The Centre for Advanced Cancer Therapies (ACT)
Visions and Goals
To generate scientific discoveries that can be rapidly translated into the clinic for the benefit of patients and society.
Establish efficient, innovative, and targeted approaches to treat cancer
Develop novel methods and strengthen existing technical platforms
Train the next generation of experimental and clinical researchers at different stages of their career
Strategic Recruitment and Renewal
ACT efficiently promotes young, talented scientists and has successfully recruited four junior researchers including three Assistant Professors and one Researcher/Senior Assistant Professor, all with unique and complementary skills. ACT is are in the process of recruiting clinical researcher to the Centre, with the experience in pharmacology/cancer biology as a coordinator of innovative clinical trials, who will promote the transition of promising investigational drugs into clinical trials and assist towards establishing new clinical trials of repositioned drugs.
We have set up a new infrastructure in the form of technical platforms for key functions such as:
Screening of chemical libraries and imaging-based validation of hits in clinical samples
Multi-variant analysis of the response to candidate drugs in clinical samples, using systems biology
Integration of Research Groups
Participating groups are already working together in 18 collaborative projects
We have established a formalized system for close interactions between all researchers within the Centre. This involves monthly research seminars and project meetings, as well as an annual retreat.
We are using a multidisciplinary approach that integrates clinical research with state of the art HTP screening of chemical libraries and target identification/validation technologies, including cell and molecular biology, transcriptomics, proteomics, computational biology and in vivo imaging techniques. We have a number of projects at different stages of drug discovery from identification of hits by screening chemical libraries all the way to clinical trials of identified compounds. Many of these projects show promising results and the centre is well set to fulfil its visions.
Director Galina Selivanova MTC, Karolinska Institutet
Galina Selivanova Research Group Website
Co-director Sören Lehmann Dept. of Medicine, Hematology Center, Huddinge
Sören Lehmann Group Website
Marie Arsenian Henriksson MTC, Karolinska Institutet
Marie Arsenian Henriksson Research Group Website
David Lane, MTC
David Lane Research Group Website
Svetlana Lagercrantz, Department of Molecular Medicine and Surgery, Karolinska Institutet
Svetlana Lagercrantz Project Group Website
Laszlo Szekely, Karolinska University Hospital
Ola Winqvist Research Group Website
Sten Nilsson, Onc-Path, Radiumhemmet, Karolinska Sjukhuset
Sten Nilsson Group Website
Yihai Cao, MTC, Karolinska Institutet
Yihai Cao Research Group Website
Sonia Lain, MTC, Karolinska Institutet
Sonia Lain Research Group Website
Lars-Gunnar Larsson, MTC, Karolinska Institutet
Lars-Gunnar Larsson Research Group Website
Per Kogner, CCK, Astrid Lindgren Childrens Hospital
Per Kogner Website
Birgitta Sander, Laboratory Medicine, Path-Cytol, Huddinge
Birgitta Sander Research Group Website
Klas Wiman, Department of Oncology-Pathology, Karolinska Institutet
Klas Wiman Research Group Website
Professor Anders Österberg
Phone: +46 8 517 733 85
Assistant Professor (Senior) in Chemical Biology Giovanna Zinzalla
Phone: +46 (0) 8524 81262 (office)
Mobile: +46 735 668336
Science for Life Laboratory
Alpha house, Level 5,
Rooms: A5590 (office), A5672 (laboratory)
171 65 Stockholm, Sweden
Science for Life Laboratory
171 21 Stockholm, Sweden
Giovanna Zinzalla Website
Upcoming ACT Seminars
Regular monthly seminars and board meetings:
Every third Thursday (unless otherwise stated) of each month at Room A302, Karolinska Institutet- Solna campus- MTC
Past Annual Retreats:
- November 28th 2014. Radisson Blu Royal Park Hotel, Stockholm,
- January 15th 2010. First ACT meeting
- September 14th 2010, Villa Brevik, Lidingo
- August 24-25th 2011, Sandhamn
- August 23-24th 2012, Sandhamn
- August 29-30 2013, Sandhamn
StratCan Interactive Summer School on Targeted Cancer Therapies was on June 10-14, 2013 at Sandhamn Seglarhotell, Stockholm
Targeted therapies, which include monoclonal antibodies and small-molecules, have significantly changed the treatment of cancer over the past 10 years. Although traditional cytotoxic chemotherapy is still the widely applied treatment for different types of cancer, targeted therapies are now an important component of treatment for many common malignancies. Targeted therapy has raised new questions about the tailoring of cancer treatment to an individual patient's tumor, the assessment of drug effectiveness and toxicity, and the economics of cancer care.
Report From the Meeting
Plenary Session Topics
- Targeting Oncogenic and Tumour Suppressor Transcription Factors: MYC and p53
- Biologics for Cancer Therapies
- Tyrosine Kinase Signal Transduction Pathways
- Gerard Evan (Cambridge University, UK)
- Mien-Chie Hung (MD Anderson Cancer Center, USA)
- Brian Huntly (Cambridge University, UK)
- David Lane (A*Star Biomedical Science Institutes, Singapore)
- Greg Winter (Medical Research Council, Cambridge, UK)
Documents to download
• ACT Cell Bank Sheet (password protected) (Pdf file, 203 Kb)
• ACT! Investigational Anticancer Compounds (password protected) (Pdf file, 209 Kb)
• ACT Cell Lines (password protected) (Pdf file, 218 Kb)
• Overlap between ACT! cell lines and Sanger/CCLE/NCI60 (Pdf file, 44 Kb)
• Expertise List Within ACT! (password protected) (Pdf file, 63 Kb)
• Cancer Cell Line Encyclopedia
• Cancer RX Gene (Genomics of Drug Sensitivity in Cancer project)
Jordi Barretina, Giordano Caponigro, Nicolas Stransky et al
The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity
Nature 483, 603607 (29 March 2012)
Full article text
Mathew J. Garnett, Elena J. Edelman, Sonja J. Heidorn et al
Systematic identification of genomic markers of drug sensitivity in cancer cells
Nature 483, 570575 (29 March 2012)
Full Article Text
ACT Animal Models
FDA approved oncology drugs set
Structural Biology Tools
3-D Multicellular Spheroids
Li H, Lakshmikanth T, Garofalo C, Enge M, Spinnler C, Anichini A, Szekely L, Kärre K, Carbone E, Selivanova G
Pharmacological activation of p53 triggers anticancer innate immune response through induction of ULBP2.
2011 Cell Cycle. Oct 1; 10(19).
Zhao CY, Szekely L, Bao W, Selivanova G
Rescue of p53 function by small- molecule RITA in cervical carcinoma by blocking E6-mediated degradation
2012 Cancer Res 70: 3372-81.
Jakob Lovén, Nikolay Zinin, Therese Wahlström, Inga Müller, Petter Brodin, Erik Fredlund, Ulf Ribackea, Andor Pivarcsi, Sven Påhlman, and Marie Henriksson
MYCN-regulated microRNAs repress estrogen receptor ± (ESR1) expression and neuronal differentiation in human neuroblastoma
PNAS 2010 Jan 26; 107(4) 1553-8
Stuber G, Flaberg E, Petranyi G, Otvos R, Rokaeus N, Kashuba E, Wiman KG, Klein G, Szekely L
PRIMA-1MET induces nucleolar translocation of Epstein-Barr virus- encoded EBNA-5 protein
2009. Mol Cancer 8: 23.
Rökaeus, N., Shen, J., Eckhardt, I., Bykov, V.J., Wiman, K.G., Wilhelm, M.T
PRIMA-1MET/APR-246 targets mutant forms of p53 family members p63 and p73
2010 Oncogene 29, 6442-51.
Vilborg, A., Bersani, B., Wickström, M., Segerström, L., Kogner, P., and Wiman, K.G
Wig-1, a novel regulator of N-Myc mRNA and N-Myc-driven tumor growth
Cell Death and Disease 3, e298; doi:10.1038/cddis.2012.33 Published online 19 April 2012
Lehmann, S., Bykov, V.J.N., Ali, D., Andrén, O., Cherif, H., Tidefelt, U., Uggla, B., Yachnin, J., Juliusson, G., Moshfegh, A., Paul, C., Wiman, K.G., and Andersson, P.-O.
Targeting p53 in vivo: A first-in-man study with the p53-targeting compound APR-246 in refractory hematological malignancies and prostate cancer
J Clin Oncol. 2012 Oct 10;30(29):3633-9. doi: 10.1200/JCO.2011.40.7783
Hydbring, P., Bahram, F., Su, Y., Tronnersjö, S., Högstrand, K., von der Lehr, N., Lilischkis, R., Hein, N., Wu, S., Vervoorts, J., Henriksson, M., Grandien, A., Lüscher, B., and Larsson, LG.
Myc/Ras cooperativity in transformation: Phosphorylation by cdk2 is required for Myc to repress Ras-induced senescence.
PNAS 107, 58-63 (2010).
Zirath H, Frenzel A, Segerström L, Westermark U, Persson M, Påhlman S, Kogner P, and Arsenian Henriksson, M.
Inhibition of MYCN/Max signaling induces Apoptosis and TrkA- mediated Differentiation in Human Neuroblastoma.
Guerra, L., Albihn, A., Tronnersjö, S., Yan, Q., Guidi, R., Stenerlöw, B., Sterzenbach, T., Josenhans, C., Fox, JG., Schauer, DB., Thelestam, M., Larsson, L-G., Henriksson, M. & Frisan, T
Myc is required for activation of the ATM-dependent checkpoints in response to DNA damage
PLoS One 5, e8924, 2010.
Högstrand, K., Hejll, E., Sander, B., Rozell, B., Larsson, LG. and Grandien, A
Inhibition of the intrinsic but not the extrinsic apoptosis pathway accelerates and drives Myc-driven tumorigenesis towards acute myeloid leukemia
PLoS One 7, e31366, 2012.
Rao B, van Leeuwen IM, Higgins M, Campbell J, Thompson AM, Lane DP, Lain S
Evaluation of an Actinomycin D/VX-680 aurora kinase inhibitor combination in p53-based cyclotherapy
Oncotarget. 2010 Nov;1(7):639-50.
Cepeda D, Sharifi HR, Ng HF, Mahmoudi S, Cerrato VS, Nilsson H, Fredlund E, Rantala J, Magnusson K, Malyukova A, Klevebring D, Viñals F, Grotegut S, Al-Khalili Szigyarto C, Sun D, Lerner M, Navani S, Jirström K, Pontén, F, Uhlén, M, Widschwendter, M, Wohlschlegel, J, Grandér, D, Spruck, C, Larsson, LG and Sangfelt, O
FBXO28 targets Myc for ubiquitylation and predicts poor prognosis in breast cancer.
Hejll, E., Bocci, M., Tabor, V., Hydbring, P., Grandien, A, Sander B, Lehmann S and Larsson, L-G.
Restoration of senescence upon Cdk2 inactivation delays MYC-driven acute myeloblastic leukemia
Ridderstråle K, Yan Q, Castell A, Hydbring, P, Fredlund, E, Mannich-Uggla, C, Fryknäs M, Kogner P, Johnsen JI, Larsson, L-G.
Identification of a small molecule that increases Myc turnover and induces apoptosis in Myc- and transformation-dependent manner
Ridderstråle, K, Yan, Q, Castell, A., Zinzalla G., Hydbring, P, Kogner P, Johnsen JI, Larsson, L-G
Identification of a low molecular weight compounds that targets the Myc-Max interactions and inhibits Myc-dependent transformation
M Burmakin, E Hedström, Y Shi, P. Kogner and G. Selivanova.
Dual targeting of wt and mutp53 by small molecule RITA results in the inhibition of N-Myc and key survival oncogenes and kills neuroblastoma cells in vivo and in vitro
Manuscript ready for submission
Zawacka-Pankau J, Grinkevich V, Vema A, Ridderstrale K, Andreotti V, Inga A, Larsson LG, Karlén A, Filz O, Poroikov V, Wilhelm M, Okorokov A, and Selivanova G
Dual inhibition of p53/MDM2 and p53/MDMX interaction by small molecules via a novel allosteric mechanism
Zawacka-Pankau J, Grinkevich VV, Hünten S, Nikulenkov F, Gluch A, Li H, Enge M, Kel A, Selivanova G.
Inhibition of glycolytic enzymes mediated by pharmacologically activated p53: targeting Warburg effect to fight cancer.
J Biol Chem. 2011 Dec 2;286(48):41600-15. Epub 2011 Aug 23.
Hedström E, Eriksson S, Zawacka-Pankau J, Arnér ES, Selivanova G
p53-dependent inhibition of TrxR1 contributes to the tumor-specific induction of apoptosis by RITA.
Cell Cycle. 2009 Nov 1;8(21):3576-83. Epub 2009 Nov 1.
Larsson, LG and Arsenian Henriksson, M
The Yin and Yang functions of the Myc oncoprotein in cancer development and as targets for therapy
Exp. Cell Res. 316,1429-37 (2010).
Lane DP, Cheok CF, Lain S
p53-based cancer therapy
Cold Spring Harb Perspect Biol. 2010 Sep;2(9):a001222.
Vilborg A, Bersani C, Wilhelm MT, Wiman KG.
The p53 target Wig-1: a regulator of mRNA stability and stem cell fate?
Cell Death Differ. 2011 Sep;18(9):1434-40. doi: 10.1038/cdd.2011.20. Epub 2011 Mar 11. Review.
Vilborg A, Wilhelm MT, Wiman KG
Regulation of tumor suppressor p53 at the RNA level
J Mol Med (Berl). 2010 Jul;88(7):645-52. Epub 2010 Mar 21. Review.
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Aprea announces positive data from a clinical Phase I/II study with APR-246 in patients with advanced cancers
STOCKHOLM - September 18, 2012. Aprea today announced positive data from a completed Phase I/II clinical study with its investigational drug APR-246. The results from the study have been published in the Journal of Clinical Oncology. Based on the positive data, Aprea is planning to advance APR-246 into a Phase II proof-of-concept study in ovarian cancer. Aprea is a Karolinska Development portfolio company.
In the Phase I/II-trial, escalating doses of APR-246 were administered as monotherapy to 22 patients with advanced blood- or prostate cancer during up to four consecutive days. Dose limiting toxicity was shown at plasma levels well above predicted therapeutic plasma levels. The study also demonstrated dose-proportional and time-independent pharmacokinetics for APR-246 over the dose range studied.
The results from the study have been published in the Journal of Clinical Oncology. In addition to reporting that the drug was well tolerated, the authors conclude from the study that APR-246 induces biological effects and that there are cases of clinical effects on tumor burden. One patient with advanced blood cancer demonstrated a 50 percent reduction in the number of blast cells in the bone marrow.
Ulf Björklund, CEO, Aprea:
These are very encouraging study results. We are now planning to take the p53-activating compound APR-246 forward into a Phase II-trial in epithelial ovarian cancer with mutated p53 in combination with conventional chemotherapy.
In the new proof-of-concept study, APR-246 will be administered in combination with the reintroduction of a carboplatin-based regimen. A striking synergistic effect between APR-246 and the very active and frequently used cancer product carboplatin has been observed in pre-clinical experiments.
Torbjörn Bjerke, CEO, Karolinska Development:
This is indeed promising data. Although it was primarily a safety trial, the data indicates that APR-246 has an anti-tumor effect. APR-246 was well tolerated and, importantly, the safety profile is different from traditional cytostatic drugs. With these new results we can see a clear path forward for APR-246, especially in carboplatin-resistant patients.
For further information, please contact:
CEO, Aprea AB Ulf Björklund
Phone: +46 (0)8 508 845 04
CEO, Karolinska Development AB Torbjörn Bjerke
Phone: +46 (0)72 744 41 23
Innovative Clinical Trials
Today ACT is in a strong position to facilitate the drug discovery process. Since the start of ACT 2,5 years ago we have already launched four clinical trials, including a first-in-man clinical trial with the mutant p53-targeting compound APR-246.
In a unique translational study we have taken APR-246, which was identified by a chemical library screen, all the way from the lab bench via preclinical studies to a first-in-man clinical trial. The close collaboration between Klas G. Wiman, Galina Selivanova and Sören Lehmnann, has been imperative for this translational process and will be decisive for future clinical development of APR-246 in phase II trials, the ultimate goal of our joint efforts.
Nyheter (på svenska)
Is on the way to start a pediatric phase I study of Omega 3 fatty acids DHA and EPA in childhood cancer patients.
Has initiated a new clinical phase I/IIa, first-in-man trial of his compound ODX, designed to inhibit bone metastasis in patients with castration-resistant prostate cancer failing docetaxel therapy.
Has begun the first clinical trial for personalized cancer therapy based on his new digital high throughput imaging system.