Pancreatic cancer is one of the deadliest tumors. The survival rate for pancreatic ductal adenocardionoma, the most common form of the disease, stands at 8.6%, the lowest percentage of all common tumors, according to data from the Spanish Society of Medical Oncology.
Much is still unknown about this tumor, which is often diagnosed when it is already in advanced stages, although research is advancing. The latest noteworthy novelty is signed by a team with Spanish participation that has managed to reveal why the wick of this type of cancer begins. Details of the process are published in the latest issue of the journal Science.
It has long been known that in pancreatic tumors, as in other types of cancer, mutations in the KRAS oncogene are key. The team that now publishes news about the disease, formed by researchers from Memorial Sloan Kettering Cancer Center (MSKCC), in New York, and researcher Direna Alonso-Curbelo, who now works at the Institute for Research in Biomedicine of Barcelona (IRB), also previously demonstrated the inducing role played in triggering the disease by external factors such as, For example, an injury to tissue that causes inflammation (such as pancreatitis). And now, scientists have shown that cell plasticity, the ability of some cells to change identity in response to genetic alterations or the influence of external stimuli, is also fundamental to the process.
The interactions between genetic mutations and external factors, the researchers stress, modify the identity of some subpopulations of cells, transform them. And, as a result, the ability of these cells to communicate and interact with other cells in their environment increases enormously, which contributes to the development of cancer.
Specifically, scientists have shown that in the earliest stages of pancreatic cancer there are subpopulations of diverse cells that have high plasticity and are more sensitive to the oncogenic action of KRAS and non-genetic factors (pancreatitis) that predispose to cancer. According to their data, those cells have, on the one hand, a different and specific epigenome; and, on the other, an increased ability to respond and send signals to their environment.
Driven by the influence of mutations and inflammation, those cells generate aberrant communication networks, triggering a feedback loop that leads to cancer development and progression.
"Our work is designed to deepen the knowledge of pancreatic cancer, but having identified and unmasked the characteristics of these cells with greater propensity to change identity, more plastic, can serve as a guide to search for useful molecules against this type of cancer," says Alonso-Curbelo, co-lead author of the study.
In mouse models, the team showed that it was possible to block the aforementioned aberrant communication and that these conversations between cells played a fundamental role in the development of cancer. "Our analyses showed that these expansive communication networks that are established in the early stages of pancreatic cancer are functionally relevant and direct pancreatic tumorigenesis in mice," adds the researcher, who stresses that the work has been possible thanks to an interdisciplinary team.
The research combined sophisticated genetically modified mouse models and advanced computational methods to map the distinct cell states that lead to cancer and unravel the characteristics of individual cell subpopulations of the pancreas at each stage of tumor progression.
The computational area of the research has been led by Cassandra Burdziak, PhD student in Dr. Pe'er's laboratory at MSKCC; while the experimental and conceptual part has been led by Alonso-Curbelo herself, who initiated the research during her stay at the New York institution, in the laboratory of Scott Lowe (MSKCC).
Pancreatic cancer mRNA vaccines
On the other hand, an article published this week in Nature has shown promising results from an experimental vaccine based on messenger RNA technology, the same that was used in vaccines against Covid-19, against the most aggressive pancreatic cancer.
The results of a phase I clinical trial show that personalized vaccines are capable of inducing an immune response against cancer.
The authors of the work, also researchers at Memorial Sloan Kettering Cancer Center in New York, administered 16 patients with pancreatic ductal adenocarcinoma a personalized mRNA vaccine the first stage of clinical research, The first results of a clinical trial with 16 volunteers has shown that the vaccine induces substantial immune response and potentially delays the relapse of patients into a form of cancer, since they were made with neoantigens identified in their own tumors. Treatment was given in combination with chemotherapy and immunotherapy.
In eight patients, the researchers observed an increase in T cells versus the antigens administered in the vaccine. These same patients had not experienced cancer reactivation at 18 months of follow-up, while the eight patients in whom the therapy did not work relapsed within 13 months on average after surgery.
"The study is very well designed and its scientific quality is undoubted. It demonstrates something that has been suggested before many times (with less robust data), namely that personalized vaccination with mRNA of tumor antigens is effective in inducing a response and can, at a minimum, increase survival periods. In this work it is confirmed that it can generate responses with clearly very reduced adverse effects against one of the tumors with the highest mortality, pancreatic ductal adenocarcinoma, "said Manel Juan, head of the Immunology Service at the Hospital Clínic de Barcelona.
The most important limitation of the work, continues the specialist, "is that the sample size (of treated patients) is clearly very small and with a single-arm design without randomization. In any case, once the safety of the proposal is confirmed, it seems that the next step to study is to see if simply advancing this 'vaccination' before giving the checkpoint inhibitor [the other type of immunotherapy used] can be more reasonable and may allow better clinical results than vaccinating after administering the antibody as has been the case (surely as an ethical criterion of giving first the treatment that has shown certainty). functionality, although physiopathogenically it makes less sense). In any case, it is an important contribution to the area, although we cannot give it as disruptive or definitive".
- Articles Cristina G. Lucio
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