The Project

TARGET aims at testing for the first time the hypothesis that therapeutic inactivation of DNA repair pathways in cancer cells can be exploited for patient benefit by reawakening an anti-tumor immune response against cancer cells. Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality, ranking second in frequency and lethality worldwide. Despite recent advancements in targeted and immunological therapies, the overall survival of metastatic CRC (mCRC) patients remains poor. Importantly, the vast majority (95%) of mCRC patients do not benefit from immune checkpoint blockade (ICB). Notably, molecular defects in the mismatch repair (MMR) machinery are present in 5% of metastatic mCRCs and 15% of all CRC stages. MMR deficient (MMRd) tumors known as microsatellite unstable (MSI) show better prognosis and favorable clinical outcomes when compared to microsatellite stable (MSS) tumors of the same histology. Importantly, MMRd tumors display remarkable response to therapies based on immune checkpoint inhibitors likely due to the accumulation of mutations, which triggers immunosurveillance (Fig. 1).  

This led to the ‘pan cancer’ approval of immune therapeutic regimens for MMR deficient solid tumor. Based on these premises TARGET was conceived to address these questions:

  • What are the bases of the extraordinarily long-lasting responses of patients with MMRd tumors?
  • Are there other DNA repair defects able to increase immune surveillance and response to immunotherapy?
  • Can we pharmacologically inhibit DNA repair proteins to promote the production of tumor neoantigens allowing the immune system to detect cancer cells?

 

Using a multidisciplinary approach and the exploitation of both patient-derived organoids and animal models (Fig. 2), TARGET aims at systematically:

  • assess whether and how inactivation of DNA repair pathways triggers anticancer immunity and restricts cancer;
  • identify DNA repair pathways which, when disabled, reawaken the immune system;
  • discover and develop inhibitors of DNA repair proteins able to induce significant increase of immunogenic neoantigens and tumor immunity;
  • establish how DNA repair inhibitors and immune modulators can be combined in cancer treatments.