Work carried out by Brazilians innovated by overstimulating and stressing tumor cells, meaning that the alternative for survival is to behave like healthy cells
A combination of two drugs has been able to suppress tumors in an unconventional way. Instead of inhibiting tumor cell division, 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 cells that are under stress. The approach is expected to be tested in patients with bowel tumors in the Netherlands in 2024.
Published in the magazine Cancer Discoverythe work has as its first author the Brazilian Matheus Henrique Dias, currently a senior postdoctoral fellow at the NKI (Netherlands Cancer Institute).
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 was carried out at CeTICs (Center for Toxins, Immune Response and Cell Signaling), a Cepid (Center for Research, Innovation and Diffusion) 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 declared to Fapesp Agency.
At that time, a study on the role of FGF2 was published in the journal 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. But, in reality, 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 like trying to stop a speeding car, but instead of trying to slow it down, we accelerate even more until the engine overheats. And when the engine gets too hot, we turn off the cooling system.”compares Dias.
Double attack
One of the study’s co-authors, Marcelo Santos da Silva, professor at IQ-USP (Institute of Chemistry at the University of São Paulo), supported by Fapesp, was carrying out a post-doctorate at Butantan at the same time as Dias. He developed an assay to quantify tumor cell stress.
“When overactivated, tumor cells replicate DNA even faster than normal. As they are not prepared to deal with this replication speed, they end up generating DNA damage, the so-called replication stress.”he declared.
When he realized that the overactivation of FGF2 was leading to the inhibition of cell proliferation due to the stress caused to them, Dias went in search of a 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, in order to survive this approach, cancer cells deactivate oncogenic pathways, starting to behave like healthy cells”said 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 the success in colorectal cancer models, the researchers tested the combination in pancreatic adenocarcinoma and cholangiocarcinoma (of the tubes that carry bile from the liver) cell lines – rarer and more aggressive forms of cancer with few 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 one is ours.”declared 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”said Silva.
The article “Paradoxical Activation of Oncogenic Signaling as a Cancer Treatment Strategy” can be read for free here.
With information from FAPESP Agency.
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