University of São Paulo: Theoretical modeling of physics proposes a new therapeutic approach for metastatic cancer

a theoretical modeling of physics helped a group of researchers in designing a new therapeutic approach that reduces the expression of a network of tumor metastases signals. The strategy, which uses low doses of multiple drugs, reduced the compensatory effects (creating new pathways for the dissemination of cancer cells), adaptation to treatment and disease recurrence. Modeling is the theoretical basis of the genetic study carried out in mice with breast cancer at The Ben May Department for Cancer Research, University of Chicago, USA, in partnership with USP’s School of Arts, Sciences and Humanities (EACH) and the Translational Research Center in Oncology, of the Cancer Institute of the State of São Paulo (Icesp), and the Faculty of Medicine of USP (FMUSP). An article on the subject was published in the magazine eLife , Limited inhibition of multiple nodes in a driver network blocks metastasis , May 2021.

“Cancer is a complex disease and the metastatic phase (when cells detach from the original tumor and colonize new tissue) is characterized by numerous biochemical processes typical of cellular stress. These act in a network of multiple pathways (as if it were a data traffic organization) through which cancer cells create the ability to move to colonize other tissues of the body, via the bloodstream”, explains physicist Alexandre to Jornal da USP Ramos, professor of Mathematical Calculus at EACH and responsible for the mathematical model.

To prevent the spread of cancer, conventional chemotherapy treatments use high doses of a single drug or combinations of them (cocktails) to block the functioning of this network and prevent the spread of tumor cells. In general, these approaches, in addition to being highly toxic to patients, causing unwanted side effects (hair loss, diarrhea, mouth sores, nausea and vomiting, and even infertility), induce the activation of compensatory pathways in this network that enable the diseased cells to adapt to the treatment and continue to multiply within this metastatic process.

The physical approach made it possible to describe and understand the functioning of this information flow network that takes place inside the cells, understand how it is impacted by conventional chemotherapy treatments and quantitatively elaborate a new approach that would allow interfering in the transmission of signals in this network, so that could contribute to the improvement of cancer treatment in the metastasis stage.
RKIP: protein that regulates signaling pathways
The first steps in participating in this project were taken in 2016, at a congress at the University of Chicago, when Professor Ramos strengthened academic ties with Professor Marsha Rosner, from the University of Chicago, who, at the time, was already working with the protein that inhibited Raf kinase (RKIP), a metastasis suppressor. Professor Marsha designed the study and the therapeutic proposal and presented them to her advisee, Ali Ekrem Yesilkanal, who carried out the experiments and the analysis of bioinformatics. Here in Brazil, the theoretical part of the physical model was coordinated by Professor Ramos and had the contribution of his advisor Alan Utsuni Sabino, from the Postgraduate Program in Oncology at FMUSP.

Professor Ramos explains that, in adequate amounts in the body, RKIP fulfills very important functions in the process of preventing the spread of cancer, blocking the signaling of this signal network, causing the cells to stop producing inputs (several proteins associated with the process of cell mobility) needed to move and cause metastasis. “RKIP represses the effects of stress signaling in cells,” says Professor Ramos.

The RKIP protein plays very important roles in the process of preventing the spread of cancer – Photo: Personal archive

According to the researcher, under normal conditions, the RKIP protein is present in high amounts in healthy cells, however, when cancer at a more advanced stage occurs, this protein tends to fall to very low levels and, on the other hand, the level of another protein called BACH1. Unlike RKIP, it is associated with the process of activating the expression of genes linked to metastasis, that is, BACH1 stimulates the movement of cancer cells. “It would be something similar to what happens when we hurt ourselves: the cells around the wound go through a transition and begin to acquire the capacity to multiply in order to recover the injured tissue”, he compares.

“The mathematical model for the operating scheme of this network was used to describe the result resulting from the reduction in drug dosages and to predict, qualitatively, the emergence of compensatory effects of activation of alternative networks”, explains the researcher.

Returning to chemotherapeutics, the reasoning was that the administration of high doses of drugs in cancer patients that totally interrupted the flow of information in this network was not being so effective, then a treatment with multiple drugs at low doses was proposed.

“The mathematical model for the operating scheme of this network was used to describe the result resulting from the reduction in drug dosages and to predict, qualitatively, the emergence of compensatory effects of activation of alternative networks”, explains the researcher to Jornal da USP .

In his experiments in Chicago, Yesikanal developed a mimic of four drugs (the same ones used in chemotherapy and that behaved like the RKIP protein, which suppresses the ability of cancer cells to multiply), but in low doses, and administered it in mice with metastatic cancer. What the researchers wanted to verify is whether with lower doses there would be only partial interruption of these ducts (and not total interruption, as happened in chemotherapy treatments) through which the signals that induced metastases would pass.

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The results were better than expected and proved to be a relevant and anti-metastasis strategy, reports the researcher: the administration of low-dose multidrugs inhibited the signaling capacity of the network; there was no activation of compensation pathways through which cancer cells continued to multiply and, therefore, adapt to the treatment; and tumor cells returned to the pre-metastatic stage, that is, they returned to the stage in which they would have a greater susceptibility to respond positively to conventional treatment.

This experiment was tested only for breast cancer in mice, however, Ramos believes that the same general principles can be applied to other types of cancer and adapted to the context of the Unified Health System (SUS). In fact, he is already in negotiations with the Cancer Institute of the State of São Paulo (Icesp) and with professor Marsha Rosner to carry out experimental and possibly clinical studies, in cooperation with the University of Chicago.

According to Professor Ramos, improvements in the physical model applied to biology are underway with a view to future experiments that will be carried out by the research group. This work had the financial support of the Coordination for the Improvement of Higher Education Personnel (Capes) and the Public Notice of Support for Research in Intelligent Digital Systems of the Dean of Research at USP.

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