, short plasma half-life, drug efflux by the multidrug-resistance ABC transporters, and the severe diarrhea produced by irinotecan, indenoisoquinoline TOP1 inhibitors (LMP400, LMP776, and LMP744), which overcome these limitations, have been developed and are in clinical development. Further modifications of the indenoisoquinolines led to the fluoroindenoisoquinolines, one of which, LMP517, is the focus of this study. LMP517 showed better antitumor activity than its parent compound LMP744 against H82 (small cell lung cancer) xenografts. Genetic analyses in DT40 cells showed a dual TOP1 and TOP2 signature with selectivity of LMP517 for DNA repair-deficient tyrosyl DNA phosphodiesterase 2 (TDP2)- and Ku70-knockout cells. RADAR assays revealed that LMP517, and to a lesser extent LMP744, induce TOP2 cleavage complexes (TOP2cc) in addition to TOP1ccs. Histone γH2AX detection showed that, unlike classical TOP1 inhibitors, LMP517 targets cells independently of their position in the cell cycle. Our study establishes LMP517 as a dual TOP1 and TOP2 inhibitor with therapeutic potential.

  • tyrosyl dna phosphodiesterase 1 and topoisomerase i activities as predictive indicators for glioblastoma susceptibility to genotoxic agents
    Cancers, 2019
    Co-Authors: Wenjie Wang, Yves Pommier, Monica Rodriguezsilva, Arlet Acanda M De La Rocha, Aizik L Wolf, Yanhao Lai, Yuan Liu, William C Reinhold, Jeremy W Chambers, Yukching Tsedinh
    Abstract:

    Glioblastoma (GBM) patients have an estimated survival of ~15 months with treatment, and the standard of care only modestly enhances patient survival. Identifying biomarkers representing vulnerabilities may allow for the selection of efficacious chemotherapy options to address personalized variations in GBM tumors. Irinotecan targets topoisomerase I (TOP1) by forming a ternary DNA-TOP1 cleavage complex (TOP1cc), inducing apoptosis. Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a crucial repair enzyme that may reduce the effectiveness of irinotecan. We treated GBM cell lines with increasing concentrations of irinotecan and compared the IC50 values. We found that the TDP1/TOP1 activity ratio had the strongest correlation (Pearson correlation coefficient R = 0.972, based on the average from three sets of experiments) with IC50 values following irinotecan treatment. Increasing the TDP1/TOP1 activity ratio by the ectopic expression of wild-type TDP1 increased in irinotecan IC50, while the expression of the TDP1 catalytic-null mutant did not alter the susceptibility to irinotecan. The TDP1/TOP1 activity ratio may be a new predictive indicator for GBM vulnerability to irinotecan, allowing for the selection of individual patients for irinotecan treatment based on risk-benefit. Moreover, TDP1 inhibitors may be a novel combination treatment with irinotecan to improve GBM patient responsiveness to genotoxic chemotherapies.

  • tyrosyl dna phosphodiesterase 1 and topoisomerase i activities as predictive indicators for glioblastoma susceptibility to genotoxic agents
    bioRxiv, 2019
    Co-Authors: Wenjie Wang, Yves Pommier, Monica Rodriguezsilva, Arlet Acanda M De La Rocha, Aizik L Wolf, Yanhao Lai, Yuan Liu, William C Reinhold, Jeremy W Chambers, Yukching Tsedinh
    Abstract:

    Abstract Background Glioblastoma (GBM) patients have an estimated survival of ∼15 months with treatment, and the standard of care only modestly enhances patient survival. Identifying biomarkers representing vulnerabilities may allow for selection of efficacious chemotherapy options to address personalized variations in GBM tumors. Irinotecan, currently in clinical trials for GBM, targets topoisomerase I (TOP1) by forming a ternary DNA-TOP1 cleavage complex (TOP1cc) inducing apoptosis. Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a crucial repair enzyme that may reduce the effectiveness of irinotecan. Methods We treated GBM cell lines with increasing concentrations of irinotecan and compared the IC50 values. TOP1 and TDP1 protein levels from each cell type as well as GBM patient tumors were determined by Western blot analysis, while activity levels were ascertained by specific enzymatic assays. Cellular TDP1 was elevated by ectopic expression of wild-type or mutant TDP1. Results After comparing cellular susceptibility to TDP1 and TOP1 concentrations and activities, we found that the TDP1/TOP1 activity ratio had the strongest correlation (Pearson correlation coefficient R = 0.92) with IC50 values following irinotecan treatment. Increasing the TDP1/TOP1 activity ratio by ectopic expression of wild-type TDP1 increased in irinotecan IC50, while expression of the TDP1 catalytic-null mutant did not alter the susceptibility to irinotecan. Conclusions TDP1/TOP1 activity ratio may be a new predictive indicator for GBM vulnerability to irinotecan, allowing for selection of individual patients for irinotecan treatment based on risk-benefit. Moreover, TDP1 inhibitors may be a novel combination treatment with irinotecan to improve GBM patient responsiveness to genotoxic chemotherapies. Key Points TDP1/TOP1 activity ratio correlates with irinotecan sensitivity in GBM cell lines. TDP1 and TOP1 protein levels are not reliable predictors for irinotecan activity. TDP1 inhibition is a plausible approach to improve irinotecan effectiveness in GBM. Importance of the Study The current standard of care (surgery, radiation, and chemotherapy) for GBM patients modestly enhances survival beyond ∼15 months. Thus, there is a great need for effective therapies and biomarkers that address personalized variations in GBM tumors to improve treatment outcome. Topoisomerase I (TOP1) is the target of irinotecan. The repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) is known to excise irinotecan-induced TOP1-DNA cleavage complexes (TOP1ccs). Consequently, this study examines the relationship between TOP1 and TDP1 expression and activities in GBM cells and their correlation with irinotecan sensitivity. The results reveal that the TDP1/TOP1 activity ratio predicts irinotecan vulnerability in GBM cell lines. TDP1/TOP1 activity ratio was found to vary among GBM patient tumors. This potential predictive indicator may permit selection of patients responsive to irinotecan based on the capacity to repair TOP1cc. Moreover, inhibitors of TDP1 may represent a promising approach to enhance irinotecan efficacy in GBM patients.

  • synthesis and biological evaluation of the first triple inhibitors of human topoisomerase 1 tyrosyl dna phosphodiesterase 1 tdp1 and tyrosyl dna phosphodiesterase 2 tdp2
    Journal of Medicinal Chemistry, 2017
    Co-Authors: Ping Wang, Christophe Marchand, Keli Agama, Azhar Ravji, Evgeny Kiselev, Christophe E Redon, Mohamed S A Elsayed, Caroline B Plescia, Olga Zeleznik, Yves Pommier
    Abstract:

    Tdp1 and Tdp2 are two tyrosyl–DNA phosphodiesterases that can repair damaged DNA resulting from topoisomerase inhibitors and a variety of other DNA-damaging agents. Both Tdp1 and Tdp2 inhibition could hypothetically potentiate the cytotoxicities of topoisomerase inhibitors. This study reports the successful structure-based design and synthesis of new 7-azaindenoisoquinolines that act as triple inhibitors of TOP1, Tdp1, and Tdp2. Enzyme inhibitory data and cytotoxicity data from human cancer cell cultures establish that modification of the lactam side chain of the 7-azaindenoisoquinolines can modulate their inhibitory potencies and selectivities vs TOP1, Tdp1, and Tdp2. Molecular modeling of selected target compounds bound to TOP1, Tdp1, and Tdp2 was used to design the inhibitors and facilitate the structure–activity relationship analysis. The monitoring of DNA damage by γ-H2AX foci formation in human PBMCs (lymphocytes) and acute lymphoblastic leukemia CCRF-CEM cells documented significantly more DNA dama...

  • topoisomerase i mediated cleavage at unrepaired ribonucleotides generates dna double strand breaks
    The EMBO Journal, 2017
    Co-Authors: Shar-yin N. Huang, Jessica S Williams, Thomas A. Kunkel, Mercedes E Arana, Yves Pommier
    Abstract:

    Ribonuclease activity of topoisomerase I (TOP1) causes DNA nicks bearing 2',3'-cyclic phosphates at ribonucleotide sites. Here, we provide genetic and biochemical evidence that DNA double-strand breaks (DSBs) can be directly generated by TOP1 at sites of genomic ribonucleotides. We show that RNase H2-deficient yeast cells displayed elevated frequency of Rad52 foci, inactivation of RNase H2 and RAD52 led to synthetic lethality, and combined loss of RNase H2 and RAD51 induced slow growth and replication stress. Importantly, these phenotypes were rescued upon additional deletion of TOP1, implicating homologous recombination for the repair of TOP1-induced damage at ribonuclelotide sites. We demonstrate biochemically that irreversible DSBs are generated by subsequent TOP1 cleavage on the opposite strand from the TOP1-induced DNA nicks at ribonucleotide sites. Analysis of TOP1-linked DNA from pull-down experiments revealed that TOP1 is covalently linked to the end of DNA in RNase H2-deficient yeast cells, supporting this model. Taken together, these results define TOP1 as a source of DSBs and genome instability when ribonucleotides incorporated by the replicative polymerases are not removed by RNase H2.

Christophe Marchand - One of the best experts on this subject based on the ideXlab platform.

  • discovery synthesis and evaluation of oxynitidine derivatives as dual inhibitors of dna topoisomerase ib TOP1 and tyrosyl dna phosphodiesterase 1 tdp1 and potential antitumor agents
    Journal of Medicinal Chemistry, 2018
    Co-Authors: Xiaoru Zhang, Christophe Marchand, Haowen Wang, Wenlin Tang, Yu Zhang, Hui Yang, Azhar Ravji, Evgeny Kiselev, Kwabena Oforiatta, Keli Agama
    Abstract:

    Tyrosyl–DNA phosphodiesterase 1 (TDP1) is a recently discovered enzyme repairing DNA lesions resulting from stalled topoisomerase IB (TOP1)–DNA covalent complex. Inhibiting TDP1 in conjunction with TOP1 inhibitors can boost the action of the latter. Herein, we report the discovery of the natural product oxynitidine scaffold as a novel chemotype for the development of TOP1 and TDP1 inhibitors. Three kinds of analogues, benzophenanthridinone, dihydrobenzophenanthridine, and benzophenanthridine derivatives, were synthesized and evaluated for both TOP1 and TDP1 inhibition and cytotoxicity. Analogue 19a showed high TOP1 inhibition (+++) and induced the formation of cellular TOP1cc and DNA damage, resulting in cancer cells apoptosis at nanomolar concentration range. In vivo studies indicated that 19a exhibits antitumor efficiency in HCT116 xenograft model. 41a exhibited additional TDP1 inhibition with IC50 value of 7 μM and synergistic effect with camptothecin in MCF-7 cells. This work will facilitate future ef...

  • synthesis and biological evaluation of the first triple inhibitors of human topoisomerase 1 tyrosyl dna phosphodiesterase 1 tdp1 and tyrosyl dna phosphodiesterase 2 tdp2
    Journal of Medicinal Chemistry, 2017
    Co-Authors: Ping Wang, Christophe Marchand, Keli Agama, Azhar Ravji, Evgeny Kiselev, Christophe E Redon, Mohamed S A Elsayed, Caroline B Plescia, Olga Zeleznik, Yves Pommier
    Abstract:

    Tdp1 and Tdp2 are two tyrosyl–DNA phosphodiesterases that can repair damaged DNA resulting from topoisomerase inhibitors and a variety of other DNA-damaging agents. Both Tdp1 and Tdp2 inhibition could hypothetically potentiate the cytotoxicities of topoisomerase inhibitors. This study reports the successful structure-based design and synthesis of new 7-azaindenoisoquinolines that act as triple inhibitors of TOP1, Tdp1, and Tdp2. Enzyme inhibitory data and cytotoxicity data from human cancer cell cultures establish that modification of the lactam side chain of the 7-azaindenoisoquinolines can modulate their inhibitory potencies and selectivities vs TOP1, Tdp1, and Tdp2. Molecular modeling of selected target compounds bound to TOP1, Tdp1, and Tdp2 was used to design the inhibitors and facilitate the structure–activity relationship analysis. The monitoring of DNA damage by γ-H2AX foci formation in human PBMCs (lymphocytes) and acute lymphoblastic leukemia CCRF-CEM cells documented significantly more DNA dama...

  • synthesis and biological evaluation of nitrated 7 8 9 and 10 hydroxyindenoisoquinolines as potential dual topoisomerase i TOP1 tyrosyl dna phosphodiesterase i tdp1 inhibitors
    Journal of Medicinal Chemistry, 2015
    Co-Authors: Trung Xuan Nguyen, Yves Pommier, Christophe Marchand, Keli Agama, Monica Abdelmalak, Mark Cushman
    Abstract:

    The structure–activity relationships and hit-to-lead optimization of dual TOP1–TDP1 inhibitors in the indenoisoquinoline drug class were investigated. A series of nitrated 7-, 8-, 9-, and 10-hydroxyindenoisoquinolines were synthesized and evaluated. Several compounds displayed potent dual TOP1–TDP1 inhibition. The 9-hydroxy series exhibited potencies and cytotoxicities vs TOP1 that surpassed those of camptothecin (CPT), the natural alkaloid that is being used as a standard in the TOP1-mediated DNA cleavage assay. One member of this series was a more potent TOP1 inhibitor at a concentration of 5 nM and produced a more stable ternary drug–DNA–TOP1 cleavage complex than CPT.

  • design synthesis and biological evaluation of o 2 modified indenoisoquinolines as dual topoisomerase i tyrosyl dna phosphodiesterase i inhibitors
    Journal of Medicinal Chemistry, 2014
    Co-Authors: Keli Agama, Yves Pommier, Christophe Marchand, Mark Cushman
    Abstract:

    Tyrosyl-DNA phosphodiesterase I (TDP1) repairs stalled topoisomerase I (TOP1)–DNA covalent complexes and has been proposed to be a promising and attractive target for cancer treatment. Inhibitors of TDP1 could conceivably act synergistically with TOP1 inhibitors and thereby potentiate the effects of TOP1 poisons. This study describes the successful design and synthesis of 2-position-modified indenoisoquinolines as dual TOP1–TDP1 inhibitors using a structure-based drug design approach. Enzyme inhibition studies indicate that indenoisoquinolines modified at the 2-position with three-carbon side chains ending with amino substituents show both promising TOP1 and TDP1 inhibitory activity. Molecular modeling of selected target compounds bound to TOP1 and TDP1 was used to rationalize the enzyme inhibition results and structure–activity relationship analysis.

  • Identification of novel PARP inhibitors using a cell-based TDP1 inhibitory assay in a quantitative high-throughput screening platform
    DNA repair, 2014
    Co-Authors: Junko Murai, Christophe Marchand, Sampada A. Shahane, Hongmao Sun, Ruili Huang, Yiping Zhang, Adel Chergui, James H. Doroshow, Ajit Jadhav
    Abstract:

    Anti-cancer topoisomerase I (TOP1) inhibitors (camptothecin and its derivatives irinotecan and topotecan, and indenoisoquinolines) induce lethal DNA lesions by stabilizing TOP1-DNA cleavage complex (TOP1cc). These lesions are repaired by parallel repair pathways including the tyrosyl-DNA phosphodiesterase 1 (TDP1)-related pathway and homologous recombination. As TDP1-deficient cells in vertebrates are hypersensitive to TOP1 inhibitors, small molecules inhibiting TDP1 should augment the cytotoxicity of TOP1 inhibitors. We developed a cell-based high-throughput screening assay for the discovery of inhibitors for human TDP1 using a TDP1-deficient chicken DT40 cell line (TDP1-/-) complemented with human TDP1 (hTDP1). Any compounds showing a synergistic effect with the TOP1 inhibitor camptothecin (CPT) in hTDP1 cells should either be a TDP1-related pathway inhibitor or an inhibitor of alternate repair pathways for TOP1cc. We screened the 400,000-compound Small Molecule Library Repository (SMLR, NIH Molecular Libraries) against hTDP1 cells in the absence or presence of CPT. After confirmation in a secondary screen using both hTDP1 and TDP1-/- cells in the absence or presence of CPT, five compounds were confirmed as potential TDP1 pathway inhibitors. All five compounds showed synergistic effect with CPT in hTDP1 cells, but not in TDP1-/- cells, indicating that the compounds inhibited a TDP1-related repair pathway. Yet, in vitro gel-based assay revealed that the five compounds did not inhibit TDP1 catalytic activity directly. We tested the compounds for their ability to inhibit poly(ADP-ribose)polymerase (PARP) because PARP inhibitors are known to potentiate the cytotoxicity of CPT by inhibiting the recruitment of TDP1 to TOP1cc. Accordingly, we found that the five compounds inhibit catalytic activity of PARP by ELISA and Western blotting. We identified the most potent compound (Cpd1) that offers characteristic close to veliparib, a leading clinical PARP inhibitor. Cpd1 may represent a new scaffold for the development of PARP inhibitors.

Nils Brünner - One of the best experts on this subject based on the ideXlab platform.

  • Topoisomerase I copy number alterations as biomarker for irinotecan efficacy in metastatic colorectal cancer.
    BMC cancer, 2017
    Co-Authors: Jesper Andreas Palshof, Nils Brünner, Estrid Høgdall, Tim Svenstrup Poulsen, Dorte Linnemann, Benny Vittrup Jensen, Per Pfeiffer, Line Schmidt Tarpgaard, Jan Stenvang, Mette Karen Yilmaz
    Abstract:

    No biomarker exists to guide the optimal choice of chemotherapy for patients with metastatic colorectal cancer. We examined the copy numbers (CN) of topoisomerase I (TOP1) as well as the ratios of TOP1/CEN-20 and TOP1/CEN-2 as biomarkers for irinotecan efficacy in patients with metastatic colorectal cancer. From a national cohort, we identified 163 patients treated every third week with irinotecan 350 mg/m2 as second-line therapy. Among these 108 were eligible for analyses and thus entered the study. Primary tumors samples were collected and tissue microarray (TMA) blocks were produced. FISH analysis was performed using two probe-mixes: TOP1/CEN-20 and TOP1/CEN-2. Only samples harboring all three signals (TOP1, CEN-20 and CEN-2) using FISH were included in the analyses. In the TOP1/CEN-20 probe-mix the median TOP1- and CEN-20 CN were 4.46 (range: 1.5–9.5) and 2.00 (range: 0.55–4.55), respectively. The median TOP1- and CEN-2 CN in the TOP1/CEN-2 probe-mix, were 4.57 (range: 1.82–10.43) and 1.98 (range: 1.22–6.14), respectively. The median TOP1/CEN-20 ratio and TOP1/CEN-2 ratio were 1.25 (range: 0.92–2.90) and 2.05 (range: 1.00–6.00), respectively. None of the markers TOP1 CN, TOP1/CEN-20-ratio or TOP1/CEN-2-ratio were associated with progression free survival, overall survival or baseline characteristics. Yet, we observed a borderline association for a stepwise increase of the TOP1 CN in relation to objective response as hazard ratio were 1.35 (95% CI 0.96–1.90; p = 0.081). We verified a borderline significant association between increasing TOP1 CN and objective response as previously reported. Applying the probes representing CEN-20 and CEN-2, in order to investigate the ratios of TOP1/CEN-20 and TOP1/CEN-2 provided no further information in search of a biomarker driven patient stratification. Other biomarkers to be paired with TOP1 CN are therefore highly warranted.

  • DNA Topoisomerase I Gene Copy Number and mRNA Expression Assessed as Predictive Biomarkers for Adjuvant Irinotecan in Stage II/III Colon Cancer
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2015
    Co-Authors: Sune Boris Nygård, Nils Brünner, Ben Vainer, Signe Lykke Nielsen, Fred T. Bosman, Sabine Tejpar, Arnaud Roth, Mauro Delorenzi, Eva Budinská
    Abstract:

    Purpose: Prospective–retrospective assessment of the TOP1 gene copy number and TOP1 mRNA expression as predictive biomarkers for adjuvant irinotecan in stage II/III colon cancer. Experimental Design: Formalin-fixed, paraffin-embedded tissue microarrays were obtained from an adjuvant colon cancer trial (PETACC3) where patients were randomized to 5-fluorouracil/folinic acid with or without additional irinotecan. TOP1 copy number status was analyzed by fluorescence in situ hybridization (FISH) using a TOP1 /CEN20 dual-probe combination. TOP1 mRNA data were available from previous analyses. Results: TOP1 FISH and follow-up data were obtained from 534 patients. TOP1 gain was identified in 27% using a single-probe enumeration strategy (≥4 TOP1 signals per cell) and in 31% when defined by a TOP1 /CEN20 ratio ≥ 1.5. The effect of additional irinotecan was not dependent on TOP1 FISH status. TOP1 mRNA data were available from 580 patients with stage III disease. Benefit of irinotecan was restricted to patients characterized by TOP1 mRNA expression ≥ third quartile (RFS: HR adjusted , 0.59; P = 0.09; OS: HR adjusted , 0.44; P = 0.03). The treatment by TOP1 mRNA interaction was not statistically significant, but in exploratory multivariable fractional polynomial interaction analysis, increasing TOP1 mRNA values appeared to be associated with increasing benefit of irinotecan. Conclusions: In contrast to the TOP1 copy number, a trend was demonstrated for a predictive property of TOP1 mRNA expression. On the basis of TOP1 mRNA, it might be possible to identify a subgroup of patients where an irinotecan doublet is a clinically relevant option in the adjuvant setting of colon cancer. Clin Cancer Res; 22(7); 1621–31. ©2015 AACR .

  • TOP1 gene copy numbers are increased in cancers of the bile duct and pancreas.
    Scandinavian journal of gastroenterology, 2015
    Co-Authors: Mie Grunnet, Nils Brünner, Dan Calatayud, Nicolai Aagaard Schultz, Jane Preuss Hasselby, Morten Mau-sørensen, Jan Stenvang
    Abstract:

    AbstractBackground. Bile duct and pancreatic cancer (PC) have poor prognoses and treatment options for inoperable patients are scarce. In order to improve outcome for these patients, there is an urgent need for biomarkers predictive of treatment effect. Irinotecan is a topoisomerase 1 (TOP1) poison. TOP1 protein, TOP1 gene copy number and mRNA expression, respectively, have been proposed as predictive biomarkers of response to irinotecan in other cancers. Here we investigate the occurrence of TOP1 gene aberrations in cancers of the bile ducts and pancreas. Material and methods. TOP1 and centromere 20 (CEN-20) numbers were investigated by fluorescence in situ hybridization analyses in tumor tissue from 226 patients. The frequencies of aberration in the TOP1 gene copy number, the CEN-20 copy number and the TOP1/CEN-20 ratio were analyzed. As TOP1 is located on chromosome 20, the CEN-20 probe was included to distinguish between chromosomal and gene amplifications. Results. In PC, 29.8% had an increased TOP1 ...

  • Mechanisms of Topoisomerase I (TOP1) Gene Copy Number Increase in a Stage III Colorectal Cancer Patient Cohort
    PloS one, 2013
    Co-Authors: David Hersi Smith, Ib Jarle Christensen, Niels Frank Jensen, Bo Markussen, Maria Unni Rømer, Sune Boris Nygård, Sven Müller, Hans Jørgen Nielsen, Nils Brünner, Kirsten Vang Nielsen
    Abstract:

    Background Topoisomerase I (TOP1) is the target of TOP1 inhibitor chemotherapy. The TOP1 gene, located at 20q12-q13.1, is frequently detected at elevated copy numbers in colorectal cancer (CRC). The present study explores the mechanism, frequency and prognostic impact of TOP1 gene aberrations in stage III CRC and how these can be detected by fluorescent in situ hybridization (FISH). Methods Nine CRC cell line metaphase spreads were analyzed by FISH with a TOP1 probe in combination with a reference probe covering either the centromeric region of chromosome 20 (CEN-20) or chromosome 2 (CEN-2). Tissue sections from 154 chemonaive stage III CRC patients, previously studied with TOP1/CEN-20, were analyzed with TOP1/CEN-2. Relationships between biomarker status and overall survival (OS), time to recurrence (TTR) in CRC and time to local recurrence (LR; rectal cancer only) were determined. Results TOP1 aberrations were observed in four cell line metaphases. In all cell lines CEN-2 was found to reflect chromosomal ploidy levels and therefore the TOP1/CEN-2 probe combination was selected to identify TOP1 gene gains (TOP1/CEN-2≥1.5). One hundred and three patients (68.2%) had TOP1 gain, of which 15 patients (14.6%) harbored an amplification (TOP1/CEN-20≥2.0). TOP1 gene gain did not have any association with clinical endpoints, whereas TOP1 amplification showed a non-significant trend towards longer TTR (multivariate HR: 0.50, p = 0.08). Once amplified cases were segregated from other cases of gene gain, non-amplified gene increases (TOP1/CEN-2≥1.5 and TOP1/CEN-20

  • mechanisms of topoisomerase i TOP1 gene copy number increase in a stage iii colorectal cancer patient cohort
    PLOS ONE, 2013
    Co-Authors: David Hersi Smith, Ib Jarle Christensen, Niels Frank Jensen, Bo Markussen, Maria Unni Rømer, Sune Boris Nygård, Sven Müller, Hans Jørgen Nielsen, Nils Brünner
    Abstract:

    Background Topoisomerase I (TOP1) is the target of TOP1 inhibitor chemotherapy. The TOP1 gene, located at 20q12-q13.1, is frequently detected at elevated copy numbers in colorectal cancer (CRC). The present study explores the mechanism, frequency and prognostic impact of TOP1 gene aberrations in stage III CRC and how these can be detected by fluorescent in situ hybridization (FISH). Methods Nine CRC cell line metaphase spreads were analyzed by FISH with a TOP1 probe in combination with a reference probe covering either the centromeric region of chromosome 20 (CEN-20) or chromosome 2 (CEN-2). Tissue sections from 154 chemonaive stage III CRC patients, previously studied with TOP1/CEN-20, were analyzed with TOP1/CEN-2. Relationships between biomarker status and overall survival (OS), time to recurrence (TTR) in CRC and time to local recurrence (LR; rectal cancer only) were determined. Results TOP1 aberrations were observed in four cell line metaphases. In all cell lines CEN-2 was found to reflect chromosomal ploidy levels and therefore the TOP1/CEN-2 probe combination was selected to identify TOP1 gene gains (TOP1/CEN-2≥1.5). One hundred and three patients (68.2%) had TOP1 gain, of which 15 patients (14.6%) harbored an amplification (TOP1/CEN-20≥2.0). TOP1 gene gain did not have any association with clinical endpoints, whereas TOP1 amplification showed a non-significant trend towards longer TTR (multivariate HR: 0.50, p = 0.08). Once amplified cases were segregated from other cases of gene gain, non-amplified gene increases (TOP1/CEN-2≥1.5 and TOP1/CEN-20<2.0) showed a trend towards shorter TTR (univariate HR: 1.57, p = 0.07). Conclusions TOP1 gene copy number increase occurs frequently in stage III CRC in a mechanism that often includes CEN-20. Using CEN-2 as a measurement for tumor ploidy levels, we were able to discriminate between different mechanisms of gene gain, which appeared to differ in prognostic impact. TOP1 FISH guidelines have been updated.

Maria Unni Rømer - One of the best experts on this subject based on the ideXlab platform.

  • Topoisomerase-1 gene copy aberrations are frequent in patients with breast cancer.
    International journal of cancer, 2015
    Co-Authors: Iben Kümler, Ib Jarle Christensen, Maria Unni Rømer, Sune Boris Nygård, Estrid Høgdall, Tim Svenstrup Poulsen, Signe Lykke Nielsen, Eva Balslev, José M.a. Moreira, Dorte Nielsen
    Abstract:

    Topoisomerase-1 (TOP1) targeting drugs have shown promising efficacy in patients with metastatic breast cancer (BC). However, these drugs are rather toxic calling for development and validation of predictive biomarkers to increase the therapeutic index. As these drugs are targeting the TOP1 protein and since no validated anti-TOP1 antibodies for immunohistochemistry have been reported, we raised the hypothesis that TOP1 gene amplifications may serve as a proxy for the TOP1 protein and thereby a biomarker of response to treatment with TOP1 inhibitors in BC. The aim was to determine the prevalence of TOP1 gene copy gain in BC. The prevalence of TOP1 gene copy gain was investigated by fluorescence in situ hybridization with a TOP1/CEN-20 probemix in normal breast tissue (N = 100) and in tissue from patients with metastatic BC in a discovery (N = 100) and a validation cohort (N = 205). As amplification of 20q including CEN-20 is common in BC a TOP1/CEN-2 probemix was applied to the validation cohort. More than 30% of the patients had gene copy numbers of ≥ 4 and ∼20% of the patients had TOP1/CEN-20 ratios ≥ 1.5. The CEN-2 probe did not add any information. Gain of the TOP1 gene appears to be common in BC making the gene a potential biomarker for response to treatment with TOP1 inhibitors. As 20q amplification is a common finding in BC and as no other suitable reference gene has yet been identified, TOP1 copy number may be a more valid method of detecting gain than using a gene/centromere ratio.

  • Mechanisms of Topoisomerase I (TOP1) Gene Copy Number Increase in a Stage III Colorectal Cancer Patient Cohort
    PloS one, 2013
    Co-Authors: David Hersi Smith, Ib Jarle Christensen, Niels Frank Jensen, Bo Markussen, Maria Unni Rømer, Sune Boris Nygård, Sven Müller, Hans Jørgen Nielsen, Nils Brünner, Kirsten Vang Nielsen
    Abstract:

    Background Topoisomerase I (TOP1) is the target of TOP1 inhibitor chemotherapy. The TOP1 gene, located at 20q12-q13.1, is frequently detected at elevated copy numbers in colorectal cancer (CRC). The present study explores the mechanism, frequency and prognostic impact of TOP1 gene aberrations in stage III CRC and how these can be detected by fluorescent in situ hybridization (FISH). Methods Nine CRC cell line metaphase spreads were analyzed by FISH with a TOP1 probe in combination with a reference probe covering either the centromeric region of chromosome 20 (CEN-20) or chromosome 2 (CEN-2). Tissue sections from 154 chemonaive stage III CRC patients, previously studied with TOP1/CEN-20, were analyzed with TOP1/CEN-2. Relationships between biomarker status and overall survival (OS), time to recurrence (TTR) in CRC and time to local recurrence (LR; rectal cancer only) were determined. Results TOP1 aberrations were observed in four cell line metaphases. In all cell lines CEN-2 was found to reflect chromosomal ploidy levels and therefore the TOP1/CEN-2 probe combination was selected to identify TOP1 gene gains (TOP1/CEN-2≥1.5). One hundred and three patients (68.2%) had TOP1 gain, of which 15 patients (14.6%) harbored an amplification (TOP1/CEN-20≥2.0). TOP1 gene gain did not have any association with clinical endpoints, whereas TOP1 amplification showed a non-significant trend towards longer TTR (multivariate HR: 0.50, p = 0.08). Once amplified cases were segregated from other cases of gene gain, non-amplified gene increases (TOP1/CEN-2≥1.5 and TOP1/CEN-20

  • mechanisms of topoisomerase i TOP1 gene copy number increase in a stage iii colorectal cancer patient cohort
    PLOS ONE, 2013
    Co-Authors: David Hersi Smith, Ib Jarle Christensen, Niels Frank Jensen, Bo Markussen, Maria Unni Rømer, Sune Boris Nygård, Sven Müller, Hans Jørgen Nielsen, Nils Brünner
    Abstract:

    Background Topoisomerase I (TOP1) is the target of TOP1 inhibitor chemotherapy. The TOP1 gene, located at 20q12-q13.1, is frequently detected at elevated copy numbers in colorectal cancer (CRC). The present study explores the mechanism, frequency and prognostic impact of TOP1 gene aberrations in stage III CRC and how these can be detected by fluorescent in situ hybridization (FISH). Methods Nine CRC cell line metaphase spreads were analyzed by FISH with a TOP1 probe in combination with a reference probe covering either the centromeric region of chromosome 20 (CEN-20) or chromosome 2 (CEN-2). Tissue sections from 154 chemonaive stage III CRC patients, previously studied with TOP1/CEN-20, were analyzed with TOP1/CEN-2. Relationships between biomarker status and overall survival (OS), time to recurrence (TTR) in CRC and time to local recurrence (LR; rectal cancer only) were determined. Results TOP1 aberrations were observed in four cell line metaphases. In all cell lines CEN-2 was found to reflect chromosomal ploidy levels and therefore the TOP1/CEN-2 probe combination was selected to identify TOP1 gene gains (TOP1/CEN-2≥1.5). One hundred and three patients (68.2%) had TOP1 gain, of which 15 patients (14.6%) harbored an amplification (TOP1/CEN-20≥2.0). TOP1 gene gain did not have any association with clinical endpoints, whereas TOP1 amplification showed a non-significant trend towards longer TTR (multivariate HR: 0.50, p = 0.08). Once amplified cases were segregated from other cases of gene gain, non-amplified gene increases (TOP1/CEN-2≥1.5 and TOP1/CEN-20<2.0) showed a trend towards shorter TTR (univariate HR: 1.57, p = 0.07). Conclusions TOP1 gene copy number increase occurs frequently in stage III CRC in a mechanism that often includes CEN-20. Using CEN-2 as a measurement for tumor ploidy levels, we were able to discriminate between different mechanisms of gene gain, which appeared to differ in prognostic impact. TOP1 FISH guidelines have been updated.

  • Abstract P3-06-32: Topoisomerase 1 gene copy aberration is a frequent finding in clinical breast cancer samples
    Poster Session Abstracts, 2012
    Co-Authors: Jan Stenvang, Maria Unni Rømer, Eva Balslev, Dorte Nielsen, Marcel Smid, Søren Jensby Nielsen, Mieke Timmermans, S Nygaard, I. J. Christensen, J.a. Foekens
    Abstract:

    Background: The topoisomerase-1 (TOP1) targeting drug irinotecan may be a new effective drug in the treatment of metastatic breast cancer patients 1,2 . However, the use of irinotecan should be guided by predictive biomarkers to avoid drug-induced site effects in the non-responding subgroup of patients. A newly developed TOP1 fluorescence in situ hybridization (FISH) 3 probe mix (Dako, Denmark) may represent such a novel predictive biomarker assay. Materials and Methods: The TOP1 /CEN-20 FISH probe mix was applied to normal breast tissue (n = 100) and human breast cancer biopsy material (n = 42). TOP1 copy number variations (Affymetrix GeneChip 100k SNP array) and TOP1 mRNA levels (Affymetrix u133a GeneChip) were studied in 313 breast cancer samples 4 . Results: Employing FISH, the mean diploid TOP1 copy number in normal breast epithelium was 1.7 (range 1.45–1.90) and the diploid CEN-20 number was 1.6 (range 1.38–1.82). The normal diploid range was defined as the mean plus/minus 0.5 times the haploid gene copy number (Table 1 and 2). Using these values as cut-off, 13 (30.9%) of the 42 breast cancer samples had TOP1 gene copy number in the diploid range, 18 (42.9%) had 1 extra copy and 11 (26.2%) had ≥ 2 extra copies. CEN-20 counts showed that 19 (45.5%) had CEN-20 values within the diploid range, 21 (50%) had 1 extra copy and 2 (4.8%) had ≥ 2 extra copies. Calculating the TOP1 /CEN-20 ratio showed that 6 (14.3%) of the patients samples had a ratio above 1.5, while none had a ratio TOP1 and CEN-20 counts in the 42 breast cancer samples analyzed with FISH was 0.73. In the 313 breast cancer samples 34/313 (10.9%) had TOP1 copy gain and a significant association (p TOP1 copy number and TOP1 mRNA. Conclusions: This study shows that about 25% of breast cancers have ≥2 extra copies of TOP1 as determined by FISH analyses. The high correlation between TOP1 and CEN20 in the 42 breast cancer samples challenges the use of the ratio. Moreover, the significant association between TOP1 gene copy number (SNP array) and TOP1 mRNA expression in breast cancer biopsies suggests that TOP1 FISH results will correlate with TOP1 protein amounts and may therefore be used to predict sensitivity to the TOP1 targeting drug irinotecan in breast cancer. However, a prospective clinical study is needed to prove or disprove this hypothesis. References 1. Perez EA et al. J Clin Oncol. 2004, 22(14):2849–55. 2. Lee KS et al. Invest New Drugs. 2012 May 5. 3. Romer MU et al. Scand J Gastroenterol. 2012, 47(1):68–79. 4. Zhang Y et al. Cancer Res 2009, 69(9):3795–3801. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-32.

  • An explorative analysis of TOP1 copy number alterations in a chemonaive stage III CRC patient cohort.
    Journal of Clinical Oncology, 2012
    Co-Authors: David Hersi Smith, Ib Jarle Christensen, Niels Frank Jensen, Maria Unni Rømer, Sven Müller, Hans Jørgen Nielsen, Nils Brünner, Sune Boris Nygaard, Kirsten Vang Nielsen
    Abstract:

    66 Background: Topoisomerase I (TOP1) is the target of TOP1 inhibitor chemotherapy. The TOP1 gene, located at 20q12, is frequently gained in colorectal cancer (CRC). The present study explores the mechanism, frequency and prognostic impact of TOP1 gene alterations in advanced CRC. Methods: Nine CRC cell line metaphase spreads were analyzed with a TOP1 probe in combination with a reference probe covering either the centromeric region of chromosome 20 (CEN20) or chromosome 2 (CEN2). Tissue sections from 154 stage III CRC patients, previously studied with TOP1/CEN20, were analyzed with TOP1/CEN2. Relationships between biomarker status and overall survival (OS), time to recurrence (TTR) in CRC and to local recurrence (LR; rectal cancer only) were analyzed using multivariate statistics. Results: TOP1 alterations were observed in 4 cell line metaphases. In 3 cases, TOP1 gain involved CEN20, indicating either gain of chromosome 20 or 20q. In all cell lines CEN2 was found to reflect chromosomal ploidy levels and ...

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  • discovery synthesis and evaluation of oxynitidine derivatives as dual inhibitors of dna topoisomerase ib TOP1 and tyrosyl dna phosphodiesterase 1 tdp1 and potential antitumor agents
    Journal of Medicinal Chemistry, 2018
    Co-Authors: Xiaoru Zhang, Christophe Marchand, Haowen Wang, Wenlin Tang, Yu Zhang, Hui Yang, Azhar Ravji, Evgeny Kiselev, Kwabena Oforiatta, Keli Agama
    Abstract:

    Tyrosyl–DNA phosphodiesterase 1 (TDP1) is a recently discovered enzyme repairing DNA lesions resulting from stalled topoisomerase IB (TOP1)–DNA covalent complex. Inhibiting TDP1 in conjunction with TOP1 inhibitors can boost the action of the latter. Herein, we report the discovery of the natural product oxynitidine scaffold as a novel chemotype for the development of TOP1 and TDP1 inhibitors. Three kinds of analogues, benzophenanthridinone, dihydrobenzophenanthridine, and benzophenanthridine derivatives, were synthesized and evaluated for both TOP1 and TDP1 inhibition and cytotoxicity. Analogue 19a showed high TOP1 inhibition (+++) and induced the formation of cellular TOP1cc and DNA damage, resulting in cancer cells apoptosis at nanomolar concentration range. In vivo studies indicated that 19a exhibits antitumor efficiency in HCT116 xenograft model. 41a exhibited additional TDP1 inhibition with IC50 value of 7 μM and synergistic effect with camptothecin in MCF-7 cells. This work will facilitate future ef...

  • synthesis and biological evaluation of the first triple inhibitors of human topoisomerase 1 tyrosyl dna phosphodiesterase 1 tdp1 and tyrosyl dna phosphodiesterase 2 tdp2
    Journal of Medicinal Chemistry, 2017
    Co-Authors: Ping Wang, Christophe Marchand, Keli Agama, Azhar Ravji, Evgeny Kiselev, Christophe E Redon, Mohamed S A Elsayed, Caroline B Plescia, Olga Zeleznik, Yves Pommier
    Abstract:

    Tdp1 and Tdp2 are two tyrosyl–DNA phosphodiesterases that can repair damaged DNA resulting from topoisomerase inhibitors and a variety of other DNA-damaging agents. Both Tdp1 and Tdp2 inhibition could hypothetically potentiate the cytotoxicities of topoisomerase inhibitors. This study reports the successful structure-based design and synthesis of new 7-azaindenoisoquinolines that act as triple inhibitors of TOP1, Tdp1, and Tdp2. Enzyme inhibitory data and cytotoxicity data from human cancer cell cultures establish that modification of the lactam side chain of the 7-azaindenoisoquinolines can modulate their inhibitory potencies and selectivities vs TOP1, Tdp1, and Tdp2. Molecular modeling of selected target compounds bound to TOP1, Tdp1, and Tdp2 was used to design the inhibitors and facilitate the structure–activity relationship analysis. The monitoring of DNA damage by γ-H2AX foci formation in human PBMCs (lymphocytes) and acute lymphoblastic leukemia CCRF-CEM cells documented significantly more DNA dama...

  • synthesis and biological evaluation of nitrated 7 8 9 and 10 hydroxyindenoisoquinolines as potential dual topoisomerase i TOP1 tyrosyl dna phosphodiesterase i tdp1 inhibitors
    Journal of Medicinal Chemistry, 2015
    Co-Authors: Trung Xuan Nguyen, Yves Pommier, Christophe Marchand, Keli Agama, Monica Abdelmalak, Mark Cushman
    Abstract:

    The structure–activity relationships and hit-to-lead optimization of dual TOP1–TDP1 inhibitors in the indenoisoquinoline drug class were investigated. A series of nitrated 7-, 8-, 9-, and 10-hydroxyindenoisoquinolines were synthesized and evaluated. Several compounds displayed potent dual TOP1–TDP1 inhibition. The 9-hydroxy series exhibited potencies and cytotoxicities vs TOP1 that surpassed those of camptothecin (CPT), the natural alkaloid that is being used as a standard in the TOP1-mediated DNA cleavage assay. One member of this series was a more potent TOP1 inhibitor at a concentration of 5 nM and produced a more stable ternary drug–DNA–TOP1 cleavage complex than CPT.

  • design synthesis and biological evaluation of o 2 modified indenoisoquinolines as dual topoisomerase i tyrosyl dna phosphodiesterase i inhibitors
    Journal of Medicinal Chemistry, 2014
    Co-Authors: Keli Agama, Yves Pommier, Christophe Marchand, Mark Cushman
    Abstract:

    Tyrosyl-DNA phosphodiesterase I (TDP1) repairs stalled topoisomerase I (TOP1)–DNA covalent complexes and has been proposed to be a promising and attractive target for cancer treatment. Inhibitors of TDP1 could conceivably act synergistically with TOP1 inhibitors and thereby potentiate the effects of TOP1 poisons. This study describes the successful design and synthesis of 2-position-modified indenoisoquinolines as dual TOP1–TDP1 inhibitors using a structure-based drug design approach. Enzyme inhibition studies indicate that indenoisoquinolines modified at the 2-position with three-carbon side chains ending with amino substituents show both promising TOP1 and TDP1 inhibitory activity. Molecular modeling of selected target compounds bound to TOP1 and TDP1 was used to rationalize the enzyme inhibition results and structure–activity relationship analysis.

  • Synthesis and Biological Evaluation of Indenoisoquinolines That Inhibit Both Tyrosyl-DNA Phosphodiesterase I (Tdp1) and Topoisomerase I (TOP1)
    Journal of medicinal chemistry, 2012
    Co-Authors: Martin Conda-sheridan, Christophe Marchand, Adel Chergui, Keli Agama, P. V. Narasimha Reddy, Andrew Morrell, Brooklyn T. Cobb, Amelie Renaud, Andrew G. Stephen, Lakshman Bindu
    Abstract:

    Tyrosyl-DNA phosphodiesterase I (Tdp1) plays a key role in the repair of damaged DNA resulting from the topoisomerase I (TOP1) inhibitor camptothecin and a variety of other DNA-damaging anticancer agents. This report documents the design, synthesis, and evaluation of new indenoisoquinolines that are dual inhibitors of both Tdp1 and TOP1. Enzyme inhibitory data and cytotoxicity data from human cancer cell cultures were used to establish structure–activity relationships. The potencies of the indenoisoquinolines against Tdp1 ranged from 5 μM to 111 μM, which places the more active compounds among the most potent known inhibitors of this target. The cytotoxicity mean graph midpoints ranged from 0.02 to 2.34 μM. Dual Tdp1–TOP1 inhibitors are of interest because the TOP1 and Tdp1 inhibitory activities could theoretically work synergistically to create more effective anticancer agents.

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