Mission

To identify innovative treatment opportunities represented by targeting transcription factors (TFs) involved in carcinogenesis.

Vision

To save lives of people with cancer by designing a novel, combinatorial, and targeted treatment strategies utilizing TF activity modulation.

Reseach Philosophy

Cancer is the most complex and complicated medical challenge mankind faces today and the leading cause of premature death in 57 most developed countries including Czech Republic¹. Due to cancer our society loses an enormous amount of experience, performance, and talent every year since about half of the cancer deaths concerns economically active people². Czechs have ~30% chance of developing a cancer before 75 years of age³. Despite of tremendous advance in life expectancy of patients diagnosed with cancer over the last decades, more than 27 000 people die of cancer in Czech Republic annually³. Furthermore, current chemotherapy is linked to a broad range of adverse effects including lasting cognitive impairment⁴ and secondary cancer^5-9. Therefore, novel treatment strategies based on thorough understanding of molecular mechanisms of the disease are essential for improving survivability and quality of life of patients diagnosed with cancer.

Cancer occurs from genetic and epigenetic alterations resulting in deregulated transcriptional programs¹⁰, which are associated with virtually all hallmarks of cancer¹¹. Aberrant activity of TFs constitutes cancer dependency and earmarks TFs as targets in the treatment of particular malignancies, such as cancers dependent on nuclear hormone receptors¹². Acting both as oncogenes and tumor suppressors, TFs are no longer considered as “undruggable”^13,14 as ever-increasing portfolio of compounds is available for research and treatment applications while novel technologies increase drug specificity¹⁵. Taken together, TFs represent a prime target for designing innovative treatment strategies and facilitating personalized medicine.

Reseach Areas

TP53 – a mighty ally in our fight against cancer

“It’s a machine gun in the world of peashooters.” Jo Nesbø, Headhunters, 2011

TP53 is the most frequently mutated tumor suppressor gene in our genome. Protein product of the TP53 gene, TF p53 regulates expression of hundreds of genes which in a concert mediate the tumor suppressive functions of TP53¹⁶. It is no surprise that TP53 is the most often studied gene ever¹⁷. Some say that it is the 20 copies of TP53 gene what keeps elephants alive for about 65 years without notable incidence of cancer in their large bodies¹⁸. Others see p53 nuclear accumulation as a prerequisite of African naked mole-rat longevity¹⁹, since these small critters live for 30 years, six times longer than other rodents on average. Moreover, by 2024 we have drugs which very specifically activate p53 for 20 years²⁰. And yet, we don’t have a viable strategy for using p53 activation in targeted cancer treatment.

Activated by various kinds of cellular stress, p53 controls several cellular programs constraining cancer progression including cell cycle arrest, senescence, and apoptosis²¹(Fig.1). However, targeted activation of p53 by small molecule inhibitors of its endogenous repressor MDM2 results in a reversible cell cycle arrest response in most cancer cell types, which may explain the limited therapeutic value of these drugs so far²².

Recently, Dr. Andrysik published a novel treatment strategy augmenting the p53 response to the level required for apoptosis initiation²³. Simultaneous induction of p53 and Integrated Stress Response leads to cancer cell elimination in vitro and arrested tumor growth in vivo (Fig.2). This discovery opens the door to both mechanistic studies elucidating underpinnings of the p53-dependent apoptosis and translational-medicine oriented works improving efficacy this promising treatment approach in vivo.

Figure 1. Upon activation by numerous stress stimuli, p53 activates transcription of a broad range of genes involved in tumor suppression. Apoptosis represents the desired outcome of p53 induction in cancer therapy.

Figure 2. (A) Joint activation of p53 by MDM2 inhibitor nutlin and ISR by nelfinavir leads to strong apoptotic response in vitro. (B) Milademetan, a MDM2 inhibitor designed for use in vivo, in combination with nelfinavir extends significantly life of animals with xenograft tumors(Andrysik, 2022).

Hypoxia and p53 – when two do the same thing, it is not the same thing after all

Low levels of oxygen tension are characteristic to majority of solid tumors growing in size. Hypoxia stimulates adaptive changes in metabolism and contributes to therapy resistance²⁴ Our scRNA-seq analysis in tumors as well as mapping of transcriptomes regulated by p53 and hypoxia showed that both networks overlap at genes associated with cell cycle arrest^23,25 (Fig. 3). Elucidation of the p53 and hypoxia crosstalk is critical for designing an effective therapy based on targeted induction of the tumor suppressor p53.

Figure 3. (A) Both hypoxia and p53 induce substantial changes in cellular transcriptome measured here by RNA-seq. (B) p53 and hypoxia regulatory networks intersect through indirect/secondary mechanisms. (C) scRNA-seq in tumor tissue allows scoring clusters for both hypoxia and p53 activities.

References

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16 Andrysik, Z. et al. Identification of a core TP53 transcriptional program with highly distributed tumor suppressive activity. Genome Res 27, 1645-1657 (2017). https://doi.org/10.1101/gr.220533.117

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18 Bartas, M. et al. The Changes in the p53 Protein across the Animal Kingdom Point to Its Involvement in Longevity. Int J Mol Sci 22 (2021). https://doi.org/10.3390/ijms22168512

19 Deuker, M. M. et al. Unprovoked Stabilization and Nuclear Accumulation of the Naked Mole-Rat p53 Protein. Sci Rep 10, 6966 (2020). https://doi.org/10.1038/s41598-020-64009-0

20 Vassilev, L. T. et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303, 844-848 (2004). https://doi.org/10.1126/science.1092472

21 Vousden, K. H. & Prives, C. Blinded by the Light: The Growing Complexity of p53. Cell 137, 413-431 (2009). https://doi.org/10.1016/j.cell.2009.04.037

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23 Andrysik, Z., Sullivan, K. D., Kieft, J. S. & Espinosa, J. M. PPM1D suppresses p53-dependent transactivation and cell death by inhibiting the Integrated Stress Response. Nat Commun 13, 7400 (2022). https://doi.org/10.1038/s41467-022-35089-5

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25 Andrysik, Z., Bender, H., Galbraith, M. D. & Espinosa, J. M. Multi-omics analysis reveals contextual tumor suppressive and oncogenic gene modules within the acute hypoxic response. Nat Commun 12, 1375 (2021). https://doi.org/10.1038/s41467-021-21687-2