Ändra sökning
Länk till posten
Permanent länk

Direktlänk
Häggblad, Maria
Publikationer (10 of 10) Visa alla publikationer
Bonagas, N., Gustafsson, N. M. S., Henriksson, M., Marttila, P., Gustafsson, R., Wiita, E., . . . Helleday, T. (2022). Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress. Nature cancer, 3(2), 156-172
Öppna denna publikation i ny flik eller fönster >>Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
Visa övriga...
2022 (Engelska)Ingår i: Nature cancer, ISSN 2662-1347, Vol. 3, nr 2, s. 156-172Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.

Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:su:diva-203237 (URN)10.1038/s43018-022-00331-y (DOI)000762300200004 ()35228749 (PubMedID)2-s2.0-85125665402 (Scopus ID)
Tillgänglig från: 2022-03-28 Skapad: 2022-03-28 Senast uppdaterad: 2022-03-28Bibliografiskt granskad
Johansson, P., Krona, C., Kundu, S., Doroszko, M., Baskaran, S., Schmidt, L., . . . Nelander, S. (2020). A Patient-Derived Cell Atlas Informs Precision Targeting of Glioblastoma. Cell Reports, 32(2), Article ID 107897.
Öppna denna publikation i ny flik eller fönster >>A Patient-Derived Cell Atlas Informs Precision Targeting of Glioblastoma
Visa övriga...
2020 (Engelska)Ingår i: Cell Reports, E-ISSN 2211-1247, Vol. 32, nr 2, artikel-id 107897Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Glioblastoma (GBM) is a malignant brain tumor with few therapeutic options. The disease presents with a complex spectrum of genomic aberrations, but the pharmacological consequences of these aberrations are partly unknown. Here, we report an integrated pharmacogenomic analysis of 100 patient-derived GBM cell cultures from the human glioma cell culture (HGCC) cohort. Exploring 1,544 drugs, we find that GBM has two main pharmacological subgroups, marked by differential response to proteasome inhibitors and mutually exclusive aberrations in TP53 and CDKN2A/B. We confirm this trend in cell and in xenotransplantation models, and identify both Bcl-2 family inhibitors and p53 activators as potentiators of proteasome inhibitors in GBM cells, We can further predict the responses of individual cell cultures to several existing drug classes, presenting opportunities for drug repurposing and design of stratified trials. Our functionally profiled biobank provides a valuable resource for the discovery of new treatments for GBM.

Nyckelord
biobank, combination therapy, data integration, glioblastoma, multi-omics, p53 reactivators, patient-derived cells, primary cells, proteasome
Nationell ämneskategori
Biologiska vetenskaper
Identifikatorer
urn:nbn:se:su:diva-184480 (URN)10.1016/j.celrep.2020.107897 (DOI)000548535600002 ()32668248 (PubMedID)
Tillgänglig från: 2020-09-18 Skapad: 2020-09-18 Senast uppdaterad: 2024-01-17Bibliografiskt granskad
Carreras-Puigvert, J., Zitnik, M., Jemth, A.-S., Carter, M., Unterlass, J. E., Hallström, B., . . . Helleday, T. (2017). A comprehensive structural, biochemical and biological profiling of the human NUDIX hydrolase family. Nature Communications, 8, Article ID 1541.
Öppna denna publikation i ny flik eller fönster >>A comprehensive structural, biochemical and biological profiling of the human NUDIX hydrolase family
Visa övriga...
2017 (Engelska)Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 8, artikel-id 1541Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The NUDIX enzymes are involved in cellular metabolism and homeostasis, as well as mRNA processing. Although highly conserved throughout all organisms, their biological roles and biochemical redundancies remain largely unclear. To address this, we globally resolve their individual properties and inter-relationships. We purify 18 of the human NUDIX proteins and screen 52 substrates, providing a substrate redundancy map. Using crystal structures, we generate sequence alignment analyses revealing four major structural classes. To a certain extent, their substrate preference redundancies correlate with structural classes, thus linking structure and activity relationships. To elucidate interdependence among the NUDIX hydrolases, we pairwise deplete them generating an epistatic interaction map, evaluate cell cycle perturbations upon knockdown in normal and cancer cells, and analyse their protein and mRNA expression in normal and cancer tissues. Using a novel FUSION algorithm, we integrate all data creating a comprehensive NUDIX enzyme profile map, which will prove fundamental to understanding their biological functionality.

Nyckelord
Cellular signalling networks, Hydrolases, Molecular biology
Nationell ämneskategori
Biokemi Molekylärbiologi
Identifikatorer
urn:nbn:se:su:diva-149800 (URN)10.1038/s41467-017-01642-w (DOI)000415323000014 ()29142246 (PubMedID)2-s2.0-85034433549 (Scopus ID)
Tillgänglig från: 2017-12-19 Skapad: 2017-12-19 Senast uppdaterad: 2025-02-20Bibliografiskt granskad
Gustafsson, R., Jemth, A.-S., Gustafsson, N. M. S., Färnegårdh, K., Loseva, O., Wiita, E., . . . Stenmark, P. (2017). Crystal Structure of the Emerging Cancer Target MTHFD2 in Complex with a Substrate-Based Inhibitor. Cancer Research, 77(4), 937-948
Öppna denna publikation i ny flik eller fönster >>Crystal Structure of the Emerging Cancer Target MTHFD2 in Complex with a Substrate-Based Inhibitor
Visa övriga...
2017 (Engelska)Ingår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77, nr 4, s. 937-948Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

To sustain their proliferation, cancer cells become dependent on one-carbon metabolism to support purine and thymidylate synthesis. Indeed, one of the most highly upregulated enzymes during neoplastic transformation is MTHFD2, a mitochondrial methylenetetrahydrofolate dehydrogenase and cyclohydrolase involved in one-carbon metabolism. Because MTHFD2 is expressed normally only during embryonic development, it offers a disease-selective therapeutic target for eradicating cancer cells while sparing healthy cells. Here we report the synthesis and preclinical characterization of the first inhibitor of human MTHFD2. We also disclose the first crystal structure of MTHFD2 in complex with a substrate-based inhibitor and the enzyme cofactors NAD(+) and inorganic phosphate. Our work provides a rationale for continued development of a structural framework for the generation of potent and selective MTHFD2 inhibitors for cancer treatment.

Nationell ämneskategori
Biologiska vetenskaper
Forskningsämne
biokemi
Identifikatorer
urn:nbn:se:su:diva-141414 (URN)10.1158/0008-5472.CAN-16-1476 (DOI)000393887800014 ()27899380 (PubMedID)
Tillgänglig från: 2017-04-18 Skapad: 2017-04-18 Senast uppdaterad: 2022-02-28Bibliografiskt granskad
Llona-Minguez, S., Häggblad, M., Martens, U., Throup, A., Loseva, O., Jemth, A.-S., . . . Helleday, T. (2017). Diverse heterocyclic scaffolds as dCTP pyrophosphatase 1 inhibitors. Part 1: Triazoles, triazolopyrimidines, triazinoindoles, quinoline hydrazones and arylpiperazines. Bioorganic & Medicinal Chemistry Letters, 27(16), 3897-3904
Öppna denna publikation i ny flik eller fönster >>Diverse heterocyclic scaffolds as dCTP pyrophosphatase 1 inhibitors. Part 1: Triazoles, triazolopyrimidines, triazinoindoles, quinoline hydrazones and arylpiperazines
Visa övriga...
2017 (Engelska)Ingår i: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1464-3405, Vol. 27, nr 16, s. 3897-3904Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

A high-throughput screening campaign using a commercial compound library (ChemBridge DiverSET) revealed diverse chemotypes as inhibitors of the human dCTP pyrophosphatase 1 (dCTPase). Triazole, triazolopyrimidine, triazinoindole, quinoline hydrazone and arylpiperazine hits were clustered, confirmed by IC50 determinations, and their preliminary structure-activity-relationships (SAR) and ligand efficiency scores are discussed in this letter.

Nationell ämneskategori
Kemi
Identifikatorer
urn:nbn:se:su:diva-146994 (URN)10.1016/j.bmcl.2017.06.038 (DOI)000407532900051 ()28687206 (PubMedID)
Tillgänglig från: 2017-09-18 Skapad: 2017-09-18 Senast uppdaterad: 2022-02-28Bibliografiskt granskad
Llona-Minguez, S., Häggblad, M., Martens, U., Johansson, L., Sigmundsson, K., Lundbäck, T., . . . Helleday, T. (2017). Diverse heterocyclic scaffolds as dCTP pyrophosphatase 1 inhibitors. Part 2: Pyridone- and pyrimidinone-derived systems. Bioorganic & Medicinal Chemistry Letters, 27(15), 3219-3225
Öppna denna publikation i ny flik eller fönster >>Diverse heterocyclic scaffolds as dCTP pyrophosphatase 1 inhibitors. Part 2: Pyridone- and pyrimidinone-derived systems
Visa övriga...
2017 (Engelska)Ingår i: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1464-3405, Vol. 27, nr 15, s. 3219-3225Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Two screening campaigns using commercial (Chembridge DiverSET) and proprietary (Chemical Biology Consortium Sweden, CBCS) compound libraries, revealed a number of pyridone- and pyrimidinone-derived systems as inhibitors of the human dCTP pyrophosphatase 1 (dCTPase). In this letter, we present their preliminary structure-activity-relationships (SAR) and ligand efficiency scores (LE and LLE).

Nyckelord
DCTPP1, Nucleotide metabolism, Pyridone, Pyrimidone
Nationell ämneskategori
Kemi Farmakologi och toxikologi
Identifikatorer
urn:nbn:se:su:diva-145862 (URN)10.1016/j.bmcl.2017.06.039 (DOI)000405106500002 ()28655422 (PubMedID)
Tillgänglig från: 2017-08-23 Skapad: 2017-08-23 Senast uppdaterad: 2022-02-28Bibliografiskt granskad
Llona-Minguez, S., Höglund, A., Wiita, E., Almlöf, I., Mateus, A., Calderon-Montano, J. M., . . . Helleday, T. (2017). Identification of Triazolothiadiazoles as Potent Inhibitors of the dCTP Pyrophosphatase 1. Journal of Medicinal Chemistry, 60(5), 2148-2154
Öppna denna publikation i ny flik eller fönster >>Identification of Triazolothiadiazoles as Potent Inhibitors of the dCTP Pyrophosphatase 1
Visa övriga...
2017 (Engelska)Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 60, nr 5, s. 2148-2154Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The dCTP pyrophosphatase 1 (dCTPase) is involved in the regulation of the cellular dNTP pool and has been linked to cancer progression. Here we report on the discovery of a series of 3,6-disubstituted triazolothiadiazoles as potent dCTPase inhibitors. Compounds 16 and 18 display good correlation between enzymatic inhibition and target engagement, together with efficacy in a cellular synergy model, deeming them as a promising starting point for hit -to-lead development.

Nationell ämneskategori
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) Läkemedelskemi
Identifikatorer
urn:nbn:se:su:diva-141203 (URN)10.1021/acs.jmedchem.6b01786 (DOI)000396296100037 ()28145708 (PubMedID)
Tillgänglig från: 2017-04-28 Skapad: 2017-04-28 Senast uppdaterad: 2022-02-28Bibliografiskt granskad
Schmidt, L., Baskaran, S., Johansson, P., Padhan, N., Matuszewski, D., Green, L. C., . . . Nelander, S. (2016). Case-specific potentiation of glioblastoma drugs by pterostilbene. Oncotarget, 7(45), 73200-73215
Öppna denna publikation i ny flik eller fönster >>Case-specific potentiation of glioblastoma drugs by pterostilbene
Visa övriga...
2016 (Engelska)Ingår i: Oncotarget, E-ISSN 1949-2553, Vol. 7, nr 45, s. 73200-73215Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Glioblastoma multiforme (GBM, astrocytoma grade IV) is the most common malignant primary brain tumor in adults. Addressing the shortage of effective treatment options for this cancer, we explored repurposing of existing drugs into combinations with potent activity against GBM cells. We report that the phytoalexin pterostilbene is a potentiator of two drugs with previously reported anti-GBM activity, the EGFR inhibitor gefitinib and the antidepressant sertraline. Combinations of either of these two compounds with pterostilbene suppress cell growth, viability, sphere formation and inhibit migration in tumor GBM cell (GC) cultures. The potentiating effect of pterostilbene was observed to a varying degree across a panel of 41 patient-derived GCs, and correlated in a case specific manner with the presence of missense mutation of EGFR and PIK3CA and a focal deletion of the chromosomal region 1p32. We identify pterostilbene-induced cell cycle arrest, synergistic inhibition of MAPK activity and induction of Thioredoxin interacting protein (TXNIP) as possible mechanisms behind pterostilbene's effect. Our results highlight a nontoxic stilbenoid compound as a modulator of anticancer drug response, and indicate that pterostilbene might be used to modulate two anticancer compounds in well-defined sets of GBM patients.

Nyckelord
glioblastoma, glioblastoma initiating cells, stilbenoids, drug repurposing, cancer therapeutics
Nationell ämneskategori
Cellbiologi Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:su:diva-136745 (URN)10.18632/oncotarget.12298 (DOI)000387452100060 ()
Tillgänglig från: 2016-12-15 Skapad: 2016-12-14 Senast uppdaterad: 2024-01-17Bibliografiskt granskad
Gad, H., Svensson, L. M., Saleh, A., Berntsson, R.-A. P. A., Gustafsson, R., Johansson, F., . . . Helleday, T. (2014). MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool. Nature, 508(7495), 215-221
Öppna denna publikation i ny flik eller fönster >>MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
Visa övriga...
2014 (Engelska)Ingår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 508, nr 7495, s. 215-221Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bind in the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.

Nationell ämneskategori
Biologiska vetenskaper
Forskningsämne
biokemi
Identifikatorer
urn:nbn:se:su:diva-102367 (URN)10.1038/nature13181 (DOI)000333979900038 ()
Tillgänglig från: 2014-04-02 Skapad: 2014-04-03 Senast uppdaterad: 2022-02-23Bibliografiskt granskad
Schmidt, L., Kling, T., Monsefi, N., Olsson, M., Hansson, C., Baskaran, S., . . . Nelander, S. (2013). Comparative drug pair screening across multiple glioblastoma cell lines reveals novel drug-drug interactions. Neuro-Oncology, 15(11), 1469-1478
Öppna denna publikation i ny flik eller fönster >>Comparative drug pair screening across multiple glioblastoma cell lines reveals novel drug-drug interactions
Visa övriga...
2013 (Engelska)Ingår i: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 15, nr 11, s. 1469-1478Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Glioblastoma multiforme (GBM) is the most aggressive brain tumor in adults, and despite state-of-the-art treatment, survival remains poor and novel therapeutics are sorely needed. The aim of the present study was to identify new synergistic drug pairs for GBM. In addition, we aimed to explore differences in drug-drug interactions across multiple GBM-derived cell cultures and predict such differences by use of transcriptional biomarkers. We performed a screen in which we quantified drug-drug interactions for 465 drug pairs in each of the 5 GBM cell lines U87MG, U343MG, U373MG, A172, and T98G. Selected interactions were further tested using isobole-based analysis and validated in 5 glioma-initiating cell cultures. Furthermore, drug interactions were predicted using microarray-based transcriptional profiling in combination with statistical modeling. Of the 5 465 drug pairs, we could define a subset of drug pairs with strong interaction in both standard cell lines and glioma-initiating cell cultures. In particular, a subset of pairs involving the pharmaceutical compounds rimcazole, sertraline, pterostilbene, and gefitinib showed a strong interaction in a majority of the cell cultures tested. Statistical modeling of microarray and interaction data using sparse canonical correlation analysis revealed several predictive biomarkers, which we propose could be of importance in regulating drug pair responses. We identify novel candidate drug pairs for GBM and suggest possibilities to prospectively use transcriptional biomarkers to predict drug interactions in individual cases.

Nyckelord
drug combination responses, glioblastoma therapy, glioblastoma stem cell cultures, predictive medicine
Nationell ämneskategori
Cancer och onkologi Neurologi Biologiska vetenskaper
Identifikatorer
urn:nbn:se:su:diva-97663 (URN)10.1093/neuonc/not111 (DOI)000326747900005 ()
Anmärkning

AuthorCount:15;

Tillgänglig från: 2013-12-18 Skapad: 2013-12-16 Senast uppdaterad: 2022-02-24Bibliografiskt granskad
Organisationer

Sök vidare i DiVA

Visa alla publikationer