# Targeting Ischemia-Induced Dependencies on the Metabolic Stress Response in Hepatocellular Carcinoma Through Image-Guided, Locoregional Therapy

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $417,256

## Abstract

Surgical resection or liver transplantation remain the only curative options for patients with hepatocellular
carcinoma (HCC). However, fewer than 20% of patients with HCC are candidates for resection. Transarterial
chemoembolization (TACE) is an endovascular locoregional embolotherapy that involves hepatic artery
embolization with intra-arterial infusion of a chemotherapeutic agent and is considered the standard of care for
treating unresectable HCC in the remaining 80% of patients with this disease. While TACE has a proven survival
benefit, local recurrence is common, and long-term survival rates are poor. Moreover, only 44% of treated HCCs
demonstrate extensive necrosis on pathology following TACE, indicating that tumor cells develop an adaptive
metabolic stress response (MSR) enabling their survival under TACE-induced nutrient and oxygen deprivation.
In preliminary studies, we have demonstrated that HCC cells may be pre-programmed to survive TACE-induced
ischemia through enhanced function of the MSR, including autophagy and hypoxia-inducible factors (HIFs).
Moreover, TACE-induced ischemia results in quiescence in surviving HCC cells and further activation of the
MSR. These data demonstrate that TACE offers a unique opportunity to constrain metabolic phenotypes in order
to generate targetable dependencies in HCC. The proposed project will build on this prior work to: 1) further
characterize the role of targetable MSR pathways in enabling HCC cell survival under TACE-like ischemia and
2) validate a synergistic therapeutic strategy that targets this MSR dependence in order to define a novel, and
more effective, approach to TACE. Gene editing will be used to examine the roles of fructose bisphosphatase 1
and urea cycle enzymes in influencing the basal activity of HIFs and autophagy, respectively in HCC cells. The
dependence of HCC cell survival on each of the MSR pathways individually and in combination will be
determined through gene editing and pharmacologic inhibition. Our recently developed, unique autochthonous
rat model of HCC and TACE will be utilized to assess the TACE-induced essentiality of each MSR pathway in
vivo using pharmacological inhibitors of the MSR.
We hypothesize that the induction of quiescence in HCC cells surviving TACE-induced ischemia renders them
dependent on MSR pathways which can be targeted to potentiate the cytotoxic effects of TACE. To test this
hypothesis the proposed project will pursue three aims: (1) to define genetic alterations that contribute to
molecular and cellular stress response pathway activation in HCC in vitro and in vivo; (2) to functionally
demonstrate the dependence of HCC cells surviving severe ischemia on induction of the MSR in vitro; and (3)
to determine the efficacy of potentiating TACE-induced ischemia by individual and simultaneous pharmacologic
targeting of the MSR in vivo. Importantly, the proposed project emphasizes a translational approach, so that the
achievement of these aims will dir...

## Key facts

- **NIH application ID:** 10400072
- **Project number:** 5R01CA234005-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Terence P Gade
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $417,256
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10400072

## Citation

> US National Institutes of Health, RePORTER application 10400072, Targeting Ischemia-Induced Dependencies on the Metabolic Stress Response in Hepatocellular Carcinoma Through Image-Guided, Locoregional Therapy (5R01CA234005-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10400072. Licensed CC0.

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