# Targeting Ischemia-Induced Autophagy Dependence in hepatocellular Carcinoma through Image-guided Locoregional Therapy

> **NIH VA I01** · PHILADELPHIA VA MEDICAL CENTER · 2024 · —

## 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
embolization with or without chemotherapy (TA(C)E) is an endovascular locoregional embolotherapy that
involves hepatic artery embolization with intra-arterial infusion of a chemotherapeutic agent. TA(C)E is
considered the standard of care for treating unresectable HCC in the remaining 80% of patients. While TA(C)E
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 TA(C)E, indicating tumor cells
develop an adaptive metabolic stress response (MSR) enabling their survival under TA(C)E-induced nutrient
and oxygen deprivation.
In preliminary studies, we have demonstrated that HCC cells are pre-programmed to survive TA(C)E-induced
ischemia through enhanced function of autophagy. Moreover, TA(C)E-induced ischemia results in quiescence
in surviving HCC cells and a dependence on autophagy. As such, these data demonstrate that TA(C)E offers a
unique opportunity to constrain metabolic phenotypes in order to generate this targetable dependency in HCC.
The proposed project will build on this prior work to: 1) study a novel TA(C)E paradigm which targets this
ischemia-induced dependency on autophagy using hydroxychloroquine (HCQ) and 2) characterizes the efficacy
and evolution of autophagy inhibition using HCQ as well as associated alterations in anti-tumor immunity. To
achieve these goals, this submission proposes a first in human, early phase prospective clinical trial to
assess the safety and efficacy of autophagy inhibition using intra-arterial (IA) HCQ with TAE followed by
maintenance of autophagy inhibition with daily oral HCQ for 6 weeks following embolization. Follow-up tumor
biopsies and serum sampling 3-4 and 5-6 weeks after embolization will inform on the on-target efficacy of
autophagy inhibition and its effect on the tumor microenvironment and immune response.
We hypothesize that the induction of quiescence in HCC cells surviving embolization-induced ischemia renders
them dependent on autophagy which can be targeted to potentiate the cytotoxic effects of TAE as well enhance
the anti-tumor immune response. To test this hypothesis the proposed project will pursue three aims: (1) to
establish the clinical safety of the combination of the autophagy inhibitor HCQ with TAE to treat patients with
intermediate stage HCC (phase 1); (2) to compare the short-term efficacy of HCQ with TAE versus TAE alone
in patients with intermediate stage HCC (phase 2); and (3) to characterize differences in local and systemic
immune modulation following TAE as compared to IA HCQ TAE. The achievement of the proposed aims holds
the potential to transform treatment paradigms for patients with unresectable HCC, an incurable disease.

## Key facts

- **NIH application ID:** 10841397
- **Project number:** 5I01CX002542-02
- **Recipient organization:** PHILADELPHIA VA MEDICAL CENTER
- **Principal Investigator:** Terence P Gade
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2023-08-01 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10841397

## Citation

> US National Institutes of Health, RePORTER application 10841397, Targeting Ischemia-Induced Autophagy Dependence in hepatocellular Carcinoma through Image-guided Locoregional Therapy (5I01CX002542-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10841397. Licensed CC0.

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