Enhancement of therapeutic response to standard-of-care drugs employed against hepatocellular carcinoma by hitting metabolic dependencies

Abstract:

State of the art. Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide. Metabolic syndrome is awaited to become one of the major risk factors for HCC, at least in western countries. Accumulating evidences link metabolic syndrome to carcinogenesis, through the modulation of the immune system, which may be relevant in the response to therapy too. An underlying NAFLD or NASH was shown to be a negative factor for the efficacy of immunotherapy in HCC. Resistance to sorafenib was linked to alterations of the serine pathway. Hence, dysregulated metabolism affecting either malignant cells or microenvironment appears to be relevant for cancer initiation, progression as well as for therapy response.

Hypothesis. The work hypothesis is that drugs with metabolic targets can enhance the efficacy of drugs currently employed as standard of care against advanced HCC (sorafenib, lenvatinib or immunotherapy), either by increasing their effectiveness or helping to contain resistance phenomena. Hence, objective is not only to recognize the altered metabolic processes that could affect response to antitumor therapies but also discover and test whether such processes represent potential vulnerabilities that can be hit by specific drugs.

Specific Aims. Based on extensive supporting preliminary results, the main specific aims of the project are: (1) to identify the existence of metabolic addictions in drug-resistant cells / tumors, (2) to test pharmacological approaches that can hit such dependencies; (3) to understand how steatotic / fibrotic liver microenvironment can affect therapeutic outcomes, (4) to test pharmacological approaches to correct the underlying dysmetabolic condition.

Experimental design. Through the use of various experimental models, we plan to demonstrate anti-tumor synergistic effects produced by the combinations of metabolic-targeted drugs with sorafenib / lenvatinib or immune checkpoint inhibitors. Most of the studies will be performed in HCC cell lines and in rodent models. In addition, correlations with clinical data will be also established.

Scientific outcomes. Expected results include the identification of metabolic addictions that hinder the efficacy of anti-tumor therapies, the identification of drugs that could restore efficacy of standard therapies by hitting metabolic targets, possible identification of biomarkers that could predict treatment responses. The project will investigate a largely not explored area for the treatment of advanced HCC. The foreseen results might provide the basis for novel therapeutic opportunities.