Annabelle Ballesta: Individualizing Treatments with Mathematics and Chronobiology

Annabelle Ballesta is a mathematician whose research laboratory is housed by Inserm. In close collaboration with biologists, she is developing models that mime the biological rhythm specific to healthy and sick cells. She is attempting to use these models to establish the most effective therapeutic protocol that is the best tolerated for each cancer patient.

Annabelle Ballesta
Annabelle Ballesta

You are a mathematician. How did your path lead you to Inserm?

I studied mathematical engineering at the Insa (National Institute of Applied Sciences), an engineering school. I developed an interest in biology on an Erasmus study-abroad trip to the University of Leeds in England, where I took classes in applying mathematics to biology. It was then that I decided I wanted to work at the interface where these two disciplines meet. The subject of my thesis, which I prepared at the Inria, was an answer to this objective as it aimed to develop an experimental and mathematical combined approach to customize cancer treatments, specifically by relying on chronobiology. I have been pursuing this area of research ever since.

Why is chronobiology so important in treating cancer?

We know that our physiological functions vary over the course of 24 hours, following what is known as a circadian rhythm. Depending on their nature, most of our cells have activity paced by a specific rhythm over the course of the day. The effectiveness or toxicity of a treatment differ depending on what time of day the medicine is administered. This is true both for healthy cells and for cancerous ones. Cancerous cells also have their own rhythm, which is often very different from the rhythm of healthy cells. During my thesis, the goal was to customize what is known as chronotherapeutics by studying how to improve the efficacy or reduce the toxicity of irinotecan, a drug known to be effective in treating colorectal cancer and, more recently, pancreatic cancer.

How does math improve our understanding of these biological mechanisms?

I develop mathematical models based on cellular physiology. Data from the literature and research conducted specifically for the occasion in the field of chronobiology allow us to create a virtual model that is cellular, animal, and then human, with the aim of reproducing in silico what happens biologically. The parameters we use in the models are adjusted to the biological data to ensure the model is valid. Once optimized, they make it possible to modelize the impact of a treatment according to the time of day it is administered. These models integrate gene or protein networks that are described as interacting with the drugs studied, such as those that govern DNA repair processes, the cell cycle, or cell die-off. The value of using mathematics is to reduce the number of experiments to be carried out by testing in silico a vast number of hypotheses. Only those that turn out to be relevant to developing biological knowledge are tested experimentally.

How close are the links between mathematical and biological science?

Very close. Chronobiology is truly a cross-disciplinary field and we must work together closely and continuously. This is why, once I won the Atip-Avenir Program, I wanted implant my research team within Inserm. That way I could be more effective and closer to the biologists and oncologists. This funding is a unique opportunity to recruit a team of doctoral students, post-docs, and technicians. Seeing an applied mathematics research team set up operations at Inserm is rather unprecedented. Especially since we are working on cancer chronotherapy, which remains a research discipline in which few teams are involved in France. Thanks to this program, we are conducting two projects simultaneously. The first involves studying how the chronopharmacology of three drugs prescribed for digestive cancers is influenced by factors such as age, sex, and the chronotype of the individuals (early risers or late sleepers). The second project aims to develop personalized strategies for combining “targeted” medications that only interact with one or two intracellular proteins to improve the anti-tumor efficacy of the drug. The end result of these two topics is the same: individualizing treatment according to the nature of the tumor and also according to the individual patient. Lastly, the ambition is the have models in which the biological specificities of the patient can be integrated to create an individualized therapeutic protocol specifying which drug or drugs should be prescribed and what time of day they should be administered.

Annabelle Ballesta is the head of the Atip-Avenir team Multi-scale system-pharmacology approach to customizing anticancer chemotherapy, in Inserm/Université Paris 11 in Villejuif Unit 935. She also works with the Chronotherapy team at the University of Warwick (Coventry, U.K.) in the framework of the Inserm/University of Warwick Associated European Laboratory (LEA).