Publishable Summary - M6 - May 2013

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 with the aim of clinical interventions by vaccination studies;
  • 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.

 

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 6 months was the finalization of the clinical protocols of the RAIDs project.

  • The BioRAIDs clinical trial received ethical and regulatory approval in France and first patients are expected to be recruited in France in June 2013. Ethical and regulatory submissions have been achieved in part of the other countries and are ongoing in others.
  • The targeted therapy (DNA vaccine and Cidofovir trials) are currently awaiting ethical and regulatory approval.

In parallel, an electronic CRF (clinical report form) has been established to collect clinical data and tumor-banking information. A virtual tumor-bank, allowing patient confidentiality and traceability of all samples, is in place. It is linked to and can be visualized through the eCRF.

Standard operating procedures for biopsy and blood collections have been established. Sequencing tests on the SOLiD plateform at SeqOmics in collaboration with the Curie bioinformatics team for data integration and analysis are currently ongoing. Comparative tests on SOLiD and Illumina are ongoing to evaluate the different analysis strategies prior to analysis of the first tumor biopsies. Quality controls for pathology (% cellularity in tumor cells) and for NMR imaging will be put in place. Quality control procedures for radiotherapy have been established consisting in educational tools as well as reports to be collated in the electronic CRF form.

 

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:
    • the acquisition of molecular data for better treatment decisions,
    • targeted pilot trials directed at specific alterations and
    • the continuous evaluation of standards of care by comparison of care given in multiple centers in Europe.