Our research group conducts a patient-centric translational research program aiming at the identification and validation of novel therapeutic strategies for patients with ACUTE MYELOID LEUKEMIA in preclinical programs.
The Theilgaard-Mönch Group is located at the Finsen Laboratory, a cancer research department at the Finsen Centre at Rigshospitalet, Copenhagen University Hospital.
Acute Myeloid Leukemia (AML) represents an aggressive cancer entity with a dismal clinical outcome due to relapse and primary resistance toward standard chemotherapy regimens.
Our research group aims to identify novel multi-drug therapies combining targeted inhibition of cancer-specific vulnerabilities with standard therapies to enhance the therapeutic efficacy and ultimately improve clinical outcome of ACUTE MYELOID LEUKEMIA (AML) patients.
- Demonstration that AML patients whose prognostic driver aberrations originate from hematopoietic stem cells (HSCs) have significant worse prognosis as compared to patients whose driver aberrations originate from hematopoietic progenitor cells (HPCs) (Mora-Jensen et al., 2015).
- Functional characterization of the ERG oncogene as a regulator of HEMATOPOIETIC STEM CELL (HSC) maintenance using a conditional Erg knock-out mouse model (Knudsen et al., 2015).
- Identification of aberrant oncogenic PI3K/MTOR and NFKB signaling pathway activities in patients with AML (Rapin et al., 2014) and demonstration that combinations of small molecule inhibitors targeting these pathways effectively inhibit survival of primary AML cells in vitro and in vivo (Estruch et al., 2020).
- Identification of a NOVEL HUMAN HSC MARKER (Reckzeh et al., 2018). This marker is expressed on normal human HSCs but not on AML cells. Our novel marker represents the only currently known only currently known surface marker that is conserved on mouse and human HSCs!
- Identification of a novel surface marker that is expressed by a genetically defined AML subclass as well as other rare hematologic malignancies but not normal human hematopoietic stem and progenitor cells HSPCs (unpublished data). So far, we have demonstrated that ANTIBOBDY DRUG-CONJUGATES (ADCs) targeting this surface molecule effectively eradicate AML in vitro, and in AML xenograft/PDX trials (unpublished data).
AML - development of novel therapies:
- Development of novel AML combination therapies:
Application of OMICS analyses and in vitro drug tests of primary AML patient cells for identification and therapeutic targeting of cancer vulnerabilities such as oncogenic signaling and DNA damage response pathways, in order to ultimately enhance sensitivity and overcome resistance toward chemotherapy. Effective drug combinations from our in vitro tests in preclinical trials using genetically engineered AML mouse model and AML patient-derived xenografts, to identify novel effective multi-drug therapies for future investigator-initiated trials.
- Development of novel ANTIBOBDY DRUG-CONJUGATE (ADCs) for AML treatment Identification of novel actionable surface antigens for ADC treatment of AML. So far, we have identified one relevant surface marker and shown that our own first-generation ADCs targeting this novel surface molecule effectively eradicates AML in vitro and in xenograft/PDX trials (unpublished data) without substantial toxicity toward normal. We are currently developing our own proprietary high-affinity MoAbs to generate a novel improved ADCs for AML treatment.
NOVEL HSC MARKER:
- We have generated KO mice to investigate the function of our novel HSC marker, which currently is the only known surface marker that is conserved on mouse and human HSCs!
- We are currently using our novel HSC marker to refine the human HSC immunophenotype. Given that our marker is not expressed by AML patient cells we are developing a clinical protocol for the production of purified “tumor-free” allogenic stem cell grafts for autologous stem cell transplantation, which ultimately holds great potential to reduce the risk of relapse and improve clinical outcome of cancer patients treated with high-dose chemotherapy and autologous stem cell transplantation.
- Multi-color flowcytomery analysis and sorting of HSPC populations
- “Omics analyses - NGS, RNAseq, collaboration on MS - Phosphoproteomics
- AML GEMMs (Genetically Engineered Mouse AML Models)
- AML Patient-Derived Xenografts (PDX)
- In vitro drug tests – AML GEMMs and AML patients
- Preclinical drug trials – AML GEMMs and AML PDXs
- Estruch M, Reckzeh K, Vittori C, Centio A, Ali M, Engelhard S, Zhao L, Won KJ, Liu P, Porse BT, Theilgaard-Mönch K. Targeted inhibition of cooperative mutation- and therapy-induced AKT activation in AML effectively enhances response to chemotherapy. Leukemia, 2020 Dec 9. https://doi.org/10.1038/s41375-020-01094-0
- Roy D, Thongjuea S, Theilgaard-Mönch K, Nerlov C. Identification of two distinct pathways of human myelopoiesis Science Immunology (2019):4 (35). https://doi.org/10.1126/sciimmunol.aau7148
- Jakobsen JS, Laursen LG, Schuster MB, Pundhir S, Schoof E, Ge Y, d'Altri T, Vitting-Seerup K, Rapin N, Gentil C, Jendholm J, Theilgaard-Mönch K, Reckzeh K, Bullinger L, Döhner K, Hokland P, Fitzgibbon J, Porse BT. Mutant CEBPA directly drives the expression of the targetable tumor-promoting factor CD73 in AML. Sci Adv. 2019 Jul 10;5(7):eaaw4304. https://advances.sciencemag.org/content/5/7/eaaw4304
- Reckzeh K, Kizilkaya H, Helbo AS, Estruch M, Deslauriers AG, Grover A, Rapin N, Asmar F, Grønbæk K, Porse B, Borregaard N, Vestweber D, Nerlov C, Theilgaard- Mönch K. Human adult HSCs can be discriminated from lineage-committed HPCs by the expression of endomucin. Blood Adv(2018) 2 (13): 1628–1632. DOI: https://doi.org/1182/bloodadvances.2018015743
- Theilgaard-Mönch K. Gut microbiota sustains hematopoiesis. Blood. 2017 Feb 9;129(6):662-663. https://ashpublications.org/blood/article/129/6/662/36313/Gut-microbiota-sustains-hematopoiesis
- Mora-Jensen H, Jendholm J, Rapin N, Andersen MK, Roug AS, Bagger FO, Bullinger L, Winther O, Borregaard N, Porse BT, Theilgaard-Mönch K. Cellular origin of prognostic chromosomal aberrations in AML patients. Leukemia. 2015 Aug;29(8):1785-9. https://doi.org/10.1038/leu.2015.30
- Knudsen KJ, Rehn M, Hasemann MS, Rapin N, Bagger FO, Ohlsson E, Willer A, Frank AK, Søndergaard E, Jendholm J, Thorén L, Lee J, Rak J, Theilgaard-Mönch K and Porse BT (shared last authorship). ERG promotes the maintenance of hematopoietic stem cells by restricting their differentiation. Genes Dev. 2015 Sep 15;29(18):1915-29. http://genesdev.cshlp.org/content/29/18/1915
- Rapin N, Bagger FO, Jendholm J, Mora-Jensen H, Krogh A, Kohlmann A, Thiede C, Borregaard N, Bullinger L, Winther O, Theilgaard-Mönch K and Porse BT (shared last authorship). Comparing cancer vs normal gene expression profiles identifies new disease entities and common transcriptional programs in AML patients. Blood. 2014 Feb 6;123(6):894-904. https://ashpublications.org/blood/article/123/6/894/32581/Comparing-cancer-vs-normal-gene-expression
- Theilgaard-Mönch K, Boultwood J, Ferrari S, Giannopoulos K, Hernandez-Rivas JM, Kohlmann A, Morgan M, Porse B, Tagliafico E, Zwaan CM, Wainscoat J, Van den Heuvel-Eibrink MM, Mills K, Bullinger L. Gene expression profiling in MDS and AML: potential and future avenues. Leukemia. 2011 Jun;25(6):909-20. https://doi.org/10.1038/leu.2011.48
- Marstrand TT, Borup R, Willer A, Borregaard N, Sandelin A, Porse BT, Theilgaard-Mönch K. A conceptual framework for the identification of candidate drugs and drug targets in acute promyelocytic leukemia. Leukemia. 2010 Jul;24(7):1265-75. https://www.nature.com/articles/le201095
In the media
2018 - Research story on Kristian Reckzeh´s publication on the identification of a novel human blood stem cell marker
2017 – Novo Nordisk Foundation highlighting the funding of the Program for Translational Hematology, a collaboration between scientists and clinicians at DanStem, Rigshospitalet, Finsen laboratory and BRIC
- Olaf Heidenreich: Validation of novel ADCs in t(8;21) AML PDX models.
- Astra Zeneca: Validation of an Astra Zeneca second generation DNA-PK inhibitor in combination with standard chemotherapy in preclinical AML trials.
- Bo Porse, BRIC, UCPH, DK: CD73 as a novel therapeutic target for AML.
- Prof. Claus Storagard, BRIC, UCPH, DK: Validation of novel AML combination therapies including DNA-damage inhibitors and standard chemotherapy.
- Jesper Velgaard Olsen, CPR, UCPH, DK: AML proteomics.
- Lars Bullinger Charité, Berlin, DE: AML genetics.
- Clinical reseachers of Nordic and European AML trial groups (DK, NO, SE, FI, DE, NL)
Dagmar Marshalls Fond
Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis Foundation
Tømrermester Jørgen Holm og Hustru Elisa
Brødrene Hartmans Fond, F. Hansen's Mindelegat
Svend Andersen Fonden
Group get to gether
Christmas card from Theilgaard-Mönch group