Zdeněk Andrysík

Cancer occurs from genetic and epigenetic alterations resulting in deregulated transcriptional programs, which are associated with virtually all hallmarks of cancer. 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 receptors. Acting both as oncogenes and tumor suppressors, TFs are no longer considered as “undruggable” as ever-increasing portfolio of compounds is available for research and treatment applications while novel technologies increase drug specificity. Taken together, TFs represent a prime target for designing innovative treatment strategies and facilitating personalized medicine.

Research Area

TP53 – a mighty ally in our fight against cancer

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 TP53. It is no surprise that TP53 is the most often studied gene ever. 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 bodies. Others see p53 nuclear accumulation as a prerequisite of African naked mole-rat longevity, 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 years. 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 apoptosis. 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 far.

Recently, Dr. Andrysik published a novel treatment strategy augmenting the p53 response to the level required for apoptosis initiation. Simultaneous induction of p53 and Integrated Stress Response leads to cancer cell elimination in vitro and arrested tumor growth in vivo. 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.