Research team Katja Pokrovskaja Tamm
Novel targeted therapies in cancer to overcome drug resistance
The aim of our research is to find novel therapeutic approaches to overcome primary and secondary resistance to anti-cancer therapy. Anti-cancer treatment often activates cellular protective mechanisms leading to an acquired resistance. One of them is induction of autophagy, which can protect cancer cells from stress and cytotoxic effects of drugs. Targeting autophagy for anti-cancer therapy using novel compounds against a lipid kinase Vps34 developed by several companies including Sprint Bioscience, is our strategy. In mouse studies, these compounds are shown to activate chemokine secretion and to reprogram cold into hot inflamed tumors improving the anti-PD-1/PD-L1 immunotherapy. Our goal is to reveal the mechanisms behind and to develop novel combination treatments using these compounds. STAT3 activation can also underlie resistance to therapy, such as multicellular drug resistance or to the tyrosine kinase inhibitors, and we are using novel approaches that we have developed for targeting STAT3. There is a cross-talk between autophagy and STAT3 pathway that we also explore, in particular, to eliminate resistant to treatment cancer stem cells. In collaboration with Mats Heyman and Anna Nilsson at KBH, we support a large sample collection of live-frozen cells purified from bone marrow and peripheral blood of pediatric patients with acute lymphocytic leukemia, ALL. Our goal is to identify novel biomarkers and novel targets for therapy in specific genetic sub-groups of ALL with a focus on pre-clinical validation of targeting autophagy and lysosomal pathway. We collaborate with Brinton Seashore-Ludlow, Tom Erkers and Rozbeh Jafari at SciLifeLab Solna, Martin Enge and Andreas Lundqvist at BioClinicum and Sprint Bioscience, Huddinge.
- Swedish Cancer Society (STAT3 and autophagy as targets for therapy in pediatric acute leukemia)
- Stiftelsen för Internationellt Onkologiskt Samarbete (Targeting Autophagy as a therapeutic strategy in pediatric acute lymphoblastic leukemia)
- The Cancer Society in Stockholm (Targeting STAT3 and autophagy in pediatric acute leukemia)
- Karolinska Institutet's research funds (Novel targeted therapy in acute leukemia)
Angelo de Milito, PhD, Docent, Director Tumor Biology and Therapeutics, Sprint Bioscience, Huddinge
Linda Vidarsdottir, PhD, University of Iceland
Yasmin Yu, PhD, Senior scientist, Sprint Bioscience, Huddinge
Integrative multi-omics and drug response profiling of childhood acute lymphoblastic leukemia cell lines.
Leo IR, Aswad L, Stahl M, Kunold E, Post F, Erkers T, Struyf N, Mermelekas G, Joshi RN, Gracia-Villacampa E, Östling P, Kallioniemi OP, Tamm KP, Siavelis I, Lehtiö J, Vesterlund M, Jafari R
Nat Commun 2022 Mar;13(1):1691
PTENP1-AS contributes to BRAF inhibitor resistance and is associated with adverse clinical outcome in stage III melanoma.
Vidarsdottir L, Azimi A, Das I, Sigvaldadottir I, Suryo Rahmanto A, Petri A, Kauppinen S, Ingvar C, Jönsson G, Olsson H, Frostvik Stolt M, Tuominen R, Sangfelt O, Pokrovskaja Tamm K, Hansson J, Grandér D, Egyházi Brage S, Johnsson P
Sci Rep 2021 May;11(1):11023
Irreversible TrxR1 inhibitors block STAT3 activity and induce cancer cell death.
Busker S, Qian W, Haraldsson M, Espinosa B, Johansson L, Attarha S, et al
Sci Adv 2020 03;6(12):eaax7945
Silencing of CEBPB-AS1 modulates CEBPB expression and resensitizes BRAF-inhibitor resistant melanoma cells to vemurafenib.
Vidarsdottir L, Fernandes RV, Zachariadis V, Das I, Edsbäcker E, Sigvaldadottir I, et al
Melanoma Res. 2020 Oct;30(5):443-454
STAT3 is activated in multicellular spheroids of colon carcinoma cells and mediates expression of IRF9 and interferon stimulated genes.
Edsbäcker E, Serviss JT, Kolosenko I, Palm-Apergi C, De Milito A, Tamm KP
Sci Rep 2019 Jan;9(1):536
Targeting autophagy by small molecule inhibitors of vacuolar protein sorting 34 (Vps34) improves the sensitivity of breast cancer cells to Sunitinib.
Dyczynski M, Yu Y, Otrocka M, Parpal S, Braga T, Henley AB, et al
Cancer Lett. 2018 10;435():32-43
Metabolic reprogramming of acute lymphoblastic leukemia cells in response to glucocorticoid treatment.
Dyczynski M, Vesterlund M, Björklund AC, Zachariadis V, Janssen J, Gallart-Ayala H, et al
Cell Death Dis 2018 08;9(9):846
Identification of novel small molecules that inhibit STAT3-dependent transcription and function.
Kolosenko I, Yu Y, Busker S, Dyczynski M, Liu J, Haraldsson M, et al
PLoS ONE 2017 ;12(6):e0178844
Cell crowding induces interferon regulatory factor 9, which confers resistance to chemotherapeutic drugs.
Kolosenko I, Fryknäs M, Forsberg S, Johnsson P, Cheon H, Holvey-Bates EG, et al
Int. J. Cancer 2015 Feb;136(4):E51-61
An activated JAK/STAT3 pathway and CD45 expression are associated with sensitivity to Hsp90 inhibitors in multiple myeloma.
Lin H, Kolosenko I, Björklund AC, Protsyuk D, Österborg A, Grandér D, et al
Exp. Cell Res. 2013 Mar;319(5):600-11
Glucocorticoid-induced cell death is mediated through reduced glucose metabolism in lymphoid leukemia cells.
Buentke E, Nordström A, Lin H, Björklund AC, Laane E, Harada M, et al
Blood Cancer J 2011 Jul;1(7):e31
Activation of STAT1 is required for interferon-alpha-mediated cell death.
Arulampalam V, Kolosenko I, Hjortsberg L, Björklund AC, Grandér D, Tamm KP
Exp. Cell Res. 2011 Jan;317(1):9-19
Cell death induced by dexamethasone in lymphoid leukemia is mediated through initiation of autophagy.
Laane E, Tamm KP, Buentke E, Ito K, Kharaziha P, Khahariza P, et al
Cell Death Differ. 2009 Jul;16(7):1018-29