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Galina Selivanova Group

Research

p53 reinstatement leads to impressive regression of established tumors in mice, supporting the idea that restoring p53 is a good strategy in cancer treatment. My research focuses on the development of small molecules restoring the tumor suppression functions of p53, either by refolding mutant p53 to rescue its activity, or via preventing proteasomal degradation of p53 in tumors with non-mutated p53. One of our molecules, PRIMA-1MET, which can rescue the tumor suppressor function of mutant p53, is currently being tested in first-in-man Phase I clinical trial. We are addressing the fundamental question that need to be solved for the development of novel medicines, i.e. understanding of the mechanism of action of the candidate compounds, including target specificity in vitro and in vivo and possible off-target effects.

Ablation of key oncogenic pathways by RITAreactivated p53. We found a potent inhibition of crucial oncogenes by p53 upon reactivation by small molecule RITA using microarray analysis (left). Inhibition of oncogenes by p53 reduces the cells ability to buffer pro-apoptotic signals and elicits robust apoptosis (right).

Further, using small molecules as research tools, we address important questions of p53 biology. Applying systems biology we discovered important mechanisms which control the p53 choice between induction of apoptosis and growth arrest. We show that MDM2-dependent degradation of p53 cofactor hnRNP K and cdk inhibitor p21 switches the p53 response towards cell death (Enge et al., 2009). Further, we found that upon pharmacological activation, p53 unleashes a transcriptional repression of anti-apoptotic proteins Mcl-1, Bcl-2, MAP4, and survivin, blocks the Akt pathway, which is central in the transmission of growth regulatory signals originating from cell surface receptors and c-Myc oncogene on several levels and downregulates the oncogene product cyclin E and the transcription factor ²-catenin (Grinkevich et al., 2009). Our study adds a new dimension to p53 regulation of physiological events, demonstrating that p53 reactivation triggers ablation of crucial oncogenes. The multitude of oncogenes inhibited by p53 and multiple levels on which they are targeted create external robustness of the p53 response (see Figure for more details).

If you would like to learn more about our research (or just to drop in to say hello!) you are welcome to visit us at MTC, building F, level 6.

Visiting and Mailing Address
Quarter 8c
Biomedicum
Solnavägen 9
171 65 Solna
Stockholm,
Sweden

Project groups withing the Galina Selivanova group

Giovanna Zinzalla project

Projects

Manipulation of the p53 tumor suppressor pathway : from lab bench to clinic

Half of human tumors carry mutations in the p53 gene, resulting in the expression of inactive protein. Tumors that do not carry p53 mutations, develop an alternative mechanisms of p53 inactivation, converging on enhanced proteasomal degradation. Given the extraordinary high frequency of p53 inactivation in tumors and the high potency of p53 in elimination of tumors, it appears highly desirable to restore the tumor suppressor function of p53 as a strategy to combat cancer.

We have identified a small molecule PRIMA-1 by screening the chemical library using cell-based assay. PRIMA-1 restores the active conformation to mutant p53 in cells and in vitro, re-activates the function of mutant p53 in tumor cells of different origin and suppreses the growth of human xenograft tumors in mice. Since around 50% of all human tumors carry mutations in p53, it could be widely applicable in clinic. This idea is now being tested in patients. Clinical trial with PRIMA-1 derivative PRIMA-1MET (commercial name Apr246) is currently on-going.

In tumors that retain wild type p53 its function is often impaired due to enhanced degradation by HDM-2. We have screened a chemical library and identified a small molecule, named RITA, which bound p53 and induced its accumulation in tumor cells. RITA prevents p53/HDM-2 interaction in vitro and in vivo and induces massive apoptosis in various tumor cells lines carrying wtp53 in vitro and in animal models. Notably, RITA does not suppress the growth of non-transformed cells, thus providing a convincing evidence that targeting p53 does not necessarily lead to the toxic effects in normal cells. RITA demonstrated substantial p53-dependent anti-tumor effect in vivo.

Prevention of p53/HDM2 interaction is regarded as a very promising strategy for anti-cancer treatment. Several big pharmaceutical companies are working on this approach, as for example Hoffman-La Roche, who identified HDM-2 inhibitor nutiln. Although both RITA and nutlin target HDM2/p53 interaction, their mechanism is different. Importantly, it appears that the spectrum of action is different, so that cell lines most sensitive to RITA are resistant to nutlin and vice versa. Thus, whereas the efforts of a number of labs and pharmaceutical companies are focused on inhibition of HDM-2, our studies identified a new target for pharmaceutical intervention, i.e., p53 itself, and demonstrated its feasibility and potency as a target. Our studies on small molecules reactivating p53 deepened our understanding of p53 functions and possibilities for its manipulation for cancer therapy.

In addition to applied aspects, we are actively working on important basic aspects of tumor biology, including genetic screens for p53 regulators and identification of novel factors which control p53 activity in tumor and in normal cells, which can serve as targets for therapeutic intervention in a future. In essence, to understand p53 is to understand how its interaction with proteins, and thus DNA, is controlled. We perform highly parallel and comprehensive search for p53 modulators by applying cutting-edge methodologies. We will chart p53-DNA and -protein interactions and identify their functional significance by inter-disciplinary integration of genome-wide expression profiling, ChIP-seq and proteomic approaches, followed by systems biology analysis. This will pave the way to the identification of key p53 target genes and factors contributing to alternative biological responses. These will be thoroughly validated in cells, mouse models and patient samples using functional genomics and protein-protein interaction assays. Selected factors will be used for chemical libraries screens to identify small molecules that target them. This will open the way for the development of novel therapeutic approaches.

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• Publications 1993-2004 (Pdf file, 67 Kb)

Reviews:

Galina Selivanova Reviews (pdf)

Group Members

Yara HendriksenAnknuten

yara.hendriksen@ki.se

08-524 863 11

Sylvain PeugetForskarassistent

sylvain.peuget@ki.se

08-524 863 11

Ali RihaniPostdoc

ali.rihani@ki.se

Gema Sanz SantosAnknuten, Postdoc

gema.sanz.santos@ki.se

Galina SelivanovaProfessor

Galina.Selivanova@ki.se

08-524 863 02

Madhurendra SinghPostdoc

madhurendra.singh@ki.se

Jiawei ZhuForskarstuderande

jiawei.zhu@ki.se

shiva rezaeiAnknuten

shiva.rezaei@ki.se

08-524 863 02

xiaolei zhouForskarstuderande

xiaolei.zhou@ki.se

Networks in Academia and Industry

Professor

Klas Wiman

Telefon: 08-517 793 42
Enhet: Forskargrupp Wiman, Klas
E-post: Klas.Wiman@ki.se

Professor emeritus

Sten Nilsson

Enhet: Forskargrupp Nilsson, Sten
E-post: Sten.Nilsson@ki.se

Professor

Staffan Strömblad

Telefon: 08-524 811 22
Enhet: Strömblad
E-post: Staffan.Stromblad@ki.se

Professor Joakim Lundeberg
On DNA microarray analysis of gene expression profiles induced by small molecules reactivating p53 in human tumor cells

https://www.kth.se/profile/joalun/

E-mail: joakim.lundeberg@scilifelab.se

Professor Sir Alan Fersht
on structural studies of the complexes between p53 protein and p53-reactivating compounds PRIMA-1, RITA, and MITA

Work: 1223-336341
Work: 1223-336445
E-mail: arf25@cam.ac.uk

Address:
Department of Chemistry University of Cambridge
Lensfield Road
Cambridge CB2 1EW, U.K.

Professor Taylor Jacks
on validation of PRIMA-1 in mutant p53 transgenic mouse models

Work: +1 (617) 253-0262
Fax: +1 (617) 253 9863
E-mail: tjacks@mit.edu

Address:
Howard Hughes Medical Inst.; Director, Center for Cancer Research,
Massachusetts Institute of Technology 77 Massachusetts Ave,
Rm.517A, Bldg. E17 Cambridge
MA 02139, USA

Professor Jiri Bartek
on molecular mechanisms of p53 activation in response to DNA damage

Phone: 45-3525-7357
Fax: 45-3525-7721
E-mail: bartek@biobase.dk

Address:
Department of Cell Cycle & Cancer
Institute of Cancer Biology Danish Cancer Society
Strandboulevarden 49 DK-2100
Copenhagen, Denmark

Eugene Lukanidin
on molecular pathways of p53 regulation of metastasis-promoting factor Mts-1

Phone: 45-35257313
E-mail: el@cancer.dk

Address:
Department of Molecular Cancer Biology
Institute of Cancer Biology Danish Cancer Society
Strandboulevarden 49 DK-2100
Copenhagen, Denmark

  • EU FP 6: Intergrated Project 'Mutant p53 as target for anticancer therapy'. Consortium involves 20 groups and 3 SME from 11 European countries.
  • EU FP6: Integrated Project 'Manipulating tumor suppression: a key to improve cancer treatment'. This consortium involves 19 partners and 2 SME from 10 European countries.
  • APREA AB, Fogdevreten 2A, 17177 Stockholm, is a biotech company which is working on further improvement of the compounds we have identified, using medicinal chemistry and novel screenings.

Grants

Swedish Cancer Society (Cancerfonden)
Swedish Research Council (Vetenskapsrådet, VR)
Graduate Research School in Genomics and Bioinformatics (Forskarskolan i Genomik och Bioinformatik, FGB)
Cancer Society of Stockholm (Cancerföreningen i Stockholm)
Royal Academy of Sciences (Kungliga Vetenskapsakademien, KVA)
EU FP6

Events

Marina Protopopova's PhD defense (Pdf file, 615 Kb)
Natalia's PhD defense (Pdf file, 529 Kb)
Christmas Dinner 2004 (Pdf file, 403 Kb)
Group trip to Rome 2005 (Pdf file, 2 Mb)
p53 workshop in New York 2006 (Pdf file, 1 Mb)
Madrid 2006: Martin's wedding (Pdf file, 909 Kb)