# Cross-comparison of patient-derived xenografts and derivative organoids and cell lines for translational research in hepatocellular carcinoma

> **NIH VA I01** · PHILADELPHIA VA MEDICAL CENTER · 2021 · —

## Abstract

PROJECT SUMMARY
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide with more than
745,000 fatalities in 2012 alone. The majority of patients with HCC present with unresectable disease at
diagnosis and a life expectancy of less than 20 months, with only 15% of these patients surviving more than one
year after diagnosis. This dismal prognosis underscores the limited therapeutic options for these patients. HCC
is a notoriously chemoresistant malignancy and advances in targeted therapeutics have been unsuccessful in
improving survival resulting in what some have called “a losing battle” in the development of therapies. This
deficiency issues, in large part, from limitations of current preclinical models in (i) recapitulating the inter- and
intra-tumoral heterogeneity that characterizes HCC and (ii) predicting patient response to therapeutics.
While patient-derived tumor models have been demonstrated to more faithfully recapitulate the heterogeneity of
human tumors, there has been limited validation of the translational relevance of these models with respect to
their fidelity to the intra- and inter-tumoral mutational heterogeneity that characterizes HCC as well as their ability
to provide translationally reliable information for the design, testing and/or outcome evaluation of novel or existing
therapies. Indeed, the creation of new patient-derived models of HCC requires rigorous validation of the resulting
tumors to confirm their fidelity to the cancer of interest and robust credentialing criteria to ascertain their biological
relevance and reliability as surrogates of patient response.
In preliminary studies we have: 1) demonstrated the ability to generate PDXs and PDX-derived cell lines from
percutaneous biopsies of tumors in patients with intermediate stage HCC and 2) developed methodologies to
enable the characterization, validation and optimization of these models. The proposed project will build on this
prior work to assess the fidelity and predictive potential of patient-derived models of HCC.
We hypothesize that patient-derived models of HCC derived from percutaneous biopsies recapitulate the inter-
and intra-tumoral heterogeneity of their parent biopsies and that these models are predictive of patient response
to therapy. To test this hypothesis the proposed project will pursue three aims: (1) to define the representation
of inter- and intra-tumoral clonal heterogeneity of patient-derived models of HCC through targeted sequencing
and digital polymerase chain reaction; (2) to determine the predictive potential of patient-derived models of HCC
for response to common HCC therapies; and (3) to investigate the role of HCC tumor initiating cells (TICs) in
improving the yield and predictive potential of patient-derived models of HCC. Importantly, the achievement of
the proposed aims will transform the utility of patient-derived models of HCC for translational research.

## Key facts

- **NIH application ID:** 10041707
- **Project number:** 5I01CX001933-02
- **Recipient organization:** PHILADELPHIA VA MEDICAL CENTER
- **Principal Investigator:** David E Kaplan
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10041707

## Citation

> US National Institutes of Health, RePORTER application 10041707, Cross-comparison of patient-derived xenografts and derivative organoids and cell lines for translational research in hepatocellular carcinoma (5I01CX001933-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10041707. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*