Research group - Caroline Palm Apergi
We are investigating Plk1 expression in childhood cancer patients. Our aim is to develop more specific treatments by targeting Plk1 with novel oligonucleotides and small molecules.
Leukemia is the most common type of pediatric cancer and responsible for the highest proportion of death in children with cancer. Epidemiological studies of childhood cancer survivors have revealed an alarmingly high incidence of chronic health disabilities after treatment. Therefore, more specific and personalized therapies need to be developed. Polo-like kinase 1 (Plk1) is a serine/threonine kinase that plays a key role in various events during mitosis. It is overexpressed in many human solid tumors such as ovarian and breast cancer and recently found to be overexpressed in leukemia. Although several small molecules have been developed to inhibit the Plk1 protein, they are not specific but also inhibit other proteins. Depletion of Plk1 by RNA interference (RNAi) is specific and results in G2-arrest and apoptosis in tumor cells. However, the biggest barrier for RNAi therapeutics has been to find a delivery vehicle that can transport the active short interfering RNA (siRNA) across the cell membrane into the cytoplasm where it will exert its effect.
We are working with RNAi prodrugs that enter cells without any delivery vehicle and are cleaved by cytoplasmic enzymes inside cells into wild type siRNA that induce target mRNA cleavage. Our aim is to study Plk1 with RNAi prodrugs in comparison to small molecule inhibitors in samples from cancer patients and healthy donors to analyze if tumor cells, and not healthy cells, undergo apoptosis after Plk1 depletion. We are also investigating the mechanism by which non-transformed cells may survive Plk1 depletion and if other members of the Plk family are involved.
Research group leader Caroline Palm Apergi
Cancer- och Allergifonden, Ingvar Carlsson Award 5, Stiftelsen för Strategisk Forskning, Barncancerfonden, Byggmästare Olle Engkvists Stiftelse, Magnus Bergvalls Stiftelse, Alex och Eva Wallströms Stiftelse, Karolinska Institutets Forskningsstiftelser, Dr Åke Olssons stiftelse, Åke Wibergs stiftelse, Stiftelsen Clas Groschinskys Minnesfond, Gunvor och Josef Anérs stiftelse, Marie Béves Stiftelse för Barncancerforskning.
RNAi prodrugs decrease elevated mRNA levels of Polo-like kinase 1 in ex vivo cultured primary cells from pediatric acute myeloid leukemia patients.
Kolosenko I, Goroshchuk O, Vidarsdottir L, Björklund AC, Dowdy SF, Palm-Apergi C
FASEB J 2021 May;35(5):e21476
Small-molecule inhibitors for targeting polo-like kinase 1.
Kolosenko I, Palm-Apergi C
Future Med Chem 2020 Aug;12(16):1457-1460
Targeting Plk1 with siRNNs in primary cells from pediatric B-cell acute lymphoblastic leukemia patients.
Goroshchuk O, Vidarsdottir L, Björklund AC, Hamil AS, Kolosenko I, Dowdy SF, et al
Sci Rep 2020 Feb;10(1):2688
Designing siRNA and Evaluating Its Effect on RNA Targets Using qPCR and Western Blot.
Vidarsdottir L, Goroshchuk O, Kolosenko I, Palm-Apergi C
Methods Mol. Biol. 2019 ;2036():53-72
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
Polo-like kinases and acute leukemia.
Goroshchuk O, Kolosenko I, Vidarsdottir L, Azimi A, Palm-Apergi C
Oncogene 2019 01;38(1):1-16
Induction of RNAi Responses by Short Left-Handed Hairpin RNAi Triggers.
Hagopian JC, Hamil AS, van den Berg A, Meade BR, Eguchi A, Palm-Apergi C, et al
Nucleic Acid Ther 2017 Oct;27(5):260-271
RNAi prodrugs targeting Plk1 induce specific gene silencing in primary cells from pediatric T-acute lymphoblastic leukemia patients.
Kolosenko I, Edsbäcker E, Björklund AC, Hamil AS, Goroshchuk O, Grandér D, et al
J Control Release 2017 09;261():199-206
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
Efficient delivery of RNAi prodrugs containing reversible charge-neutralizing phosphotriester backbone modifications.
Meade BR, Gogoi K, Hamil AS, Palm-Apergi C, van den Berg A, Hagopian JC, et al
Nat. Biotechnol. 2014 Dec;32(12):1256-61