Topic: Stop cell division to fight childhood leukemia

In this blog I explain my doctoral project and hope that after reading it the readers will share my excitement about the results of this work.

Background

Leukemia is a form of blood cancer that often affects children. Currently, to treat it doctors use combinations of different chemotherapeutic drugs. However, these drugs are toxic both for cancer and normal cells of the body, and lead to severe side effects during the treatment and many years after the therapy completion. Therefore, there is a permanent search for new treatments that are both efficient against cancer and have less side effects. 

First, I want to describe the biological mechanism, applied for the part of my studies. One of the modern approaches to achieve specificity in cancer treatments is focused on the process called RNA interference (RNAi). This process happens inside every cell, normal and cancer, and is induced by foreign RNA. Once inside the cell, special enzymes cut this RNA into short interfering (si)RNA, which connects to specific proteins and forms a so-called RNA-induced silencing complex. This complex induces a cascade of events that results in elimination of a protein-coding mRNA. Lack or absence of the protein leads to the lack of function. 

Now I want to talk about the target protein. Plk1 is an important protein that helps any cell to divide. Without Plk1 cancer cells cannot grow and die via a specific cell death process called apoptosis. That is why this protein was identified as a good target for anticancer treatment, and pharmaceutical companies developed several small molecule drugs that block the function of Plk1. 

What I found

In the first paper of my thesis I tried to understand what were the potential off-target proteins of these small molecule drugs. It is important, because by affecting other proteins, the drug may induce unexpected or severe side effects in patients involved in clinical trials. I used mainly western blotting and mass spectrometry to study how different proteins in the drug-treated cells change their structure upon heating. This approach, called cellular thermal shift assay, helps in practice to identify the proteins that in theory should not be affected by the drug. My work is still in progress and I hope to publish soon the final results of it.

In two other papers I studied a way based on RNAi to kill leukemic cells, called lymphoblasts. I used a special modification of siRNA to target Plk1 and showed that the cells die after treatment. Moreover, I observed that this novel modified drug was specific to Plk1 and proved to be less toxic towards normal blood cells compared to small molecule drugs.

Therefore, my thesis improved understanding of potential side effects of Plk1 small molecule inhibitors and introduced a novel drug that is more specific and might cause less side effects in children with leukemia.

Images: Joel Filipe, unsplash.org

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