Research published in the journal Scientific Reports shows that a peptide (molecule derived from a protein) developed by Brazilian scientists, called Rb4, was effective in combating the progression of cancer in an animal model —especially severe melanoma—, being a promising agent for the treatment of drug resistant tumors.
In preclinical, in vitro and in vivo phases, the work provided evidence that Rb4 triggers necrosis in murine melanoma cells (from mice). In addition, the compound inhibited the viability of human cancer cell lines. These tumor cells lose the integrity of the plasma membrane and the mitochondria (organelles that generate cellular energy) become enlarged. Scientists, however, are still not clear how this necrosis is triggered.
In animals, the peptide reduced lung metastasis and slowed the growth of subcutaneous melanoma. The results suggest that Rb4 acts directly on the tumor, inducing the expression of two molecular patterns associated with damage, called DAMPs, which trigger an immunostimulatory effect during melanoma cell death.
“We do basic science in search of new molecules. In this study, Rb4, which derives from proteolipid protein 2 [PLP2], showed a preference for causing a specific type of cell death, necrosis, especially in melanoma. But it is unclear how this necrosis occurs and develops. The article gives some indications of the morphological composition and the final effects of the contact with the peptide”, Fabrício Castro Machado, one of the authors of the article, tells Agência FAPESP.
Machado was part of the group of the Experimental Oncology Unit, Department of Microbiology, Immunology and Parasitology at Unifesp (Federal University of São Paulo), and is a researcher at Recepta Biopharma (ReceptaBio), a Brazilian biotechnology company focused on the study and development of new drugs for the treatment of cancer. Hence the name of the peptide “Rb”.
With the support of Fapesp, the research began to be developed by the group of Unifesp professor Luiz Rodolpho Travassos, who died in 2020 and is honored in the article.
Travassos has published more than 260 articles, part of which are linked to studies on the biological activities of peptides and peptidases (enzymes that break peptide bonds between amino acids in proteins) in infectious diseases and cancer. This interest brought him closer, in 2008, to ReceptaBio, whose CEO is José Fernando Perez, former scientific director of FapespP (between 1993 and 2005).
“Professor Travassos identified several sequences of small molecules, bioactive peptides based on antibodies developed by ReceptaBio. Rb4 was also identified during this search process for new molecules, although it does not derive from antibodies. We have another one, Rb9, in the process of being more advanced study, with several publications and patents, however, still in the pre-clinical phase”, explains scientist Alice Santana Morais, Research and Development analyst at the company and corresponding author of the article.
In 2016, scientists described the structures of the Rb9 peptide and its mechanisms of action in inhibiting melanoma cells as well. In a more recent publication, from 2020, the advancement of research indicated an immunomodulatory effect of Rb9 in the control of tumor progression.
“Whether in academia or in companies like ReceptaBio, it is necessary to join efforts to carry out research. We seek partnerships to help leverage the drug development process, which is time-consuming, thorough and requires discussion, details and exchange of experiences”, says Morais .
promising paths
New treatments have been used in recent years against various types of cancer, including peptide-based chemotherapy. These molecules are of interest due to some advantages, such as the ability to specifically target tumor cells and low toxicity in normal tissues. They can be used in therapies based only on peptides or conjugated with other types of medication, with application as cellular reagents, ligands and vaccines, for example.
In the research to evaluate the antitumor effect of Rb4, the group of scientists investigated the growth and morphology in cultured melanoma cells (B16F10-Nex2). The peptide was able to interfere in the morphology, replication and association of melanoma.
This is because the cells treated with Rb4 did not replicate and formed clusters quickly — a phenomenon not observed in the control group. After 24 hours of incubation, the cells also lost their natural morphology.
In addition, Rb4 reduced the number of metastatic lung nodules in the syngeneic melanoma model (twin animals). This result was detected after cancer cells were injected intravenously into the mice. They were treated with five injections of the peptide (300 micrograms/per animal) every other day, which delayed tumor growth by up to 40 days.
The survival rate of mice treated with Rb4 was higher than that of control groups, increasing survival by more than 25% and up to ten days.
Melanoma originates in the cells that produce melanin, a substance that determines skin color, and can appear in various parts of the human body. Although skin cancer is the most frequent in Brazil, accounting for about 30% of tumors, melanoma represents 3% of malignant neoplasms. However, it is the most serious type due to the high possibility of causing metastasis, that is, of spreading to other organs.
According to estimates by the National Cancer Institute (Inca), there are about 8,400 new cases a year. In 2019, there were 1,978 deaths.
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