Fusion Proteins Enhance Cancer Detection
In recent years, research laboratories have discovered that certain tumors contain a specific and abnormal protein resulting from the aberrant fusion of two chromosome fragments. This abnormal form, called a “fusion transcript,” is most often responsible for cancer development. Until now, these fusion transcripts have primarily served to better diagnose these diseases and help clinicians better understand how cancers spread.
Advancements in molecular biology techniques over the past 10-15 years have led to the discovery of an increasing number of fusion transcripts, the vast majority of which are specific to a particular tumor type. Currently, several dozen transcripts are known and used to aid in the diagnosis of several types of cancer.
About the Project
Since these proteins are specific to tumor cells, it quickly became important to search for drugs that aim to specifically block these abnormal proteins to destroy cancer cells containing them while respecting healthy tissues. These “targeted therapies” have seen significant growth in recent years and are the subject of numerous therapeutic trials with varying degrees of success. Among these targeted therapies, drugs targeting the fusion transcript known as “NTRK” have proven to be extremely effective and thus far, minimally toxic. Tumors that harbor this NTRK transcript are primarily infantile fibrosarcomas, infantile kidney tumors (mesoblastic nephroma), but also some rare adult cancers (such as “MASC salivary gland cancer” or “secretory breast cancer”). Although these are rare tumors, NTRK inhibitors currently provide an effective additional therapeutic option for cases resistant to conventional treatments. However, some of these diseases, despite carrying this specific fusion transcript, do not seem to respond to these inhibitors, and others respond only transiently.
The aim of this clinical and biological project is to perform a precise analysis of the molecular characteristics of all tumors carrying this NTRK transcript to better understand how these tumors develop and why some resist targeted treatments. These results, focusing on very rare tumors occurring in both children and adults, will aid in the development of therapeutic alternatives in cases where these targeted therapies are ineffective.
The project involves analyzing, from the somatic genetics laboratory of the Institut Curie in Paris, all tumors carrying this specific transcript at the molecular level, collecting clinical data and patient treatment information to better describe their presentation and behavior, and retrieving tissues from operated tumors to determine if their microscopic appearance allows differentiation from other tumors.
Thanks to this project, many patients have been identified through the database obtained as part of the MAPPYACTS project and have benefited from Larotrectinib, which has had spectacular therapeutic effects for children, particularly those affected by infantile fibrosarcoma. This medication, taken in the form of a syrup morning and evening, rapidly regresses these tumors and presents no side effects. This treatment is undeniable proof of the need to further intensify precision molecular medicine.
Project Progress
- Started in September 2020
- 65 patients out of 2119 tumors analyzed had a tumor sample with a characterized and molecularly validated NTRK fusion
- Some of these tumors were studied histologically, and the data were compared with those from the SCOUT database whose patients were treated with Larotrectinib (an NTRK inhibitor), in collaboration with Bayer, to aid in obtaining conditional marketing authorization (now validated)
- Opening of the EPI-VITRAKVI study based on these results to clinically test the effect of Larotrectinib, especially for fibrosarcomas
- Preliminary clinical data from 28, 40, and then 65 patients were presented in poster form at ASCO 2020, SIOP 2020, and the SIOP 2021 congress
- Publication of two articles: Neurotrophic tropomyosin receptor kinase (NTRK) fusion positive tumors: a historical cohort analysis – PubMed (nih.gov) and Imaging characterization of paediatric tumours with the neurotrophic tyrosine receptor kinase fusion transcript – PubMed (nih.gov)
Project Summary
- Promoter: Institut Curie
- Principal Investigator: Dr. Daniel Orbach
- Program Duration: September 2019 – September 2022
- Number of Patients: 65 patients
- Countries Involved: France
- Imagine for Margo Funding: €60,000
