Structural Genomic Alterations in Hepatocellular Carcinoma and Novel Combination Therapies

Abstract

[eng] INTRODUCTION: Primary liver cancer is the sixth most diagnosed cancer and the second leading cause of cancer-related death worldwide. Around 90% of cases correspond to hepatocellular carcinoma (HCC), which normally arises in the setting of a chronic liver disease. Of all HCC patients, 50-60% will be ultimately exposed to systemic therapies, where the combination of atezolizumab and bevacizumab has become the standard of care in first line. However, only around 30% of patients respond to this therapy. Therefore, there is a need for biomarkers of response/resistance and more knowledge on the mechanisms behind antitumor immunity. In line with this, aneuploidy – the presence of copy-number alterations (CNAs) in chromosome segments due to chromosomal instability- has been linked to immune evasion in some cancer types. In HCC, the biological implications of aneuploidy profiles have not been thoroughly described . The elevated rates of primary resistance to atezolizumab-bevacizumab (70%) highlight the need to develop novel therapeutic strategies. Given that immunotherapeutic agents show better results among tumors with an inflammatory microenvironment and that proangiogenic molecules are immunosuppressive, the antitumor activity of immunotherapy could be enhanced by promoting the infiltration or reactivation of immune cells in combinatorial strategies with antiangiogenic agents. In this context, the tyrosine kinase inhibitor (TKI) cabozantinib is a promising candidate for combination with ICIs. In Western countries, an increasing prevalence of obesity and metabolic syndrome is leading to a higher fraction of HCCs attributed to non-alcoholic steatohepatitis (NASH). Recently, NASH-HCC has been reported as less responsive to immunotherapy due to an expansion of a subset of exhausted infiltrating CD8+ T cells9. Considering the growing evidence for pro- and anti-tumor functions of neutrophils in cancer and HCC, neutrophil phenotype modulation could be a mechanism to overcome NASH-HCC immunotherapy resistance.

HYPOTHESIS: The identification of molecular features/structural genomic alterations linked to antitumor immunity in HCC and the assessment of novel combinatorial strategies with immunotherapies will reveal candidate biomarkers of response or resistance to immunotherapeutic agents and more effective therapeutic options to enhance the antitumor immune response.

AIMS: The specific objectives of the doctoral thesis are: 1. To determine the biological and clinical impact of chromosomal instability in hepatocellular carcinoma and to reveal its association with antitumor immunity. 2. To evaluate the impact of molecular therapies combined with ICIs in preclinical models of HCC. Specifically: 2.1. To explore the antitumoral and immunomodulatory effects of cabozantinib alone and in combination with anti-PD1. 2.2. To evaluate the capacity of a CXCR2 inhibitor to re-sensitize NASH-HCC to anti-PD1 therapy.