IdeaTMEHCC

Background. More than 70% of Hepatocellular carcinoma (HCC) are diagnosed in advanced stage, with a 5-year survival rate of ˜20%, consistent with the definition of Hard-To-Treat Cancer. Despite encouraging results, all in all the treatment for HCC is far from adequate and new therapies are imperative to improve patients’ outcome. Patient-derived-organoid (PDO), represented a breakthrough in the field of drugs screening and personalized therapeutics. In keeping with this, HCC-PDO were successfully used as a proof-of-concept to screen new drugs for HCC. Current HCC-PDO, however, lacks Tumor Micro Environment (TME) component, a major limitation taking into consideration that several HCC treatments are TME-(vascular; immune)-modulators.

Rationale. Preliminary data show that HCC vascular TME influences response to anti-angiogenic but not to immune modulators drugs. IDEA-TMEHCC is therefore based on the IDEA to explore, on an adequate preclinical model, how TME components influence HCC response to drugs.

The research hypothesis is to create HCC-PDO enriched with different types of TME and test on these models available and experimental drugs for HCC.

Aims. 1: To create TMEenriched-HCC-PDO; 2: To explore connections between TMEs and HCC drug efficacy using TMEenriched-HCC-PDO; 3: To understand the determinants of drug response using spatial and molecular approaches

Methods. Prospectively collect biological specimen from 250 HCC and generate TMEenriched PDO. Evaluate the effect of drugs for HCC on TMEenriched PDO. Understand the determinants of response by molecular characterization and spatial transcriptomic analysis.

Expected results and potential impact. We expect to establish 70 PDO with different typologies of TME; to identify TME-specific drug sensitivities and predictors of treatment benefit. The impact will be to better stratify HCC patients and improve patients’ outcome