Cancer Predisposition and DNA Repair Syndromes

This research group works in the field of genetic diseases characterized by a high predisposition to cancer. Many of these syndromes are caused by mutations in DNA repair genes. These genes are therefore important to prevent cancer transformation. Research on these syndromes is crucial not only to improve their diagnosis and treatment but also to unravel the mechanisms that protect us from cancer. In the past few years, the team has identified and studied many novel genes involved in such syndromes and performed therapeutic research leading to two orphan drug designations by the European Medicines Agency and several academic clinical trials, including gene therapy and drug repurposing. They also investigate DNA repair genes involved in these syndromes as therapeutic targets to induce cancer-specific lethality by synthetic lethality. There are an increasing number of novel therapeutic strategies based on the profound knowledge of the genetic causes of the disease. Therefore, a proper genetic diagnosis is significant not only to provide adequate genetic counseling and clinical management to the patients and their families but also to provide personalized medicine based on genomic information.

Main lines of research:

• Genetics and molecular biology of cancer-prone genetic syndromes with a focus in familiar breast cancer and Fanconi anemia and related chromosome fragility syndromes such as ataxia telangiectasia. (Bogliolo, Massimo).
• Development of new diagnostic and therapeutic tools in Fanconi anemia, including gene therapy, regenerative medicine and drug repurposing. (Surralles Calonge, Jordi).
• Mechanism of genomic instability and predisposition to cancer. Study of DNA repair mechanisms and biological and clinical consequences of DNA repair failure. (Bogliolo, Massimo).
• Fanconi/BRCA pathway in cancer. Implications of Fanconi genes in cancer and their use as therapeutic targets against cancer. Development of a DNA repair inhibitor against cancer by synthetic lethality. (Surralles Calonge, Jordi).
• Application of next-generation sequencing, genome medicine, and genome editing to better identify pathogenic mutations and perform functional studies of variants of known significance in rare diseases. (Muñoz Pujol, Gerard).

Scientific Challenges

• Optimization of our drug candidate to inhibit the FA pathway as a novel anticancer therapy based on cancer-specific synthetic lethality.
• Follow-up of functional assay to classify variants of unknown significance in cancer-predisposing genes.
• As we signed a collaboration agreement with US-based Rocket Pharma Ltd. for 10 years of follow-up of FA patients undergoing gene therapy, we will continue to do so.
• Running of the AFAN clinical trial for the repurposing of afatinib to treat Fanconi anemia patients with advanced head-and-neck cancer.
• Performing a drug screening to find drugs reactivating the Fanconi pathway in cells expressing a FANCA mutant protein.
• Develop and apply advanced genomic medicine tools and pipelines for the detection of pathogenic mutations in genes involved in rare diseases.
• Validation of gene candidates identified in a genome-wide CRISPR-Cas screen to identify synthetic lethal and viable interactions with the Fanconi/BRCA pathway.

Contact

Jordi Surrallés
jsurralles@santpau.cat