# Project 1

> **NIH NIH P50** · MAYO CLINIC ROCHESTER · 2024 · $461,849

## Abstract

Project Summary/Abstract
The goal of this proposal is to develop the first diagnostics and therapeutics for the often-fatal
pediatric liver cancer fibrolamellar hepatocellular carcinoma (FLC). Timely diagnosis of FLC is a
challenge: the symptoms are non-specific and often appear late in the disease; no useful
biomarkers have been identified; and even following biopsy, diagnosis of FLC can remain
ambiguous. Effective therapeutic options are limited, as FLC does not respond well to
chemotherapy. Surgical resection remains the mainstay of treatment. Unfortunately, FLC is often
diagnosed after the tumor has metastasized and curative resection is not an option. As a result,
the overall 5-year survival rate of FLC is only 30%-45%. Given the low survival rate and lack of
treatment options, there is a pressing need for new diagnostic and therapeutic approaches.
The overarching research objective of this project is to characterize the functional response of
FLC driven by the DNAJB1::PRKACA oncoprotein, understand the basis of this functional
response, so that precision medicines and diagnostics can be delivered for a broad class of
patients. All is in place for such advances: The driver for this cancer has been identified; the
transcriptome, proteome, phosphoproteome and metabolome have been characterized; there are
validated model systems including genetically engineered mice, patient-derived xenografts and
screens on cells fresh from patient resections (1) and patient-derived organoids.
Agents directed against the oncogenes upregulated in FLC are not effective, nor are agents
currently being explored in the clinic This indicates the need for alternative approaches. An
agnostic screen of a drug-repurposing library, identified agents that were efficacious against i)
FLC cells dissociated from patient resections ii) FLC cells dissociated from PDX and iii) preclinical
PDX models. Although these therapeutics were not predicted from the transcriptome, an
examination of their biology provided novel insights into the mechanisms of tumor growth and
explained the efficacy of these agents.
This work will expand this approach with a clinically relevant library of agents that have entered
or passed Phase I clinical trials. The goal is to bring some of these agents into the clinic in the
next 5 years. Critical to this project will be the development of new diagnostic tests for following
the efficacy of these treatments and probing for recurrence in patients.

## Key facts

- **NIH application ID:** 10935705
- **Project number:** 2P50CA210964-06A1
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** SANFORD M SIMON
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $461,849
- **Award type:** 2
- **Project period:** 2018-09-10 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10935705

## Citation

> US National Institutes of Health, RePORTER application 10935705, Project 1 (2P50CA210964-06A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10935705. Licensed CC0.

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