To understand the mechanisms of resistance to innovative therapies, Gustave Roussy has launched the Unlock medical-scientific programme as part of its Institutional Strategic Project 2020-2030. This programme aims to understand these mechanisms and identify new targets in order to develop medical strategies to prevent or bypass them.
In some patients, the therapy prescribed against the disease proves ineffective from the outset. This is known as "primary" resistance, or resistance to treatment from the outset. Other patients, on the other hand, derive immediate therapeutic benefit. However, it is not uncommon for the disease to reappear or progress after a few weeks, months or years of treatment. This means that the drug is no longer effective in combating the disease. This is known as "secondary" or "acquired" resistance to treatment.
Resistance is a major issue in the management of cancer patients because, even if therapeutic strategies are initially effective in reducing the size of tumor cells or completely destroying lesions, cancer cells implement mechanisms leading to their reappearance or proliferation.
Understanding tumor resistance
While the mechanisms of resistance are many and varied, it has been established that they are multifactorial, linked as much to tumor cells as to their environment (blood vessels, immune system, stromal cells, etc.). It is therefore necessary to develop a global approach to understanding the various components of tumors in order to elucidate resistance to innovative therapies.
This is why Gustave Roussy is developing a programme dedicated to tumor resistance to innovative treatments, as part of its 2020-2030 institutional strategic project.
The Unlock programme aims to decipher and discover genetic and non-genetic mechanisms of resistance to innovative therapies. Led by researcher Luc Friboulet and medical oncologist Dr. Yohann Loriot, the programme is based on the MATCH-R study, opened in 2014 at Gustave Roussy, aimed at identifying the cellular mechanisms involved in resistance to targeted therapies used in oncology. Biopsies from patients who have developed acquired resistance have been collected as part of this trial, then analyzed using various methods to generate as much knowledge as possible.
Modeling resistance using a large number of samples
One of the first methodological approaches of the Unlock programme is the evaluation, by physicians from Gustave Roussy's Departments of Oncology Medicine (DMO) and Therapeutic Innovation and Early Stage Trials (DITEP), of therapies deemed the most innovative or developed at a very early stage with patients included in the MATCH-R study. The aim of this first stage is to enrich the MATCH-R database by collecting a large number of tumor samples at different times (before treatment initiation, during and after the development of resistance) from patients treated with innovative therapies and likely to develop a form of resistance. Objective: to work on a base of 1,000 patients.
Understanding tumor strategy, both on a single-cell scale and within their environment
The samples collected will be analyzed using new technologies: single-cell sequencing, spectral cytometry, high-throughput molecular screening, etc., with the aim of studying and deciphering the resistance mechanisms deployed at tumor cell level.
The development of avatars, also known as organoids, will enable us to observe and understand the behavior of cancer cells and the adaptation of resistance mechanisms in a complex 3D environment. The programme also includes the creation of a dedicated research unit to study mechanisms of resistance to innovative therapies evaluated in Phase I studies.
Bringing new options to patients
In the five years following the start of the programme, by understanding the different resistance strategies that tumors develop, the Unlock programme will identify new therapeutic targets and build new management options to prevent or bypass resistance mechanisms.
The development of avatars of resistant tumors will also make it possible to evaluate new drugs in a personalized way, in the laboratory and before administration to patients, in order to identify those that would be most suitable. The data collected will be collated to generate a comprehensive atlas of resistant tumors, and to enable as many people as possible to benefit from this new knowledge.
