Project context and objectives
Cervical cancer (CC) is the second most common malignancy in women worldwide. Although CC is a single diagnostic entity and infection of high-risk HPV is recognized as an important initiating event in tumor genesis, CC exhibits differences in clinical behaviour. Stratification of CC into subclasses for progression and response to treatment remains to be defined. At present, the dominant targets under scrutiny for innovative CC treatments are the following: EGFR/PI3K pathway, proliferation/DNA checkpoint and angiogenesis inhibition as well as anti-HPV vaccines. There have been so far no publications on high resolution genetic investigations such as whole genome/exome sequencing or protein profiling. We are lacking prognostic and predictive biomarkers in CC and there is a growing need for the development of biomarkers to follow up the course of the disease.
RAIDs is a multidisciplinary co-operation between academic clinical centers, SMEs and translational research platforms. It combines Next Generation Sequencing (NGS) and Reverse Phase Protein array (RPPA) in a large patient population prior to standard therapy. It includes:
- a cognitive cohort study (BioRAIDs) intended to define patient stratification for targeted therapies,
- as well as targeted clinical trials using an HPV directed vaccine trial or direct viral targeting in association with standard therapy.
In addition, high throughput screening techniques will be performed in CC cell lines to identify new molecules of relevance for CC or CC microenvironment targeting. These molecules will be validated in preclinical mouse models.
The main objectives of RAIDs as stated in the DoW are:
- To identify prognostic and predictive biomarkers for standard and targeted therapy in cervical cancer patients using high throughput genomic and proteomic approaches in order to improve treatment response for the individual patient;
- To define a set of stratification criteria for therapy in patients with cervical cancer based on the tumor’s molecular profile;
- To identify underlying mechanisms causing immune tolerance of the viral transmitted disease allowing innovative clinical interventions by vaccination studies (together with anti-microenvironmental reagents and/or checkpoint inhibitors);
- To improve clinical outcome of patients with cervical cancer by conducting interventional targeted therapy-based trials, which will be carried out by a network of leading European centers in gynaecologic oncology: (EORTC/ENGOT)
Work performed and main results achieved
RAIDs started October 1st, 2012 in 7 European countries (France, Germany, the Netherlands, Serbia, Moldova, Romania and Hungary).
The main effort during the first 12 months was dedicated to set up the clinical trials tools and to open the clinical centers.
- The first BioRAIDs clinical centre opened in Paris end of July 2013. Two additional French centers opened in October 2013. 6 patients are recruited till date.
- Ethical and regulatory submissions are ongoing or achieved in all the other countries.
- The targeted therapy (DNA vaccine and Cidofovir trials) trials are awaiting final ethical and regulatory approval. Accrual is expected to start towards Q1 2014.
- Standard operating procedures (SOPs) for biopsy and blood collections have been established and documents have been translated in English and French as well as in Romanian/Moldovian and Serbian.
- Reports of patient data will be collated in the electronic CRF form which has been validated by the Curie clinical research team and the RAIDs consortium. Electronic controls have been introduced assuring that the data will be accurate and the need to send out queries for data validation can be kept to a minimum.
- Sequencing tests on the SOLiD platform at SeqOmics in collaboration with the Curie bioinformatics team for data integration and analysis are currently ongoing to evaluate the different strategies on tumor cell lines prior to the analysis of the first tumor biopsies.
- Quality control procedures for radiotherapy are ongoing. These consist in educational tools (web based tumour contouring workshops with expert guidance). Two Online Delineation Workshops to initiate the quality control of the radiotherapy procedures have been conducted during three weeks, in late June and early July 2013, a third workshop is planned in the weeks ahead.
- Quality control for pathology (% of tumor cells in biopsy sample) and for NMR imaging is currently being addressed.
- Our preclinical studies concerning drug sensitivity screening on cervical cancer cell lines are ongoing and preclinical mouse models for tumor microenvironmental studies are now available.
Expected final results, potential impact and use
RAIDs aims to define a set of stratification criteria based on molecular profiling. Its results should give insight into dominant genomic and protein signalling pathway alterations, enabling the identification of prognostic and predictive biomarkers for standard or targeted therapy in CC. Immunological data from trials involving vaccine or direct viral targeting will provide information on immune rejection or tolerance of this virally transmitted disease.
The RAIDs consortium aims:
- to provide a safer and more efficient therapy for the individual patient;
- to raise awareness in countries with lesser screening practices;
- to improve the quality of life for women with cancer via:
- a) the acquisition of defined molecular data for better treatment decisions
- b) targeted pilot trials directed at specific alterations and
- c) the continuous evaluation of standards of care by comparing standards and outcome in all the RAIDs centers. Other (EORTC and ENGOT) centers may wish to join this initiative in Europe.