Defining Novel Hepatocellular Carcinoma Circulating Tumor Cell Biomarkers and Drug Targets

Blood-based biomarker development in Hepatocellular carcinoma (HCC), by far the most prevalent type of liver cancer, has focused mostly on circulating free DNA (cfDNA), either looking for genomic correlates of survival or dynamics that correlate with response, but neither approach has succeeded in  predicting responses in prospective HCC immune therapy trials. Dr. Franses would like to focus instead on circulating tumor cells (CTCs) in blood, the precursors of metastasis, because CTCs contain different types of RNA and additional biomolecular cargo that have the potential to yield deeper and more mechanistic molecular correlates of anti-cancer response to immune therapies than cfDNA focused approaches.  Dr. Franses suggests that an integrative liquid biopsy-approach focused on CTCs and the ways they both spread metastatic disease and interact with immune cells when stimulated by immune therapy drugs may provide unique insights into the dynamic behavior of cancer as it spreads throughout the body and how it reacts to the body’s attempts to immunologically reject it.

In order to test his hypotheses that there are specific cancer-immune interactions, observable in both CTCs and in local tumor tissue niches, that drive immune therapy response, Dr. Franses will first compare samples from a cohort of HCC patients before, during and after immune therapy. He will then use single cell RNA sequencing to characterize exchanges between interacting CTC and immune subpopulations in patients with differing therapeutic responses.  He will use single cell spatial transcriptomic profiling to characterize how cancer-immune interactions within the tumor compare and contrast with those in circulation, with the goal of identifying interactions that correlate with specific circulating signatures and outcomes.  Using the most promising interaction identified in both of these comparisons. Dr. Franses will test antibody/inhibitor strategies in HCC, finally validating the most promising two in combination with current immunotherapies.  Dr. Franses’ hope is to create a sensitive and specific blood-based predictive biomarker to predict how patients will react to therapies as well as to identify new potential targets for novel therapies.