Project Title: Making sense of genomics: targeting protein drivers of therapeutic resistance in colorectal cancer

Aim/goals:

1. Complete the genomic profiling of our samples (580 mCRCs biopsies from 202 patients, including primary tumors, metastases before and at different times after TT).
2. Profile mCRCs for proteomic and phosphoproteomic alterations to identify new actionable knots in relevant signaling protein pathways
3. Develop an in vitro three-dimensional (3D) Patient Derived Organoids (PDO) assay to explore the determinants of targeted therapeutic failure.

Colorectal carcinoma (CRC) is the 2^nd leading cause of death by cancer. More than 60% of patients with CRC present metastases at the time of diagnosis with a 5-year survival rate that is below 15%. The development of anti-EGFR monoclonal antibodies has been a significant progress in the treatment of metastatic CRC (mCRC). However, even with a tumor harboring wild type RAS, only 40% of patients will initially respond to new generation anti-EGFR therapy, and almost all of them will eventually undergo tumor progression. This illustrates that the current approach of genomics screening has obvious limitations in the identification of patients who will benefit from targeted therapy (TT) and does not sufficiently reflect a specific tumor’s biology and microenvironment. The immune checkpoint inhibitors (CPIs) therapeutic revolution has drastically changed the therapeutic landscape and prognosis for almost all other advanced solid tumors. But in mCRC, only a small subset, 15% of the cases, benefit from CPIs, whereas the vast majority of the cases do not. Therefore, it is highly likely that the identification of the best synergistic combinations of TTs and CPIs able to both decrease the occurrence of secondary resistance to TT and turndown the immune anergy is the key to make significant progresses in mCRC treatment and survival. We hypothesize that coupling quantitative proteomics to genomic analyses will be a powerful strategy to identify novel therapeutic targets and the most synergistic combination of treatments, instead of relying on genetic profiling alone. We also hypothesize that impacting the cell signaling axis will change the immune microenvironment and reinforce the response of mCRC to CPIs.