Gustave Roussy has launched the Unlock medical-scientific programme as part of its 2020-2030 Institutional Strategic Project in a bid to understand the mechanisms of resistance to innovative therapies. This programme seeks to understand these mechanisms and identify new targets in order to develop medical strategies to prevent or overcome these mechanisms.
In some patients, the treatment prescribed for the disease in question is ineffective from the outset. This is known as "primary" resistance or initial resistance to treatment. Contrastingly, other patients will immediately benefit from their treatment. However, it is not uncommon for the disease to reappear or advance after a few weeks, months or years of treatment. This means that the drug is no longer effective in controlling the disease. This is referred to 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 tumour cells or completely destroying lesions, cancer cells develop mechanisms that lead to their recurrence or proliferation.
Understanding the phenomenon of tumour resistance
Although the mechanisms of resistance are multiple and diverse, they are known to be multifactorial, linked equally to tumour cells and their environment (blood vessels, immune system, stromal cells, etc.). A global approach is therefore needed to understand the different tumour components in order to shed light on resistance to innovative therapies.
Hence Gustave Roussy is developing a programme dedicated to tumour resistance to innovative treatments, as part of its 2020-2030 institutional strategic project.
The aim of the Unlock programme is to decipher and discover genetic and non-genetic mechanisms of resistance to innovative therapies. Led by Luc Friboulet, research scientist, and Dr Yohann Loriot, medical oncologist, the programme is based on the MATCH-R study, initiated in 2014 at Gustave Roussy, in a bid to identify the cellular mechanisms involved in resistance to targeted therapies used in oncology. During this trial, biopsies were collected from patients who had developed acquired resistance and then analysed using different methods in order to gain as much knowledge as possible.
Modelling resistance with a large number of samples
One of the first methodologies employed in the Unlock programme is the assessment by doctors in the Oncology Medicine Department (DMO) and the Department of Therapeutic Innovation and Phase I Trials (DITEP) at Gustave Roussy, of therapies deemed to be the most innovative or developed at a very early stage with patients enrolled in the MATCH-R study. The purpose of this initial stage is to enrich the MATCH-R database by collecting a large number of tumour samples at different times (before treatment is introduced, during and after the onset of resistance) from patients treated with innovative therapies and likely to develop some form of resistance. The aim is to work on a database comprising 1,000 patients.
To understand the strategy of tumours at single-cell level and in their environment
The samples collected will be analysed using novel technologies: single-cell sequencing, spectral cytometry, high-throughput molecular screening, etc., in order to investigate and decipher the resistance mechanisms deployed at the tumour cell level.
The development of avatars, also known as organoids, will facilitate the observation and understanding of cancer cell behaviour and the adaptation of resistance mechanisms in a complex 3D environment. The programme has also been devised to create a dedicated research unit to explore the mechanisms of resistance to the innovative therapies assessed in the phase I studies.
Providing new patient options
Within five years of starting the programme, the Unlock programme will be able to identify new therapeutic targets and generate new treatment options to prevent or overcome resistance mechanisms by recognising the various resistance strategies developed by tumours.
The creation of resistant tumour avatars will also allow new medicinal products to be assessed individually, in the laboratory and before being administered to patients, in order to determine the most appropriate medication. The data will be collated to provide a comprehensive review of resistant tumours and to make this new information available to a wider audience.
