FROM CHEMO-RESISTANCE PREDICTION TO THE IDENTIFICATION OF NEW POTENTIAL THERAPEUTIC STRATEGIES FOR CHEMO-RESISTANT MICROSATELLITE STABLE METASTATIC COLORECTAL CANCER: THE OCEANUS STUDY

Colorectal cancer (CRC) is one of the most common and deadly cancer worldwide. More than half of patients diagnosed with CRC will develop metastases over time, even after primary tumor resection. Despite recent immunotherapy and targeted treatment advancements, doublet or triplet chemotherapy regimens are still the most effective therapeutic opportunity to treat microsatellite stable (MSS) metastatic CRC (mCRC) patients. However, around 20% of mCRC patients are primary refractory to chemotherapy and do not benefit at all from this active but also toxic therapeutic approach. Despite that, no predictive biomarkers are available to predict resistance to chemotherapy. Accordingly, since standard of care treatments for chemo-refractory patients are scarcely effective, new therapeutic approaches are warranted to treat these patients. In this context, we designed the OCEANUS translational project with the aim to predict resistance to chemotherapy and to identify new therapeutic opportunities for chemo-refractory MSS mCRC patients. In this thesis, we first demonstrated that radio-pathomics can predict chemoresistance with a promising negative predictive value (NPV) of 75% (95%CI = 41-93%) in a population of chemo-response outliers MSS mCRC patients who had primary tumor resection ahead of first line chemotherapy. These findings stand as the first promising step to design a first-in-kind artificial intelligence (AI)-based biomarker to predict chemoresistance in MSS mCRC patients. Further validation steps, as well as the implementation of these results by immunohistochemistry and RNA sequencing profiling, are ongoing. Second, we identified a subset of MSS CRC cell lines which were proven resistant to standard chemotherapy. Here, by performing a High Throughput Screening (HTS), we found that inhibiting the enzyme nicotinamide phosphoribosyl-transferase (NAMPT) synergizes with SN-38, the active metabolite of irinotecan, to treat chemo-resistant MSS RAS/BRAF mutant CRC cell lines. Subsequently, in-vitro findings were validated in-vivo in NOD-SCID mice. All together these promising findings represent the initial and crucial step of the OCEANUS translational study ultimately aiming at predicting chemo-response and tailoring first line treatment in MSS mCRC patients.