Galina Selivanova Group

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.

Group picture of Galina Selivanova group, picture taken outside
Galina Selivanova Group
p53 reactivation illustration
Figure 1. Strategy of specific elimination of cancer cells by restoring p53 function.

Research

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

 p53 is the major tumor suppressor which eliminates damaged or oncogene-expressing cells by activating transcription of genes inducing apoptosis, cell cycle arrest or senescence. p53 inactivation via mutations or enhanced degradation by MDM2 is the most frequent alteration in human cancers, which underscores the key role of p53 in combating cancer. Reinstatement of p53 by genetic means have demonstrated remarkable tumor suppression in animal models, including inhibition of aggressive metastatic lesions. This inspires the idea of developing small molecules reactivating p53 to fight cancer (Figure 1)

Illustration Figure 2. strategy of p53 restoration by small molecules depends on the type of p53 inactivation
Figure 2. strategy of p53 restoration by small molecules depends on the type of p53 inactivation. Photo: n/a

Depending on the type of p53 inactivation, there could be envisioned two major strategies of p53 reinstatement: restoring the function of mutant p53 and preventing p53 inactivation by MDM2 (Figure 2).

A number of MDM2 inhibitors reactivating wild type p53 have been discovered, including small molecule RITA discovered by us (Issaeva et al, Nature Medicine, 2004; Enge et al, Cancer Cell 2009; Grinkevich et al, Cancer Cell, 2009).  Several of these are currently being tested in clinical trials, including derivatives of nutlin and the stapled peptide ATSP-7041, which are activating wild type (wt) p53 are in Phase I/II trials (www.cilicaltrials.gov, see also our review Sanz G et al, J Mol Cell Biol, 2019).

Mutant p53 is expressed in cancers, where it adopts an unfolded conformation resulting in loss of DNA binding and in some cases gaining oncogenic function. Thus, our hypothesis is to stabilize p53 conformation by small molecule to restore the DNA binding tumor suppressor function of p53. Since around 50% of all human tumors carry mutations in p53, it could be widely applicable in clinic. We have identified a small molecule PRIMA-1MET by screening NCI chemical library using cell-based assay (Bykov et al, Nature Medicine, 2002). PRIMA-1MET(commercial name APR-246, please see www.aprea.com)restores the active conformation and DNA binding of 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.   

  APR-246 has been tested in patients in Phase I clinical trial and in March 2020 APR-246 received Fast Track and Breakthrough Therapy designations from FDA based on outstanding results of Phase II trial in MDS patients. These prompted the start of Phase III randomized trial in MDS.

 In light of clinical developments of p53-targeting therapies, it is imperative to rationally design combinatorial treatments (since monotherapy cannot cure cancer) and find biomarkers to stratify patients. To achieve these, we need to get a deep understanding of the molecular mechanisms and pathways affected by p53 and p53-reactivating compounds.

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  Biomedicum C8.

Project groups within the Galina Selivanova group

Sylvain Peuget, PhD, Assistant Professor
p53 regulation by bacteria and its impact on tumorigenesis 
 

Increasing evidence from metagenomics study highlights the role of the microbiota composition in cancer initiation, progression and resistance to therapies. Cancers are clearly associated with bacterial dysbiosis, which could be a passenger but also a driver of the tumorigenesis process. However, little is known about how the bacteria species enriched during dysbiosis promote tumorigenesis.  

We are investigating the molecular mechanisms of the host response to bacterial dysbiosis, with a focus on the tumor suppressor p53 pathway. p53 plays a central role in cell signaling and is therefore strongly regulated in response to commensal and pathogenic bacteria signaling during inflammation. Moreover, p53 encodes a transcriptional program which in turns regulates the innate and adaptive immune response. Therefore, it is not surprising that bacteria have evolved different mechanisms to target and manipulate the host p53 pathway in order to establish and keep their niche. Finally, p53 is the major barrier against cancer in humans and its role as a regulator of immune response is emerging as a key component for its tumor suppressive function. Hence, bacterial interference with the p53 pathway could have important consequences for tumorigenesis.  

Our main questions are:  

1)  How the p53 pathway is involved in the physiological host response to bacteria, i.e. inflammation and innate immune response?  

2)  How some bacteria hijack the p53 pathway for their own benefits?  

3)  How bacteria-induced deregulation of the p53 pathway influence cancer initiation and progression?  

Our ultimate goal is to find new therapeutic targets in bacteria and/or the human host to help prevent of combat cancer.  

To investigate these fundamental questions at the molecular level both on the bacteria and host side, this project is a collaboration performed together with an expert in microbiology of pathogenic bacteria Ass. Prof. Marie-Stephanie Aschtgen in Prof Birgitta Henriques-Normark’s lab. 

Projects

Targeting p53 to kill tumor cells, reprogram cancer-associated fibroblasts and boost anti-cancer immune response

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. A number of p53-targeting therapies are currently being tested in patients.  

We are addressing the fundamental questions that need to be solved for the efficient application of p53-targeting medicines and their combinations  in clinic, i.e. thorough understanding of the mechanism of action of the  identified compounds, including target specificity in vitro and in vivo and off-target effects.

While p53 reactivating molecules have been shown to kill cancer cells, the question remains open how p53 reinstatement will affect tumor microenvironment, cancer-associated fibroblasts in particular, as well as anti-cancer immune response. 

Our ambition is to provide basis for innovative p53-based treatment strategies targeting both cancer cells and tumor microenvironment to generate synergistic anti-tumor effects that result in long term survival of patients. Defining this concept, its mechanisms and implications for novel anti-cancer therapies form the main objectives

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. In order to address these challenging questions we will employ a comprehensive and multidisciplinary approach. We will apply cutting-edge molecular and cell biology methodologies, multi-omics analyses and systems biology analysis, combined with ex vivo 3D cell & tissue culture and in vivo models. We combine hypothesis-driven strategy with unbiased multi-omics approach and apply the analysis of publicly available patient data sets (e.g., TCGA), as well as newly obtained data from patient material via my collaborations with clinicians in Sweden and abroad.

We perform highly parallel and comprehensive search for p53 modulators 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.  We hope our studies will open the way for the development of novel therapeutic approaches.

Group members

Visiting and Mailing Address

Quarter 8C
Biomedicum
Solnavägen 9
171 65 Solna
Stockholm,
Sweden

Networks in Academia and Industry

Grants

Events

Publications

Prediction of response to anti-cancer drugs becomes robust via network integration of molecular data.
Franco M, Jeggari A, Peuget S, Böttger F, Selivanova G, Alexeyenko A
Sci Rep 2019 02;9(1):2379

Prediction of response to anti-cancer drugs becomes robust via network integration of molecular data.
Franco M, Jeggari A, Peuget S, Böttger F, Selivanova G, Alexeyenko A
Sci Rep 2019 02;9(1):2379

MYC and RAS are unable to cooperate in overcoming cellular senescence and apoptosis in normal human fibroblasts.
Zhang F, Zakaria SM, Högqvist Tabor V, Singh M, Tronnersjö S, Goodwin J, et al
Cell Cycle 2018 ;17(24):2697-2715

Reactivation of mutant p53 and induction of apoptosis in human tumor cells by maleimide analogs.
Bykov VJN, Issaeva N, Zache N, Shilov A, Hultcrantz M, Bergman J, et al
J Biol Chem 2017 12;292(48):19607

Ablation of Key Oncogenic Pathways by RITA-Reactivated p53 Is Required for Efficient Apoptosis.
Grinkevich VV, Nikulenkov F, Shi Y, Enge M, Bao W, Maljukova A, et al
Cancer Cell 2017 05;31(5):724-726

APR-246/PRIMA-1MET inhibits thioredoxin reductase 1 and converts the enzyme to a dedicated NADPH oxidase.
Peng X, Zhang MQ, Conserva F, Hosny G, Selivanova G, Bykov VJ, et al
Cell Death Dis 2017 04;8(4):e2751

The use of ion mobility mass spectrometry to probe modulation of the structure of p53 and of MDM2 by small molecule inhibitors.
Dickinson ER, Jurneczko E, Nicholson J, Hupp TR, Zawacka-Pankau J, Selivanova G, et al
Front Mol Biosci 2015 ;2():39

Pharmacological reactivation of p53 as a strategy to treat cancer.
Zawacka-Pankau J, Selivanova G
J Intern Med 2015 Feb;277(2):248-259

The conserved Trp114 residue of thioredoxin reductase 1 has a redox sensor-like function triggering oligomerization and crosslinking upon oxidative stress related to cell death.
Xu J, Eriksson SE, Cebula M, Sandalova T, Hedström E, Pader I, et al
Cell Death Dis 2015 Jan;6():e1616

Modulation of the poly (ADP-ribose) polymerase inhibitor response and DNA recombination in breast cancer cells by drugs affecting endogenous wild-type p53.
Ireno IC, Wiehe RS, Stahl AI, Hampp S, Aydin S, Troester MA, et al
Carcinogenesis 2014 Oct;35(10):2273-82

Wild type p53 reactivation: from lab bench to clinic.
Selivanova G
FEBS Lett 2014 Aug;588(16):2628-38

Integrated high-throughput analysis identifies Sp1 as a crucial determinant of p53-mediated apoptosis.
Li H, Zhang Y, Ströse A, Tedesco D, Gurova K, Selivanova G
Cell Death Differ 2014 Sep;21(9):1493-502

ROS-dependent activation of JNK converts p53 into an efficient inhibitor of oncogenes leading to robust apoptosis.
Shi Y, Nikulenkov F, Zawacka-Pankau J, Li H, Gabdoulline R, Xu J, et al
Cell Death Differ 2014 Apr;21(4):612-23

APR-246/PRIMA-1MET inhibits thioredoxin reductase 1 and converts the enzyme to a dedicated NADPH oxidase.
Peng X, Zhang MQ, Conserva F, Hosny G, Selivanova G, Bykov VJ, et al
Cell Death Dis 2013 Oct;4():e881

Dual targeting of wild-type and mutant p53 by small molecule RITA results in the inhibition of N-Myc and key survival oncogenes and kills neuroblastoma cells in vivo and in vitro.
Burmakin M, Shi Y, Hedström E, Kogner P, Selivanova G
Clin Cancer Res 2013 Sep;19(18):5092-103

Insights into p53 transcriptional function via genome-wide chromatin occupancy and gene expression analysis.
Nikulenkov F, Spinnler C, Li H, Tonelli C, Shi Y, Turunen M, et al
Cell Death Differ 2012 Dec;19(12):1992-2002

Faculty of 1000 recommended article

Protein kinase Cα (PKCα) regulates p53 localization and melanoma cell survival downstream of integrin αv in three-dimensional collagen and in vivo.
Smith SD, Enge M, Bao W, Thullberg M, Costa TD, Olofsson H, et al
J Biol Chem 2012 Aug;287(35):29336-47

A novel facet of tumor suppression by p53: Induction of tumor immunogenicity.
Li H, Lakshmikanth T, Carbone E, Selivanova G
Oncoimmunology 2012 07;1(4):541-543

Pharmacological activation of p53 triggers anticancer innate immune response through induction of ULBP2.
Li H, Lakshmikanth T, Garofalo C, Enge M, Spinnler C, Anichini A, et al
Cell Cycle 2011 Oct;10(19):3346-58

Inhibition of glycolytic enzymes mediated by pharmacologically activated p53: targeting Warburg effect to fight cancer.
Zawacka-Pankau J, Grinkevich VV, Hünten S, Nikulenkov F, Gluch A, Li H, et al
J Biol Chem 2011 Dec;286(48):41600-15

Full article text

Abrogation of Wip1 expression by RITA-activated p53 potentiates apoptosis induction via activation of ATM and inhibition of HdmX.
Spinnler C, Hedström E, Li H, de Lange J, Nikulenkov F, Teunisse AF, et al
Cell Death Differ 2011 Nov;18(11):1736-45

Full article text

PRIMA-1Met/APR-246 induces apoptosis and tumor growth delay in small cell lung cancer expressing mutant p53.
Zandi R, Selivanova G, Christensen CL, Gerds TA, Willumsen BM, Poulsen HS
Clin Cancer Res 2011 May;17(9):2830-41

Full article text

PRIMA-1Met/APR-246 induces wild-type p53-dependent suppression of malignant melanoma tumor growth in 3D culture and in vivo.
Bao W, Chen M, Zhao X, Kumar R, Spinnler C, Thullberg M, et al
Cell Cycle 2011 Jan;10(2):301-7

Full article text

Rescue of the apoptotic-inducing function of mutant p53 by small molecule RITA.
Zhao CY, Grinkevich VV, Nikulenkov F, Bao W, Selivanova G
Cell Cycle 2010 May;9(9):1847-55

Full article text

Rescue of p53 function by small-molecule RITA in cervical carcinoma by blocking E6-mediated degradation.
Zhao CY, Szekely L, Bao W, Selivanova G
Cancer Res 2010 Apr;70(8):3372-81

Full article text

Therapeutic targeting of p53 by small molecules.
Selivanova G
Semin Cancer Biol 2010 Feb;20(1):46-56

Full article text

Integrins and mutant p53 on the road to metastasis.
Selivanova G, Ivaska J
Cell 2009 Dec;139(7):1220-2

p53-dependent inhibition of TrxR1 contributes to the tumor-specific induction of apoptosis by RITA.
Hedström E, Eriksson S, Zawacka-Pankau J, Arnér ES, Selivanova G
Cell Cycle 2009 Nov;8(21):3584-91

Full article text

HIPK2 regulation by MDM2 determines tumor cell response to the p53-reactivating drugs nutlin-3 and RITA.
Rinaldo C, Prodosmo A, Siepi F, Moncada A, Sacchi A, Selivanova G, et al
Cancer Res 2009 Aug;69(15):6241-8

Full article text

Ablation of key oncogenic pathways by RITA-reactivated p53 is required for efficient apoptosis.
Grinkevich VV, Nikulenkov F, Shi Y, Enge M, Bao W, Maljukova A, et al
Cancer Cell 2009 May;15(5):441-53

Link to the article (Pdf file, 1 Mb)

MDM2-dependent downregulation of p21 and hnRNP K provides a switch between apoptosis and growth arrest induced by pharmacologically activated p53.
Enge M, Bao W, Hedström E, Jackson SP, Moumen A, Selivanova G
Cancer Cell 2009 Mar;15(3):171-83

Link to the article (Pdf file, 1 Mb)

Tumor-specific induction of apoptosis by a p53-reactivating compound.
Hedström E, Issaeva N, Enge M, Selivanova G
Exp Cell Res 2009 Feb;315(3):451-61

Full article text

Hypoxia induces p53-dependent transactivation and Fas/CD95-dependent apoptosis.
Liu T, Laurell C, Selivanova G, Lundeberg J, Nilsson P, Wiman KG
Cell Death Differ 2007 Mar;14(3):411-21

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Kaposi's sarcoma herpesvirus load in biopsies of cutaneous and oral Kaposi's sarcoma lesions.
Pak F, Mwakigonja AR, Kokhaei P, Hosseinzadeh N, Pyakurel P, Kaaya E, et al
Eur J Cancer 2007 Aug;43(12):1877-82

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Protoporphyrin IX interacts with wild-type p53 protein in vitro and induces cell death of human colon cancer cells in a p53-dependent and -independent manner.
Zawacka-Pankau J, Issaeva N, Hossain S, Pramanik A, Selivanova G, Podhajska AJ
J Biol Chem 2007 Jan;282(4):2466-72

Full article text

HAMLET triggers apoptosis but tumor cell death is independent of caspases, Bcl-2 and p53.
Hallgren O, Gustafsson L, Irjala H, Selivanova G, Orrenius S, Svanborg C
Apoptosis 2006 Feb;11(2):221-33

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PRIMA-1 induces apoptosis in acute myeloid leukaemia cells with p53 gene deletion.
Nahi H, Merup M, Lehmann S, Bengtzen S, Möllgård L, Selivanova G, et al
Br J Haematol 2006 Jan;132(2):230-6

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The structure of p53 tumour suppressor protein reveals the basis for its functional plasticity.
Okorokov AL, Sherman MB, Plisson C, Grinkevich V, Sigmundsson K, Selivanova G, et al
EMBO J 2006 Nov;25(21):5191-200

Full article text

Reactivation of mutant p53 and induction of apoptosis in human tumor cells by maleimide analogs.
Bykov VJ, Issaeva N, Zache N, Shilov A, Hultcrantz M, Bergman J, et al
J Biol Chem 2005 Aug;280(34):30384-91

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915 MHz microwaves and 50 Hz magnetic field affect chromatin conformation and 53BP1 foci in human lymphocytes from hypersensitive and healthy persons.
Belyaev IY, Hillert L, Protopopova M, Tamm C, Malmgren LO, Persson BR, et al
Bioelectromagnetics 2005 Apr;26(3):173-84

PRIMA-1(MET) synergizes with cisplatin to induce tumor cell apoptosis.
Bykov VJ, Zache N, Stridh H, Westman J, Bergman J, Selivanova G, et al
Oncogene 2005 May;24(21):3484-91

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HHV-8/KSHV during the development of Kaposi's sarcoma: evaluation by polymerase chain reaction and immunohistochemistry.
Pak F, Pyakural P, Kokhaei P, Kaaya E, Pourfathollah AA, Selivanova G, et al
J Cutan Pathol 2005 Jan;32(1):21-7

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Dose-response for radiation-induced apoptosis, residual 53BP1 foci and DNA-loop relaxation in human lymphocytes.
Torudd J, Protopopova M, Sarimov R, Nygren J, Eriksson S, Marková E, et al
Int J Radiat Biol 2005 Feb;81(2):125-38

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Previous publications 1993-2004

Publications 1993-2004 (Pdf file, 67 Kb)

Reviews

Galina Selivanova Reviews (pdf)

Contact

Galina Selivanova

Professor
C1 Department of Microbiology, Tumor and Cell Biology