Liver Cancer Program

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

One of main reasons why survival for patients with primary liver cancer (PLC), including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), has not improved in the past twenty years is the lack of approved novel therapies, with the exception of the limited success of sorafenib. Multiple phase III studies have failed to demonstrate any survival advantage for patients with liver cancer. We believe that this situation will change dramatically with the advent of immunotherapy, biologicals and by the implementation of precision cancer management strategy. Our optimism is supported by recent findings in the field of HCC. CCR is in a unique position to utilize its expertise in the area of immunotherapy and biologics to test these novel treatment options in patients with liver cancer. Molecular subgrouping and biomarker-guided molecularly-targeted therapies are promising approaches that are being implemented in our ongoing and future studies. One of the key elements of the NCI-LCP is to build an infrastructure which allows intramural investigators to expand on their research and not only collaborate with each other but also with extramural investigators. Our first effort is to build an NCI IRP-based collaborative translational science network of liver cancer clinical trial data, with accompanying biospecimens and correlative laboratory data to determine why immunotherapy is effective in certain patients but not in others. This goal is encompassed in our funded Liver Cancer Study (NCI-CLARITY). In this study, we are building a national clinical network in liver cancer to 1) define at the molecular level which group of PLC patients respond to immunotherapy and which do not and why some patients develop resistance/tumor relapse and 2) to determine whether any similarities or differences in response to immunotherapy are observed in HCC versus CCA patients. This program is based on the creation of a unique and robust national information commons comprised of comprehensive clinical and molecular data which can be utilized by the cancer research community for future studies of PLC. To accomplish these aims, the NCI IRP is serving as the lead and coordinating hub to leverage ongoing immunotherapy-based clinical trials at major institutions treating PLC patients. We have partnered with clinical extramural collaborators across the U.S. to obtain longitudinal biospecimens (biopsy, blood, urine and fecal) and clinical data (medical chart data, treatment outcome and survival) from PLC patients in their ongoing clinical trials and/or standard of care patients treated with immune checkpoint inhibitors. We aim to collect biospecimens and clinical data from 500 PLC patients over a 5-year period across study sites. Comprehensive correlative data will be performed at NCI and NCI Frederick National Laboratory, along with our collaborators, including molecular (DNA and RNA-Seq), single-cell sequencing, metabolomics, microbiome, immunophenotyping by CODEX 3D-multiplex imaging (Optical Microscopy and Image Analysis Laboratory) and SNP/variant analysis. Radiogenomics, pairing data mined from comprehensive multi-modality imaging with genomics, by artificial intelligence/machine learning, will also be used to screen and predict patient response to immunotherapy. Comprehensive statistical, machine learning and bioinformatics analysis will be used to integrate correlative data and clinical data to molecularly characterize and define predictive signatures of treatment responders and nonresponders to immunotherapy in all cases or in the stratified analyses. In concert with this effort, we also initiated a pilot retrospective study of archival biopsy specimens collected before and after immunotherapy treatment (IO) from liver cancer patients from the NIH Clinical Center and Georgetown University. Samples from 89 patients undergoing immunotherapy treatment were assessed by DNA and RNA sequencing to identify mutations, transcripts and molecular signatures associated with patient outcome following IO treatment. A total of 230 primary HCC and CCA tumors and adjacent non-tumor tissues, largely stored as formalin-fixed paraffin-embedded (FFPE) and attained before and following immunotherapy treatment, using total RNA sequencing and whole exome sequencing were analyzed. We established a SOP and showed feasibility to conduct molecular analytics to monitor patient response to immune therapy utilizing FFPE tissue. We identified four stable survival-related molecular subgroups defined by orthogonal axes of tumor aggressiveness and immune infiltration, the latter associated with immunotherapy response. Furthermore, although the underlying molecular status of tumors prior to immunotherapy treatment was largely maintained following treatment, some molecular responses tracked with patient outcome. Thus, outcome-related and intersecting molecular axes are apparent in FFPE liver tumors prior to immunotherapy treatment, components of which could serve as indicators of treatment response. The pilot arm of the study was published (Budhu et al, Cell reports Medicine, 2023). Additional samples from these and other collaborating sites are being incorporated and integrated with these analyses to further assess these data. The pilot data are deposited to public databases and are being utilized for several ongoing and published studies. This includes a phase II study of the combination of pembrolizumab with capecitabine and oxaliplatin (CAPOX) in patients with advanced biliary tract carcinoma (BTC) to assess response rate and clinical efficacy. We found that capecitabine and oxaliplatin in combination with pembrolizumab is tolerable and a potentially effective treatment for refractory advanced BTC (Monge et al, Oncologist, 2022). Multi-omics analysis of immune correlates of immunotherapy has shown that certain T cell populations play important roles in treatment response (Myojin et al, Gut, 2025 and Ruf, Cell, 2023). Other studies from this program include an assessment of genomic changes at the single-cell level at baseline and in response to therapy. Published single-cell studies have provided insight into tumor cell heterogeneity and the alterations which affect outcome in certain patient subgroups (Ma et al, Nature Comm, 2022) and montoring tumor evolution in response to treatment (Revsine et al, Cell Rep Med 2024). Another example includes the comparison of the bulk transcriptome data of the pilot study with single-cell transcriptomics conducted from samples of the same patient (Ma et al, J Hep, 2021). In addition, we are exploring the differences in immunotherapy response between populations. An understanding of the molecular features contributing to differences in clinical response among populations is not known. The LCP has also initiated collaborations with the Cancer Data Science Laboratory (CDSP) to create and test new and known bioinformatic tools for their ability to predict patient response and outcome utilizing our datasets. The prospective arm of NCI-CLARITY is underway with 162 patients enrolled and over 7600 biospecimens collected. Additional studies will be initiated with these prospective specimens. Overall, we anticipate that these data will define specific subgroups of patients who are more likely to benefit from immune checkpoint inhibitor treatment. In addition, biomarkers and novel druggable targets may be identified to better determine or affect treatment response.