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Cleara Biotech

Senescent cells that accumulate in our bodies are a major cause of health problems and enable cancer development as we age. Researchers at Cleara discovered the mechanism how senescent cells escape the natural elimination process. Based on this discovery, Cleara is developing therapeutics to treat patients with a range of diseases caused by this failure to clear senescent cells.

Discovery timeline

  • The early years »

    • DAF16 homologues FOXO3 and 4 regulated by PI3K/PKB/AKT (Kops Nature. 1999 Apr 15;398(6728):630-4. Brunet Cell. 1999 Mar 19;96(6):857-68.)
    • FOXOs involved in cell cycle regulation (Medema Nature. 2000 Apr 13;404(6779):782-7.)
    • FOXOs involved in combatting cellular stress (Kops Nature. 2002 Sep 19;419(6904):316-21.)
    • FOXOs regulated by cellular stress (Essers EMBO J. 2004 Dec 8;23(24):4802-12.
    • FOXOs regulated by cellular stress (Essers Science. 2005 May 20;308(5725):1181-4.)
  • FOXO4 induces senescence in stressed cancer cells

    FOXO4 can physically interact with p53 under conditions of stress. In response to excessive stress signaling, pathways are turned on to counter the negative consequences. FOXO4-p53 signaling is important for this reponse.

  • FOXO4 inhibition induces apoptosis in senescent cells via p53

    FOXO proteins are downstream targets of the senescence response. Oncogene-mutation, as well as other forms of persistent stress can lead to a chronic damage response. As a consequence, anti-stress signaling is activated. This is for instance evident from FOXO4 phosphorylation and activation. This lead us to the following model (e.g. P.L.J. de Keizer, Ph.D. dissertation and de Keizer et al., 2010, Cancer Research):

     

  • First generation of FOXO4-p53 blocking peptides

    Identification by our team that FOXO4 is a pivot in maintaining the viability of senescent cells. Using primary senescent cells, we observed that removing FOXO4 could trigger a “clean” cell death response, known as apoptosis. This created a new window of opportunity to eliminate these deleterious cells. As we found FOXO4 to also exert a protective response to chemotherapy, it additionally opened the door towards development of methods to overcome therapy resistance of cancer cells.

  • Second generation peptide shows efficacy against senescent cells

    Generation of the first and second generation of compounds to eliminate senescent and therapy-resistant cancer cells (e.g. patent US20130288981 A1; 2012). Here, we showed for the first time that not only inhibition of FOXO4 itself, but more specifically, blocking the FOXO4-p53 binding by cell-penetrating peptides could effectively eliminate senescent cells and therapy-resistant cancer cells.

  • Tumors are also sensitive to FOXO4 inhibition

    Development of the third generation of FOXO4-based anti-senescence drugs: the FOXO4-DRI peptide, aka Proxofim. This proved to be effective in counteracting signs of chemotoxicity and, excitingly, was able to restore healthspan in models for fast and natural aging, e.g. fur density, behavior and renal function. (Baar et al., Cell, 2017). This research received worldwide media attention, including coverage in numerous TV and radio shows, newspapers and blogs.

  • Present » Next generation of FOXO4-p53 blocking therapeutics with higher specificity and low off-target toxicity

    Founding of Cleara to continue our evolution of FOXO4-based anti-senescence drugs and generate the fourth generation capable of human translation. Since the selectivity of the third generation compound, FOXO4-DRI, for senescent cells is ~10-fold, it is unfortunately still too dangerous to allow for clinical trials. At Cleara Biotech, it is our mission to improve the safety profile and potency of Proxofim and to do so, we launched the iPROX program to generate “Improved Proxofim”. We are passionate in translating iPROX to humans and combat senescence-driven age-related diseases, including therapy resistant cancer.

Cleara, the company

At Cleara Biotech, we are highly motivated to develop safe and effective treatments to counter the negative aspects of aging and target diseases like therapy-resistant late stage cancer. We aim to do so by generating compounds that are capable of selectively eliminating senescent and senescent-like cancer cells. Cleara Biotech is the exciting result of a long and proven academic history of the key members of our scientific team.

Cleara in the Press

Drug 'reverses' ageing in animal tests
Purging the body of 'retired' cells could reverse ageing, study shows
Molecule kills elderly cells, reduces signs of aging in mice
Convincing Cells to Die Could Make Us Stronger
Anti-ageing: Is it possible, and would we want it?
Turning Back the Aging Clock - in Mice
The mouse that time forgot

BBC News – Drug ‘reverses’ ageing in animal tests

The Guardian – Purging the body of ‘retired’ cells could reverse ageing, study shows

Science Magazine – Molecule kills elderly cells, reduces signs of aging in mice

Discover Magazine – Convincing Cells to Die Could Make Us Stronger

BBC Future – Anti-ageing: Is it possible, and would we want it?

US News – Turning Back the Aging Clock – in Mice

De Volkskrant – The mouse that time forgot

Team

Peter de Keizer
Peter de Keizer
PhD
Linkedin ResearchGate
James Peyer
James Peyer
PhD
Linkedin ResearchGate
Alexandra Bause
Alexandra Bause
PhD
Linkedin ResearchGate
Tobias Madl
Tobias Madl
PhD
Linkedin ResearchGate
Marco Demaria
Marco Demaria
PhD
Linkedin ResearchGate
Boudewijn Burgering
Boudewijn Burgering
Professor / PhD

Ageing is the most prominent risk factor for the majority of diseases.

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Relevant papers

Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging.

Baar MP, Brandt RMC, Putavet DA, Klein JDD, Derks KWJ, Bourgeois BRM, Stryeck S, Rijksen Y, van Willigenburg H, Feijtel DA, van der Pluijm I, Essers J, van Cappellen WA, van IJcken WF, Houtsmuller AB, Pothof J, de Bruin RWF, Madl T, Hoeijmakers JHJ, Campisi J, de Keizer PLJ.

Cell. 2017

PMID: 28340339

The Fountain of Youth by Targeting Senescent Cells?

de Keizer PL.

Trends Mol Med. 2017

PMID: 28041781

Targeted inhibition of metastatic melanoma through interference with Pin1-FOXM1 signaling.

Kruiswijk F, Hasenfuss SC, Sivapatham R, Baar MP, Putavet D, Naipal KA, van den Broek NJ, Kruit W, van der Spek PJ, van Gent DC, Brenkman AB, Campisi J, Burgering BM, Hoeijmakers JH, de Keizer PL.

Oncogene. 2016

PMID: 26279295

Activation of forkhead box O transcription factors by oncogenic BRAF promotes p21cip1-dependent senescence.

de Keizer PL, Packer LM, Szypowska AA, Riedl-Polderman PE, van den Broek NJ, de Bruin A, Dansen TB, Marais R, Brenkman AB, Burgering BM.

Cancer Res. 2010

PMID: 20959475

p53: Pro-aging or pro-longevity?

de Keizer PL, Laberge RM, Campisi J.

Aging (Albany NY). 2010

PMID: 20657035

Forkhead box o as a sensor, mediator, and regulator of redox signaling.

de Keizer PL, Burgering BM, Dansen TB.

Antioxid Redox Signal. 2011

PMID: 20626320

Mdm2 induces mono-ubiquitination of FOXO4.

Brenkman AB, de Keizer PL, van den Broek NJ, Jochemsen AG, Burgering BM.

PLoS One. 2008

PMID: 18665269

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