COSY ( Cure Overgrowth Syndromes ) is funded by the Future Investment Program, provided by the French National Research Agency (ANR), and is scheduled to run for five years. The project comprises 11 partners, including scientists, geneticists, physicians, and industrial partners that are engaged in finding new therapeutic approaches to treat overgrowth syndromes (OS) and improving patient’s medical care.
Our main goal is to transform the outcome and the medical care of patients with overgrowth syndromes (OS). We demonstrated in an initial study focused on a particular gene called PIK3CA that we can reposition drugs initially designed for oncology, to cure specific monogenic disorders. Now, our objective is to consolidate and extend this work to other OS genetic causes.
Overgrowth syndromes (OS) are a heterogeneous group of disorders characterized by tissue hypertrophy that can be either localized or generalized, affecting both latitudinal and longitudinal growth. Although these syndromes are considered as rare disorders, their exact prevalence is yet unknown. It is likely to be underestimated owing to the variability of the clinical presentation and the broad phenotypic spectrum of the diseases. For these reasons, we have decided to define OS as an asymmetrical disharmonious overgrowth, including brain overgrowth.
Despite the recent advances in understanding the genetic basis, most of the genes involved in OS are not well characterized. However, it mostly concerns the PIK3CA/AKT/mTOR pathway, implicated in controlling cell growth and proliferation. This project will focus on the most common genes involved in this pathway since these genes are frequently mutated in cancer and a huge number of inhibitors are already available or under development. Importantly, as we recently demonstrated that these drugs can be successfully repositioned or repurposed for monogenic disorders.
The main goal is to achieve personalized medicine based on molecular diagnosis, new imaging modalities and innovative care for patients. Within this project, we will:
• Create affordable and state-of-art genetic testing to all patients (Partners: Imagine, AP-HP, ICM, IntegraGen)
• Develop new imaging software to precisely evaluate and follow patient malformations (Partners: AP-HP, HCL, Kitware, Eos Imaging)
• Transfer innovative care to existing expert centers (Partners: AP-HP, HCL)
• Understand the physiopathology of OS allowing patient stratification (Partners: Inserm, ICM)
• Envision new therapeutics for precision medicine (Partners: Inserm, ICM)
• Promote and communicate the knowledge (Partners: FFRD, Inserm, AP-HP)
• Improve the care, social condition and well-being of OS patients (Partners: Inserm, AP-HP, FFRD)
〉 1- Understand the Physiopathology
In patients with OS, the mutation is not inherited but occurs during embryogenesis leading to somatic mosaicism which is responsible for an extremely heterogeneous clinical presentation. This broad clinical presentation, the absence of standardized genetic tests and our limited medical knowledge explain the unknown prevalence and incidence of these disorders.
Our strategy is to implement robust genetic diagnosis tools based on the research devices already used and understand the overgrowth physiopathology by combining complementary in vivo and in vitro approaches, new genetic mouse models, innovative new technology to explore the molecular and structural changes in OS, and to identify new treatment to purpose personalized medicine.
〉 2- Design a National Registry and Create Expert Centers
Currently, there is no available registry of OS, either nationally or internationally. As a consequence, the healthcare of these patients is not organized. Many medical specialties are potentially involved in the diagnosis and the follow up of these patients, but no dedicated centers are yet existing.
In response to this problem, we are determined to design the first national registry, enabling us to identifying optimal disease management strategies. Simultaneously, 4 multidisciplinary expert centers dedicated to OS patients will be establish in France, in this way OS patients will be provided with the best care where in a single day, they will have access to all physicians, surgeons, biopsy, DNA storage, and imaging. Our final purpose is to determine the OS incidence and define guidelines for patients care.
〉 3- Develop New Imaging Software
Radiological evaluation, including the initial diagnosis and the follow-up of patients with OS, is fundamental but complex. In order to characterize the overgrowth, patients often have multiple magnetic resonance imaging (MRI), but its interpretation is difficult. As a consequence, physicians do not have access to easy and reliable tools to use. In addition to MRI, patients have repeated X-rays for bone deformation and scoliosis monitoring, which may expose them to future cancer.
In the current strategy, we intend to establish new imaging modalities. To achieve this, we will develop a new device adapted to the patient with overgrowth to follow bones deformation and composition as well as a specific algorithm solution that will allow radiologists to easily and reproducibly evaluate patient malformations.
〉 4- Envision New Therapeutics for Precision Medicine
Currently, there are no specific treatments for patients with OS. The mechanisms of disease progression are unknown, also, mouse models to understand the physiopathology and explore pharmacological intervention, are dramatically lacking.
Our purpose is to open new therapeutic avenues. Based on our understanding of the physiopathology and the fact that the genes involved in OS are commonly mutated in cancer, we will reposition and/or repurpose drugs initially developed for oncology.
〉 5- Promote Communication and Improve Socialization
Finally, these disorders are associated with crippling disabilities resulting in deleterious social consequences characterized by a high rate of school drop out for children, desocialization and premature death.
We plan to reinforce the communication on these disorders in order to reach the maximum of OS patients in France and improve the socialization of these patients by applying the model developed at Necker-Enfants Malades hospital called “La suite” which is a new concept of care center where adolescent have access to social workers, estheticians, hairdresser, etc, with a view to better accept their body in the difficult period of transition to adulthood.
COSY is a joint initiative of 11 partners and one patient association. It combines all the necessary skills to propose innovative tools in physiopathology, genetics, imaging and care reorganization.
Conjointly, we aim to re-define a new standard of care and to offer a unique multidisciplinary service organization dedicated to OS patients.
Lead : INSERM
This work package will coordinate the entire project for all aspects of management and logistics. It will ensure that the project reaches its objectives and expected impacts and guarantee compliance with regulatory requirements.
Lead: Institut du cerveau (ICM)
Focused on genetic, this WP aims to develop a highly-sensitive sequencing gene panel in to identify mutations in genes belonging to the PIK3CA/AKT/mTOR pathway and identify new causative genes in the panel-negative patients using whole exome sequencing (WES). Finally, it will create in vitro functional assays to test the pathogenicity of novel variants.
Lead : INSERM
This WP aims to decipher the physiopathology of these syndromes to offer precision and personalized medicine. On that account, WP3 will develop appropriate animal models, in addition to mutant PIK3CA tissue specific models, test novel pharmacological treatments in an approach of personalized medicine depending on the mutated gene, and unravel the molecular signature and putative biomarkers of OS by complementing the human data and animal models with in vitro analysis of cell lines.
Lead : Assistance publique - Hopitaux (AP-HP)
Describing the natural course of the disease is crucial to identify optimal disease management strategies. With the aim of doing so, this WP will be committed in creating a national registry, standardizing the medical care for OS patients, developing a biobank, and, finally, doing the follow up of PIK3CA-Related Overgrowth Syndrome patients treated with PIK3CA inhibitor (BYL719) under compassionate use program.
Lead : AP-HP
The overall objective is the reorganization of healthcare for OS patients in France. Thus, WP5 will be responsible for the creation of 4 multidisciplinary expert centers in France, for the dissemination of the standard of care for OS patients, established in WP4, and for the creation of a website dedicated to OS patients that will allow OS patients to have access to physicians and the exchange of medical information between patients and doctors.
Lead: Hospices Civils de Lyon - HCL
In order to transform the radiological diagnosis and follow up of OS patients, WP6 will comprises:
Overall, WP7 will be dedicated to the economical evaluation of the project and social improvement. To achieve this, WP7 will conduct a cost evaluation of the project and comparison with the current cost of cares will be conducted, implement strategies to improve the socialization and well-being of OS patients, specifically apply the model developed at Necker-Enfants Malades hospital called “La suite”, and launch a specific Human and Social Sciences (HSS) call to better understand individual, familial and psychosocial consequences of OS.
Lead: Foundation for Rare Diseases - FFDR
To ensure effective dissemination of the knowledge generated outside the consortium and manage intellectual property rights and the exploitation of the results, this WP will create and maintain a public website for informing the public of COSY activities, establish contact to relevant press and media channels, increase knowledge of relevant stakeholders and the scientific community, define a product development plan and a commercial strategy, and finally protect the results with appropriate IP strategy, and sequence the events of protection and publication.