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Eriksson, Anna
Publications (10 of 10) Show all publications
Eriksson, A., Chantzi, E., Fryknäs, M., Gullbo, J., Nygren, P., Gustafsson, M. G., . . . Larsson, R. (2017). Towards repositioning of quinacrine for treatment of acute myeloid leukemia - Promising synergies and in vivo effects.. Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, 63, 41-46
Open this publication in new window or tab >>Towards repositioning of quinacrine for treatment of acute myeloid leukemia - Promising synergies and in vivo effects.
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2017 (English)In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 63, p. 41-46Article in journal (Refereed) Published
Abstract [en]

We previously reported that the anti-malarial drug quinacrine has potential to be repositioned for treatment of acute myeloid leukemia (AML). As a next step towards clinical use, we assessed the efficacy of quinacrine in an AML-PS mouse model and investigated possible synergistic effects when combining quinacrine with nine other antileukemic compounds in two AML cell lines. Furthermore, we explored the in vivo activity of quinacrine in combination with the widely used AML agent cytarabine. The in vivo use of quinacrine (100mg/kg three times per week for two consecutive weeks) significantly suppressed circulating blast cells at days 30/31 and increased the median survival time (MST). The in vitro drug combination analysis yielded promising synergistic interactions when combining quinacrine with cytarabine, azacitidine and geldanamycin. Finally, combining quinacrine with cytarabine in vivo showed a significant decrease in circulating leukemic blast cells and increased MST compared to the effect of either drug used alone, thus supporting the findings from the in vitro combination experiments. Taken together, the repositioning potential of quinacrine for treatment of AML is reinforced by demonstrating significant in vivo activity and promising synergies when quinacrine is combined with different agents, including cytarabine, the hypomethylating agent azacitidine and HSP-90 inhibitor geldanamycin.

Keywords
Acute myeloid leukemia, Drug combinations, Quinacrine, Repositioning
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-342993 (URN)10.1016/j.leukres.2017.10.012 (DOI)000416744700007 ()29100024 (PubMedID)
Available from: 2018-02-24 Created: 2018-02-24 Last updated: 2018-03-01Bibliographically approved
Eriksson, A., Gustafsson, M., Fryknäs, M., Gullbo, J., Nygren, P., Höglund, M. & Larsson, R. (2016). Repositioning Of Quinacrine For Treatment Of Acute Myeloid Leukemia - Synergies And In Vivo Effects. Paper presented at 21st Congress of the European-Hematology-Association, JUN 09-12, 2016, Copenhagen, DENMARK. Haematologica, 101, 367-368
Open this publication in new window or tab >>Repositioning Of Quinacrine For Treatment Of Acute Myeloid Leukemia - Synergies And In Vivo Effects
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2016 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, p. 367-368Article in journal, Meeting abstract (Other academic) Published
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-301452 (URN)000379484601269 ()
Conference
21st Congress of the European-Hematology-Association, JUN 09-12, 2016, Copenhagen, DENMARK
Available from: 2016-08-24 Created: 2016-08-23 Last updated: 2017-11-28Bibliographically approved
Ungerstedt, J., Eriksson, A., Olander, E., Bergfelt, E., Liljeholm, M., Kristjanssdottir, H. L., . . . Birgegård, G. (2015). Development of a Progress Test Based on the EHA Curriculum and EHA CV Passport, Used for Yearly Evaluation of Hematology Residency In Sweden. Paper presented at 20th Congress of European-Hematology-Association, JUN 11-14, 2015, Vienna, AUSTRIA. Haematologica, 100, 776-776
Open this publication in new window or tab >>Development of a Progress Test Based on the EHA Curriculum and EHA CV Passport, Used for Yearly Evaluation of Hematology Residency In Sweden
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2015 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 100, p. 776-776Article in journal, Meeting abstract (Other academic) Published
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-266180 (URN)000361204904518 ()
Conference
20th Congress of European-Hematology-Association, JUN 11-14, 2015, Vienna, AUSTRIA
Available from: 2015-11-06 Created: 2015-11-05 Last updated: 2017-12-01Bibliographically approved
Eriksson, A., Österroos, A., Hassan, S. B., Gullbo, J., Rickardson, L., Jarvius, M., . . . Larsson, R. (2015). Drug screen in patient cells suggests quinacrine to be repositioned for treatment of acute myeloid leukemia. Blood Cancer Journal, 5, Article ID e307.
Open this publication in new window or tab >>Drug screen in patient cells suggests quinacrine to be repositioned for treatment of acute myeloid leukemia
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2015 (English)In: Blood Cancer Journal, ISSN 2044-5385, E-ISSN 2044-5385, Vol. 5, article id e307Article in journal (Refereed) Published
Abstract [en]

To find drugs suitable for repositioning for use against leukemia, samples from patients with chronic lymphocytic, acute myeloid and lymphocytic leukemias as well as peripheral blood mononuclear cells (PBMC) were tested in response to 1266 compounds from the LOPAC1280 library (Sigma). Twenty-five compounds were defined as hits with activity in all leukemia subgroups (<50% cell survival compared with control) at 10 mu M drug concentration. Only one of these compounds, quinacrine, showed low activity in normal PBMCs and was therefore selected for further preclinical evaluation. Mining the NCI-60 and the NextBio databases demonstrated leukemia sensitivity and the ability of quinacrine to reverse myeloid leukemia gene expression. Mechanistic exploration was performed using the NextBio bioinformatic software using gene expression analysis of drug exposed acute myeloid leukemia cultures (HL-60) in the database. Analysis of gene enrichment and drug correlations revealed strong connections to ribosomal biogenesis nucleoli and translation initiation. The highest drug-drug correlation was to ellipticine, a known RNA polymerase I inhibitor. These results were validated by additional gene expression analysis performed in-house. Quinacrine induced early inhibition of protein synthesis supporting these predictions. The results suggest that quinacrine have repositioning potential for treatment of acute myeloid leukemia by targeting of ribosomal biogenesis.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-255299 (URN)10.1038/bcj.2015.31 (DOI)000354102400008 ()25885427 (PubMedID)
Available from: 2015-06-22 Created: 2015-06-15 Last updated: 2017-12-04Bibliographically approved
Eriksson, A., Lennartsson, A. & Lehmann, S. (2015). Epigenetic aberrations in acute myeloid leukemia: Early key events during leukemogenesis. Experimental Hematology, 43(8), 609-624
Open this publication in new window or tab >>Epigenetic aberrations in acute myeloid leukemia: Early key events during leukemogenesis
2015 (English)In: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 43, no 8, p. 609-624Article in journal (Refereed) Published
Abstract [en]

As a result of the introduction of new sequencing technologies, the molecular landscape of acute myeloid leukemia (AML) is rapidly evolving. From karyotyping, which detects only large genomic aberrations of metaphase chromosomes, we have moved into an era when sequencing of each base pair allows us to define the AML genome at highest resolution. This has revealed a new complex landscape of genetic aberrations where addition of mutations in epigenetic regulators has been one of the most important contributions to the understanding of the pathogenesis of AML. These findings, together with new insights into epigenetic mechanisms, have placed dysregulated epigenetic mechanisms at the forefront of AML development. Not only have several new mutations in genes directly involved in epigenetic regulatory mechanisms been discovered, but also previously well-known gene fusions have been found to exert aberrant effects through epigenetic mechanisms. In addition, mutations in epigenetic regulators such as DNMT3A, TET2, and ASXL1 have recently been found to be the earliest known events during AML evolution and to be present as preleukemic lesions before the onset of AML. In this article, we review epigenetic changes in AML also in relation to what is known about their mechanism of action and their prognostic role.

National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-263035 (URN)10.1016/j.exphem.2015.05.009 (DOI)000360321900003 ()26118500 (PubMedID)
Available from: 2015-09-29 Created: 2015-09-24 Last updated: 2017-12-01Bibliographically approved
Eriksson, A., Kalushkova, A., Jarvius, M., Hilhorst, R., Rickardson, L., Göransson Kultima, H., . . . Höglund, M. (2014). AKN-028 induces cell cycle arrest, downregulation of Myc associated genes and a dose dependent reduction of kinase activity in acute myeloid leukemia. Biochemical Pharmacology, 87(2), 284-291
Open this publication in new window or tab >>AKN-028 induces cell cycle arrest, downregulation of Myc associated genes and a dose dependent reduction of kinase activity in acute myeloid leukemia
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2014 (English)In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 87, no 2, p. 284-291Article in journal (Refereed) Published
Abstract [en]

AKN-028 is a novel tyrosine kinase inhibitor with preclinical activity in acute myeloid leukemia (AML), presently undergoing investigation in a phase I/II study. It is a potent inhibitor of the FMS-like kinase 3 (FLT3) but shows in vitro activity in a wide range of AML samples. In the present study, we have characterized the effects of AKN-028 on AML cells in more detail. AKN-028 induced a dose-dependent G(0)/arrest in AML cell line MV4-11. Treatment with AKN-028 caused significantly altered gene expression in all AML cell types tested (430 downregulated, 280 upregulated transcripts). Subsequent gene set enrichment analysis revealed enrichment of genes associated with the proto-oncogene and cell cycle regulator c-Myc among the downregulated genes in both AKN-028 and midostaurin treated cells. Kinase activity profiling in AML cell lines and primary AML samples showed that tyrosine kinase activity, but not serine/threonine kinase activity, was inhibited by AKN-028 in a dose dependent manner in all samples tested, reaching approximately the same level of kinase activity. Cells sensitive to AKN-028 showed a higher overall tyrosine kinase activity than more resistant ones, whereas serine/threonine kinase activity was similar for all primary AML samples. In summary, AKN-028 induces cell cycle arrest in AML cells, downregulates Myc-associated genes and affect several signaling pathways. AML cells with high global tyrosine kinase activity seem to be more sensitive to the cytotoxic effect of AKN-028 in vitro.

Place, publisher, year, edition, pages
Elsevier, 2014
Keywords
Acute myeloid leukemia, AKN-028, Tyrosine kinase inhibitor, Signal transduction
National Category
Hematology Pharmacology and Toxicology Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-182065 (URN)10.1016/j.bcp.2013.10.022 (DOI)000330332800006 ()
Available from: 2012-10-10 Created: 2012-10-03 Last updated: 2018-01-12Bibliographically approved
Ungerstedt, J., Eriksson, A., Olander, E., Theander, J., Liljeholm, M., Isaksson, C. & Birgegard, G. (2014). Development of Progress Test Based on EHA Curriculum and EHA CV Passport, Used for Yearly Evaluation of Hematology Residency in Sweden. Paper presented at 19th Congress of the European-Hematology-Association, JUN 12-15, 2014, Milan, ITALY. Haematologica (online), 99, 788-788
Open this publication in new window or tab >>Development of Progress Test Based on EHA Curriculum and EHA CV Passport, Used for Yearly Evaluation of Hematology Residency in Sweden
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2014 (English)In: Haematologica (online), ISSN 0390-6078, E-ISSN 1592-8721, Vol. 99, p. 788-788Article in journal, Meeting abstract (Other academic) Published
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-236814 (URN)000342830904041 ()
Conference
19th Congress of the European-Hematology-Association, JUN 12-15, 2014, Milan, ITALY
Available from: 2014-11-28 Created: 2014-11-24 Last updated: 2017-12-05Bibliographically approved
Eriksson, A., Osterros, A., Hassan, S. B., Gullbo, J., Rickardson, L., Jarvius, M., . . . Larsson, R. (2014). Repositioning of Quinacrine for Treatment of Acute Myeloid Leukemia. Paper presented at 56th Annual Meeting of the American-Society-of-Hematology, DEC 06-09, 2014, San Francisco, CA. Blood, 124(21)
Open this publication in new window or tab >>Repositioning of Quinacrine for Treatment of Acute Myeloid Leukemia
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2014 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal, Meeting abstract (Other academic) Published
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-247838 (URN)000349233805153 ()
Conference
56th Annual Meeting of the American-Society-of-Hematology, DEC 06-09, 2014, San Francisco, CA
Available from: 2015-03-30 Created: 2015-03-24 Last updated: 2017-12-04Bibliographically approved
Eriksson, A. (2012). Studies of New Signal Transduction Modulators in Acute Myeloid Leukemia. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Studies of New Signal Transduction Modulators in Acute Myeloid Leukemia
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Acute myeloid leukemia (AML) is a life-threatening malignant disorder with dismal prognosis. AML is characterized by frequent genetic changes involving tyrosine kinases, normally acting as important mediators in many basic cellular processes. Due to the overexpression and frequent mutations of the FMS-like receptor tyrosine kinase 3 (FLT3) in AML, this tyrosine kinase receptor has become one of the most sought after targets in AML drug development.

In this thesis, we have used a combination of high-throughput screens, direct target interaction assays and sequential cellular screens, including primary patient samples, as an approach to discover new targeted therapies. Gefitinib, a previously known inhibitor of epidermal growth factor receptor and the two novel tyrosine kinase inhibitors AKN-032 and AKN-028, have been identified as compounds with cytotoxic activity in AML.

AKN-028 is a potent inhibitor of FLT3 with an IC50 value of 6 nM in an enzyme assay, but also displaying in vitro activity in a variety of primary AML samples, irrespective of FLT3 mutation status or quantitative FLT3 expression. AKN-028 shows a sequence dependent in vitro synergy when combined with standard cytotoxic agents cytarabine or daunorubicin, with better efficacy when cells are exposed to standard chemotherapy simultaneously or for 24 hours prior to adding AKN-028. Antagonism is observed when cells are pre-treated with AKN-028, possibly explained by the cell cycle arrest induced by the compound. In vivo cytotoxic activity and good oral bioavailability have made AKN-028 a candidate drug for clinical studies and the compound is presently investigated in an international two-part multicenter phase I/II study.

Results from microarray studies performed to further elucidate the mechanism of action of AKN-028, revealed significantly altered gene expression induced by AKN-028 in both AML cell lines and in primary AML cells, with an enrichment of the Myc pathway among the downregulated genes.

Furthermore, tyrosine kinase activity profiling shows a dose-dependent kinase inhibition by AKN-028 in all AML samples tested. Interestingly, cells with a high overall kinase activity were more sensitive to AKN-028. Provided conformation in a larger set of samples, kinase activity profiling may give useful information in individualizing treatment of patients with AML.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. p. 61
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 823
Keywords
Acute myeloid leukemia, Targeted therapies, Drug development, Tyrosine kinase inhibition, AKN-032, AKN-028
National Category
Hematology Pharmacology and Toxicology
Research subject
Internal Medicine
Identifiers
urn:nbn:se:uu:diva-182440 (URN)978-91-554-8495-8 (ISBN)
Public defence
2012-11-23, Enghoffsalen, Akademiska Sjukhuset, Ingång 50, bv, Akademiska Sjukhuset, Sjukhusvägen, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2012-11-01 Created: 2012-10-10 Last updated: 2018-01-12Bibliographically approved
Eriksson, A., Hermanson, M., Wickström, M., Lindhagen, E., Ekholm, C., Jenmalm Jensen, A., . . . Höglund, M. (2012). The novel tyrosine kinase inhibitor AKN-028 has significant antileukemic activity in cell lines and primary cultures of acute myeloid leukemia. Blood Cancer Journal, 2, e81
Open this publication in new window or tab >>The novel tyrosine kinase inhibitor AKN-028 has significant antileukemic activity in cell lines and primary cultures of acute myeloid leukemia
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2012 (English)In: Blood Cancer Journal, ISSN 2044-5385, E-ISSN 2044-5385, Vol. 2, p. e81-Article in journal (Refereed) Published
Abstract [en]

Aberrantly expressed tyrosine kinases have emerged as promising targets for drug development in acute myeloid leukemia (AML). We report that AKN-028, a novel tyrosine kinase inhibitor (TKI), is a potent FMS-like receptor tyrosine kinase 3 (FLT3) inhibitor (IC50=6 nM), causing dose-dependent inhibition of FLT3 autophosphorylation. Inhibition of KIT autophosphorylation was shown in a human megakaryoblastic leukemia cell line overexpressing KIT. In a panel of 17 cell lines, AKN-028 showed cytotoxic activity in all five AML cell lines included. AKN-028 triggered apoptosis in MV4-11 by activation of caspase 3. In primary AML samples (n=15), AKN-028 induced a clear dose-dependent cytotoxic response (mean IC50 1 μM). However, no correlation between antileukemic activity and FLT3 mutation status, or to the quantitative expression of FLT3, was observed. Combination studies showed synergistic activity when cytarabine or daunorubicin was added simultaneously or 24 h before AKN-028. In mice, AKN-028 demonstrated high oral bioavailability and antileukemic effect in primary AML and MV4-11 cells, with no major toxicity observed in the experiment. In conclusion, AKN-028 is a novel TKI with significant preclinical antileukemic activity in AML. Possible sequence-dependent synergy with standard AML drugs and good oral bioavailability has made it a candidate drug for clinical trials (ongoing).

National Category
Medical and Health Sciences Hematology Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-182062 (URN)10.1038/bcj.2012.28 (DOI)000308664500001 ()22864397 (PubMedID)
Available from: 2012-10-03 Created: 2012-10-03 Last updated: 2018-01-12Bibliographically approved
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