The development of targeted therapies induces a paradigm shift in how to select and develop future drugs.
In this context, it is necessary to develop new predictive animal models for preclinical investigations and new methods for early clinical trials in order to adapt the treatment to the biology of the tumour. It is also important to determine if the prescription of targeted therapies based on molecular defects, regardless of the location of the primary tumor and its histology, would improve therapeutic management.
Tools for the selection of new targeted therapies
1) Preclinical animal models
Project coordinated by Dr Didier Decaudin (IC) and Dr Lionel Larue (Inserm / IC)
Our teams work on the generation of genetically modified mouse models (GEMS) with the objective to further characterise and validate new oncogenic lesions and evaluate new therapeutic solutions. This project builds on the expertise of the Preclinical Investigation Laboratory (LIP) developing a collection of xenograft models (PDX).
2) Methodologies for early clinical trials
This project concerns the development of new approaches to the design of Phase I clinical trials with the objective of better estimating the dynamics of toxicity.
The teams are also working on developing new clinical trial designs for phase I / II taking into account repeated toxicities and efficacies of data to define the optimal therapeutic dose.
3) Early clinical trials and precision medicine
Project coordinated by Dr Christophe Le Tourneau (IC) and Dr Véronique Diéras (IC)
The objective of this project is to develop latest generation early clinical trials. In this context, under the leadership of Dr Christophe Le Tourneau, the Institute initiated the SHIVA clinical trial in 2012. THe Shiva Trial is a proof of concept randomized Phase II clinical trial comparing targeted therapy based on the molecular profile of the tumour regardless of its location, with conventional therapy in patients with refractory cancer.
Generation of new genetically modified mouse models:
- Development of the 1st rhabdoid tumor model characterized by SMARCB1 inactivation. (Han et al, Nat Commun, 2016)
- Generation of transgenic mice with conditional activation of Notch1 receptor and a deletion of p53 in gastrointestinal epithelium (NICD / p53 (- / -). These mice develop metastatic tumours with a high penetrance (Chanrion et al, Nat Commun, 2014).
- Generation of transgenic mice demonstrate cross exchange between SHH signalling pathways and Atoh1 during cerebellar development. This cross exchange highlights the existence of a collaborative network that can be targeted in medulloblastoma (Forget et al, Dev Cell, 2014).
- Characterisation of mouse KNOC-in (KI) with the two most common mutations observed in patients with neuroblastoma demonstrated the critical role of the activation of ALK in the development of the sympathetic nervous system and its disorders and allowed to highlight the value of targeting RET in patients with a neuroblastoma ALK mutation (Cazes et al, Oncotarget, 2014).
- Studies of transgenic mouse models to assess the potential strategies targeting Mdm4 for tumours expressing mutant p53 hypomorphic suggest that transcriptional repression mediated by p53 should be considered when evaluating strategies to reactivate p53 in tumors (Fang et al, Oncogene, 2014).
- Generation of a Notch induced (intracellular notch 1, ICN1) acute lymphoblastic leukaemia (T-ALL) mouse model for which a conditional genetic deletion of calcineurin is reduced to leukaemia cells. This permitted the identification of calcineurine as a promising target for prevention against relapse in the case of acute lymphoblastic leukaemia (Gachet et al, Leukemia, 2013).
- Demonstration of the fact that in vivo, the β-catenin signalling pathway in melanoblasts reduces migration of these cells, inducing a phenotype with white spots on the stomach. The inhibition of migration by the β-catenin is dependent on MITF-M, a key transcription factor of the melanocyte lineage and CSK, a Src-inhibitor (Gallagher et al, Oncogene, 2013).
Development of new PDX models
- New uveal melanoma PDX models, melanoma of the conjunctiva, adenocarcinomas of the anal canal, ovarian cancer and breast cancer
- New, unique, hormone-resistant PDX luminal breast cancer models: a generation of luminal breast cancer PDX models with acquired resistance to endocrine treatments revealed a great diversity of resistant phenotypes associated with specific deregulations of ER-mediated gene transcription. These models offer a tool for the development of cancer treatment and for the study of emerging resistance dynamics during pharmaceutical interventions (Cottu et al, Clin Cancer Res, 2014)
- New collection of breast cancer PDXs resistant to neo-adjuvant therapy
Establishment of the SHIVA clinical trial
The feasibility study with the first 100 patients was published in 2014 and the princeps publication in 2015 (Le Tourneau et al, Lancet Oncol, 2015). The inclusion was completed in May 2014 (741 patients enrolled in 18 months in eight cancer centres, including SiRIC centres).
The efficacy results were presented at the congress of the American Society of Clinical Oncology (ASCO) in May 2015. The treatment algorithm was published in 2016 as well as the lessons learned from the trial (Le Tourneau et al, J Natl Cancer Inst, 2016 ; Nat Rev Clin Oncol, 2016).