By exploring the diversity of the structure and composition of pancreatic cancers, Rémy Nicolle wants to identify avenues that will rapidly bring new treatments to patients. This translational research, which combines genomics, transcriptomics and artificial intelligence, was selected as part of the Atip-Avenir program in 2022.
Pancreatic adenocarcinoma accounts for 85% of all pancreatic cancers. It is also one of the cancers with the poorest prognosis, with less than 10% of patients living five years after diagnosis. Many clinical trials have sought to evaluate the efficacy of the different approaches available to combat these tumors: chemotherapies, targeted therapies or immunotherapies… But the majority of them do not significantly improve life expectancy. The structural, cellular and molecular heterogeneity of the disease, observed from one patient to another but also within a given tumor, probably explains this observation: it makes it difficult to conduct clinical studies on homogeneous groups of patients with comparable characteristics. In fact, the treatments administered are now chosen according to the progression of the disease and the patient’s general condition, and not according to the specific characteristics of the tumor, with the poor results previously mentioned.
Changing the Patient Journey, a Real Motivation
In order to change this, Rémy Nicolle seeks to understand and characterize the diversity of these tumors, with the objective of identifying new therapeutic avenues. At the Inflammation Research Center in Paris, he is responsible for setting up and leading the translational research project GeNeHetX (Translational Genomics of Pancreatic Neoplasia Heterogeneity). « Pancreatic adenocarcinomas have a very specific structure, he explains. In addition to this heterogeneity, they are infiltrated by scar tissue that limits the ability of immune cells to pass through it to exert their anti-tumor action. Furthermore, although they share genetic abnormalities with other cancer sites, they are generally not very sensitive to the drugs that target them. Finally, there may be major differences in tumor behavior, even if the genetics are the same. So, all of these particularities must be characterized. By qualifying the different tumor subtypes on the genomic, transcriptomic and proteomic levels, we believe it will be possible to develop more effective treatments. »
As with many other research projects, « one of the challenges of GeNeHetX is to find the balance between improving fundamental data on the one hand and the ability to transpose them into applied research on the other, » emphasizes Nicolle. This is more broadly the objective of translational research, to which the researcher, specialized in biology and bioinformatics, was not initially destined: « During my academic career, I was drawn to basic research. It allows you to ask a thousand questions, to pull on a thread and unravel it to see where it takes you. It is intellectually very stimulating, particularly in the extraordinarily complex field of cancer. » But at the beginning of his doctorate, the researcher changed his vision by discovering the ins and outs of this translational research: « Knowing that our discoveries can change a patient’s journey motivates me on a daily basis. »
Accelerating the Transition from Phenotyping to Clinical Practice
Together with the team he recruited, Nicolle uses genomic, histological, biological and molecular analyses, combined with artificial intelligence algorithms, to profile pancreatic tumor tissue architecture on the cellular and molecular levels. « We particularly use algorithms, such as those used by Google for the recognition of objects. They gradually learn to recognize the three-dimensional structure and composition of the tissue in the different areas of the tumor. » The researcher would then like to characterize the extracellular factors (such as fibrosis or certain biochemical mediators) that limit the infiltration of the tumor by the immune cells. « This will enable us to consider targeting them with drugs and test immunotherapies. »
He would also like to be able to identify molecular signatures that will facilitate the development of appropriate treatments and clinical decision-making. « We have already described the role of signatures, obtained by analyzing the level of expression of specific genes. They are quite different from one patient to another, which can lead to variable sensitivity to chemotherapies that are now used in the treatment of pancreatic adenocarcinoma. We are currently conducting the first clinical study in which the choice of treatment is based on this molecular signature. » For the moment, and in the absence of specific treatment, identifying these different patient subgroups will undoubtedly make little difference to the prognosis of their disease. But if their utility is confirmed, these signatures will open up the development of more effective treatments.
« My dream would be to see this approach, known as phenotyping, be increasingly used in precision medicine, » insists the researcher. Unlike genotyping, which characterizes the presence or absence of genes or genetic mutations in tumor cells, the phenotype reflects the expression of the genes, i.e. the transcriptome. It involves quantifying the messenger RNA present in the tumor. And it should be recognized that it is more difficult to characterize because these RNA are not always specific to tumor cells: they can also belong to the healthy cells in or around the tumor. This is one of the reasons why phenotype characterization is still underdeveloped in oncology. But there are many perspectives. »
« Although it is still poorly accessible to patients outside of a clinical research protocol, I am convinced of the potential of transcriptomics for the future of personalized medicine. I hope that its place will rapidly develop and that it will be become established in hospitals, for the benefit of patients. In any case, that’s a movement I want to be a part of! » The day-to-day research conducted by Nicolle and his team is important to this process. « Each member of the team has their own expertise, their own analysis and brings their own vision to a subject. This sometimes changes the directions that we had initially planned for a project and it is quite extraordinary to see how enriching it can be to compare points of view. »
Rémy Nicolle leads the Translational Genomics of Pancreatic Neoplasia Heterogeneity team at the Inflammation Research Center (unit 1149 Inserm/Université Paris-Cité) in Paris.