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Possible new cancer treatment is target of Brazilian study

A combination of two drugs was able to suppress tumors in an unconventional way. Instead of inhibiting the division of tumor cells, as the best-known drugs do, the strategy consists of overactivating the signaling of these cells to the point that they become stressed. Another drug, then, attacks precisely those who are under stress. The approach is expected to be tested on patients with bowel tumors in the Netherlands later this year.

Published in the magazine Cancer Discovery, the first author of the work is Brazilian Matheus Henrique Dias, currently a senior postdoctoral fellow at the Netherlands Cancer Institute (NKI).

The idea began to be developed during his postdoctoral studies at the Butantan Institute, with an internship at the University of Liverpool, in the United Kingdom. The project took place within the scope of the Center for Toxins, Immune Response and Cellular Signaling (CeTICs), a Research, Innovation and Dissemination Center (CEPID) supported by FAPESP.

“We discovered at that time that the so-called fibroblast growth factor 2 [FGF2], a gene that should stimulate cell proliferation, did the opposite when the cells were tumorous: it inhibited multiplication. It was a curious observation, because it was the opposite of what should happen”, Dias tells Agência FAPESP.

On that occasion, a study on the role of FGF2 he was published in the magazine Molecular Oncology.

In the current work, the researchers show that cancer cells begin to proliferate less not because they are directly inhibited by a drug, as occurs with the most commonly used chemotherapy treatments. On the contrary, one of the drugs used in this strategy overactivates tumor cell signaling, to the point that they become stressed and, therefore, sensitive to other drugs specific to cells in this state.

“It’s as if we wanted to stop a car at high speed, but instead of trying to slow it down, we accelerated even more until the engine overheated. And, when the engine was too hot, we would deactivate the cooling system”, compares Dias.

Double attack

One of the study’s co-authors, Marcelo Santos da Silva, professor at the Chemistry Institute of the University of São Paulo (IQ-USP) supported by FAPESP, was doing his postdoctoral work at Butantan at the same time as Dias, and developed an assay to quantify stress of tumor cells.

“When overactivated, tumor cells replicate DNA even faster than normal. As they are not prepared to deal with this speed of replication, they end up causing damage to the DNA, called replication stress,” he explains.


Marcelo Santos da Silva in his laboratory at IQ-USP: strategy for cancer treatment should be tested on parasites that cause Chagas disease and leishmaniasis (photo: personal collection)

When he realized that the overactivation of the FGF2 was leading to the inhibition of cell proliferation due to the stress caused to them, Dias went in search of some molecule that could induce this process. LB-100, currently in clinical trials on lung tumors to make them sensitive to other chemotherapy drugs, has become a promising candidate.

To attack cells stressed by the action of LB-100, the researchers opted for inhibitors of the WEE1 protein, precisely responsible for correcting DNA damage in tumors. Without this mechanism working, tumor cells enter cell division before finishing DNA replication. As a result, they die in the process.

“The most interesting thing is that, to survive this approach, cancer cells deactivate oncogenic pathways, starting to behave like healthy cells”, explains Dias.

The tests were carried out on colorectal tumors taken from human biopsies and implanted in mice. Treatment with both drugs inhibited the growth of tumors in the animals’ intestines.

Due to its success in colorectal cancer models, the researchers tested the combination in lines of pancreatic adenocarcinoma and cholangiocarcinoma (of the tubes that carry bile through the liver), rarer and more aggressive forms of cancer and without many treatment options. The results were also promising.

“This is a growing field of study, with large companies investing in signaling activators and small companies being created to develop this type of drug. In the coming years, some should be on the market among oncology treatment options, we hope that one will be ours”, says Dias.

At USP, Silva intends to apply the same principle of potential cancer treatment to eliminate parasites that cause neglected diseases. This is because the protozoa that cause Chagas disease and leishmaniasis behave similarly to cancer cells, replicating very quickly within the host cell.

“The idea is to use a drug that further stimulates the signaling pathway for the proliferation of these parasites, to the point of generating the same type of DNA damage, and then we give another drug to inhibit DNA repair, eliminating the parasites without harming the host cell”, concludes Silva.

The article Paradoxical Activation of Oncogenic Signaling as a Cancer Treatment Strategy can be read for free at: https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-23-0216/745111/ .

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Source: CNN Brasil

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