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Molecular mechanism of new apoptosis induction strategy in the experimental anticancer targeted therapy.

Etiuda Program. National Science Centre.  

PI - Damian Klóska. (to be completed in 2020).

 Cancer is a leading cause of death worldwide and currently available therapies do not always give positive and long-lasting results. A better understanding of cancer biology can in some perspective contribute to the development of new, more effective therapies. One of the latest trends in the oncology is so-called molecularly targeted therapy, in which drug is based on the well-defined molecular goals directly targets cancer cells without affecting healthy tissue homeostasis. From the selectivity point of view, presence of functional death receptors (pro-apoptotic receptors for which the ligand is TRAIL), seems to be a good target, distinguishing between cancer and normal cells. The problem remains, however, that some types of cancer are resistant to apoptosis induced by TRAIL which results from the inhibition of intracellular signal transduction pathways from death receptors. This problem can be overcome by so-called combination therapy which strikes to two different molecular targets. Endothelial cells and inhibition of angiogenesis, the new blood vessels formation process, necessary for tumor growth and metastatic capacity, may be such an additional goal in cancer therapy. One of the key drivers of this process is vascular endothelial growth factor (VEGF), which as shown by the literature is often upregulated within tumors1. Moreover, tumour cells possess also on their surface receptor for VEGF, which in their case is responsible for the transmission of pro-survival signals2.

 Research within my dissertation focused on understanding the molecular mechanism of antitumor activity of the recombinant protein-based on the fusion of TRAIL ligand with three copies of the peptide derived from VEGF that blocks the signal from its receptor.  This fusion protein has strong anti-tumour activity proven in a mouse xenograft model. However, the exact molecular mechanism of action was unknown. The main goal of my research was to describe the molecular pathways involved in the anti-tumour and anti-angiogenic activity of this recombinant protein.

It was shown that the fusion protein leads to the activation of apoptosis of cancer cells, but not healthy ones, including TRAIL sensitive and resistant cells, both in in vitro and in vivo model. In contrast to the VEGF receptor, the presence of TRAIL receptors on the cancer cells is crucial for the initiation of the apoptotic signal by this molecule. However, in TRAIL-resistant cells, this effect is not fully associated with signal transduction from death receptors, which is classically regulated by intracellular FADD protein and the DISC complex formation. We demonstrated, that this partially independent of FADD and independent of the inhibition of the VEGF receptor signal transduction induction of apoptosis is associated with the positive charge present on the peptide of the fusion protein. Death receptors on tumour cells are required for anchoring the fusion protein to the cell membrane, and the positive charge of the peptides leads to the shortening of the glycocalyx specifically in cancer cells sparing healthy cells, which is associated with disturbances in the actin cytoskeleton architecture and dynamics including deregulation of FAK phosphorylation which in turns leads to apoptosis induction, also in TRAIL-resistant cells. In case of TRAIL-sensitive cells, the proapoptotic signal from death receptors is further amplified by a pathway derived from cytoskeletal disruption. This effect is dependent on p53, which is an intracellular mediator of apoptosis induced positive charge of the effector peptide. 

Using in vitro models of 2D and 3D angiogenesis and imaging model of functional vessels in vivo, it was shown that this fusion molecule inhibits the formation of new blood vessels without cytotoxicity to the endothelial cells. This mechanism most likely is directly related to the inhibition of VEGF receptor signal transduction. However, it cannot be ruled out that the fusion protein also interacts with endothelial cells in other ways, e.g. by affecting cellular metabolism.

The results of research carried out as part of my doctoral dissertation will broaden general knowledge on cancer biology and shed new light on the importance of non-receptor interactions of molecules with the tumour cell membrane that can lead to cytoskeleton-induced apoptosis.

1. Carmeliet, P. VEGF as a key mediator of angiogenesis in cancer. Oncology 69 Suppl 3, 4–10 (2005). 2. Pidgeon GP. Vascular endothelial growth factor (VEGF) upregulates BCL-2 and inhibits apoptosis in human and murine mammary adenocarcinoma cells. Br J Cancer 85(2):273-278 (2001).

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