In search of new therapies, Butantan proposes to stimulate cancer cells

Using the main defect of cancer cells against them: this is a strategy discovered at the Butantan Institute that could help in the development of new therapies against the disease in the future. Unlike conventional therapies, the proposal is to hyperstimulate the mechanism of uncontrolled cell division and, at the same time, inhibit the pathways that regulate stress (the overload that division itself causes in the cell). As a result, the tumor cell becomes destabilized and leads to death.

The technology was validated in a study recently published in the journal Cancer Discovery by biomedical scientist Matheus Henrique Dias, who began investigating the approach during his doctorate and post-doctorate at the Butantan Cell Cycle Laboratory, under the guidance of scientific researcher Hugo Armelin. Today, Matheus continues his post-doctorate at the Dutch Cancer Institute, in Amsterdam.

The results showed that the treatment is highly lethal and specific for cancer cells, being able to reduce tumors in animal models of colorectal cancer without affecting healthy cells.

Traditionally, cancer therapies attempt to inhibit the uncontrolled proliferation of cells. The problem is that malignant cells have several mechanisms to circumvent treatments and may end up developing resistance. “In addition, chemotherapy drugs attack all cells that divide very quickly, including healthy ones, resulting in the side effects we know,” explains Matheus.

With that in mind, the study tried to do the opposite, overloading the tumor cells. As they naturally already have a much higher level of stress than healthy cells, when they are overstimulated and do not have access to the mechanisms to control this stress, they end up dying.

“It’s as if the tumor cell were a car at high speed. Instead of trying to stop the car, what we are doing is accelerating even more and, at the same time, turning off the engine’s cooling system”, says the biomedical scientist.

Another advantage observed in the study is that tumor cells that developed resistance, despite not dying, ended up becoming less malignant, that is, unable to generate a tumor. The growing resistance of some types of cancer to chemotherapy drugs is one of the factors that leads scientists to look for new ways to combat the disease.

The video below shows how cancer cells divide and how this process is affected after experimental therapy:

Inside the technology

The starting point was a article published in 2019 at Molecular Oncology, in which the Butantan team demonstrated that the growth factor FGF2, discovered by Hugo Armelin in 1973, generates great stress for the cancer cell by stimulating the mitogenic pathway (which induces mitosis, that is, cell division). When associated with chemotherapy, the stress became unbearable and the tumor cell died.

“When cancer cells are stimulated to multiply, they sink into stress that is only controlled because they have the means to activate regulatory pathways. Then the trick became clear to us: combining growth stimulation with an inhibitor of the stress control mechanism to overload the tumor”, says Hugo Armelin.

In the current study, to combine the two effects, two experimental drugs were used to inhibit the proteins PP2A and WEE1, which act on the pathways of interest. More than 160 molecules were tested to find the most effective combination. The selected molecules have already been evaluated separately in clinical trials and have been shown to be safe.

Another combination of molecules is being tested at Butantan, as part of biomedical scientist Thompson Torres’ doctorate, and the results should be published soon. The group led by Hugo Armelin is also carrying out experiments with other cancer strains to see how different types of the disease behave in the face of therapy. Positive results have already been obtained against a triple negative breast tumorone of the most aggressive types.

Follow the “Governo de São Paulo” channel on WhatsApp:
https://bit.ly/govspnozap