Medical University of Vienna
Ludwig Boltzmann Institute for Hematology and Oncology and
Department of Medicine I
Waehringer Guertel 18-20
1090 Vienna, Austria
Phone: +43 1 40400-60850
Fax: +43 1 40400-4040
The overarching aim of our research is to develop new therapeutic concepts in cancer research aiming at eliminating cancer stem cells in leukemias and myeloid neoplasms. To achieve this aim we apply molecular- and stem cell research for development of new strategies to improve treatment in leukemia and myeloid neoplasms. The research objectives are determined by new concepts for clinical applications that are the outcome of results from our in vitro studies.
Identification of targets responsible for leukemic stem cell (LSC) resistance
LSC have been identified as a critical target of therapy in various myeloid malignancies, including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and chronic myelomonocytic leukemia (CMML). The concept of LSC assumes that hematopoietic neoplasms are organized hierarchically and that only a sub-fraction of immature clonal cells exhibit self-renewal capacity and the related ability to propagate the malignancy, whereas more mature clonal cells have no long-term disease propagating activity. As a consequence, any type of therapy has curative potential only when LSCs can be eradicated. Although much has been learned about LSC phenotypes and expression profiles, targeting LSC to develop curative therapies remains a nontrivial task.
Our hypothesis is that LSC and/or the stem cell niche express distinctive markers that can be targeted in order to improve therapy or even achieve cure in patients.
In this project we will analyze patient-derived AML, CML, CMML samples and established cell line models to characterize the expression of LSC markers, immune checkpoint antigens and drug-resistance markers. Vascular- and osteoblastic bone marrow (BM) niche cells will be characterized for stem cell modulating cytokines, checkpoint molecules and their ligands, and epigenetic targets. Markers will also be analyzed in paraffin-embedded BM specimens and microdissected niche cells at the time of diagnosis, best response and relapse; patterns will be correlated with clinical parameters. LSCs and progenitor cells will be co-cultured with niche cells to evaluate the contribution of LSC-niche interactions to sensitivity to diverse targeted drugs (ponatinib, nilotinib and imatinib) alone, or combination with niche-targeting drugs (e.g. lenalidomide, CC-122, bevacizumab JQ1, PKC412, gliptins). Select combinations will also be analyzed in xenotransplant-models employing NSG-SGM3 mice. Identification of targets responsible for LSC resistance will pave the way for the development of specific LSC-eradicating (immuno)therapies.
- Valent P. Targeting of leukemia-initiating cells to develop curative drug therapies: straightforward but nontrivial concept. Curr Cancer Drug Targets. 2011 Jan;11(1):56-71. Review. PubMed PMID: 21062243.
- Zuber J, Shi J, Wang E, Rappaport AR, Herrmann H, Sison EA, Magoon D, Qi J, Blatt K, Wunderlich M, Taylor MJ, Johns C, Chicas A, Mulloy JC, Kogan SC, Brown P, Valent P, Bradner JE, Lowe SW, Vakoc CR. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature. 2011 Aug 3;478(7370):524-8. doi: 10.1038/nature10334.
- Valent P, Bonnet D, De Maria R, Lapidot T, Copland M, Melo JV, Chomienne C, Ishikawa F, Schuringa JJ, Stassi G, Huntly B, Herrmann H, Soulier J, Roesch A, Schuurhuis GJ, Wöhrer S, Arock M, Zuber J, Cerny-Reiterer S, Johnsen HE, Andreeff M, Eaves C. Cancer stem cell definitions and terminology: the devil is in the details. Nat Rev Cancer. 2012 Nov;12(11):767-75. doi: 10.1038/nrc3368.
- Valent P, Bonnet D, Wöhrer S, Andreeff M, Copland M, Chomienne C, Eaves C. Heterogeneity of neoplastic stem cells: theoretical, functional, and clinical implications. Cancer Res. 2013 Feb 1;73(3):1037-45. doi: 10.1158/0008-5472.CAN-12-3678.
- Herrmann H, Sadovnik I, Cerny-Reiterer S, Rülicke T, Stefanzl G, Willmann M, Hoermann G, Bilban M, Blatt K, Herndlhofer S, Mayerhofer M, Streubel B, Sperr WR, Holyoake TL, Mannhalter C, Valent P. Dipeptidylpeptidase IV (CD26) defines leukemic stem cells (LSC) in chronic myeloid leukemia. Blood. 2014 Jun 19;123(25):3951-62. doi: 10.1182/blood-2013-10-536078.
- Valent P, Akin C, Arock M, Bock C, George TI, Galli SJ, Gotlib J, Haferlach T, Hoermann G, Hermine O, Jäger U, Kenner L, Kreipe H, Majeti R, Metcalfe DD, Orfao A, Reiter A, Sperr WR, Staber PB, Sotlar K, Schiffer C, Superti-Furga G, Horny HP. Proposed Terminology and Classification of Pre-Malignant Neoplastic Conditions: A Consensus Proposal. EBioMedicine. 2017 Dec;26:17-24. doi: 10.1016/j.ebiom.2017.11.024.