Among human malignancies, primary liver tumors account for 9% of all cancer deaths worldwide and 12% in developingcountries.HCCaccountsforupto85%oflivercancersandisoneoftheleadinglethalmalignancies worldwide. Chronic liver damage caused by viral infection (HBV and HCV), alcohol, non-alcoholic fatty liver disease (NAFLD)-associated chronic inflammation, fibrosis, cirrhosis, or a combination of these factors increasestheriskforHCC.Notably,NAFLD,ahepaticmanifestationofmetabolicsyndrome,affectsnearly25% of the US population, and its incidence is rapidly increasing since obesity and metabolic syndrome are growing epidemics worldwide. Although the risk factors are well defined, HCC is still an aggressive and difficult-to-treat malignant disease with poor outcome and limited therapeutic options. In fact, major obstacles for effective treatment of this cancer is that HCC is frequently resistant to chemotherapy and radiotherapy, and there is a high frequency of tumor recurrence after curative surgical resection. Currently, there is a strong rationale for immuneinterventioninHCC,butrecentclinicaltrialshavedemonstratedthatthebenefitsofimmunotherapyare relegated to a small fraction (~20%) of cancer patients, including these with HCC. This prompts the need for greater understanding of the mechanisms underlying liver cancer cell plasticity and adaptation, as well as developingnoveltherapeuticapproachestoachievemoreeffectiveandselectivecureofthisdisease. Hsf1, as the master activator of the classical heat shock response and guardian of the proteome, has been implicated in the pathogenesis of cancer. We have discovered that genetic inactivation of Hsf1 in pre-clinical mouse cancer models leads to remarkable inhibition of HCC development. On the basis of published and preliminary studies we propose a novel pathogenic mechanism whereby Hsf1 activation promotes HCC development by stimulating both the protein folding capacity of the cell and regulating anabolic metabolic pathways, thus perpetuating chronic hepatic metabolic disease. Our recent research revealed that the Hsf1 transcriptional program enables malignant cells to escape immune surveillance. This may provide a new approach to improve HCC treatment by improving the anti-tumor immune capacity targeting Hsf1 activity. Our experimentalstrategyentailsthefollowingthreemajorapproaches:1.Determinetheimpactofhsf1deletionon livercancerinitiationandexploreitstherapeuticimplicationsforadvancedHCC,2.Determinethemetabolicand epigenetic mechanisms by which Hsf1 ablation induces an effective anti-tumor CD8+ T cell response, and 3. Investigate the impact of Hsf1 deletion on improved CD8+ T cell-based immunotherapy for HCC. In summary, the long-term translational goal of the project is to test the potential of Hsf1 targeting in human HCC. It will also provide proof-of-concept for targeting Hsf1-mediated metabolic programs for immunotherapeutic application of livercancer.

Public Health Relevance

Therapeutic exploitation of oncogene addiction has become a central aim of modern cancer therapy, but effectivetargetedtherapiesforaggressivecancertypesincludinghepatocellularcarcinoma(HCC)arelacking. In this proposal, a collaborating team of experts will investigate whether a valid approach for therapeutic interventions in HCC can be based on a strategy to inhibit supportive non-oncogene addiction pathways, interfering with tumor-promoting metabolic reprogramming and improving the predicted power of anti-tumor immunity through depletion of Hsf1. This research will provide the rationale to develop novel strategies to prevent,andperhapstreat,cancers,includingHCC,thatariseonthebackgroundofchronichepaticinjurydue toimpairedlivermetabolism,proteinhomeostasisandsuppressionofanti-tumorimmunity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA062130-25
Application #
10107775
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Mccarthy, Susan A
Project Start
1996-07-01
Project End
2025-01-31
Budget Start
2021-02-01
Budget End
2022-01-31
Support Year
25
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Augusta University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
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Jin, Xiongjie; Qiao, Aijun; Moskophidis, Demetrius et al. (2018) Modulation of Heat Shock Factor 1 Activity through Silencing of Ser303/Ser307 Phosphorylation Supports a Metabolic Program Leading to Age-Related Obesity and Insulin Resistance. Mol Cell Biol 38:
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Eroglu, Binnur; Min, Jin-Na; Zhang, Yan et al. (2014) An essential role for heat shock transcription factor binding protein 1 (HSBP1) during early embryonic development. Dev Biol 386:448-60
Eroglu, Binnur; Kimbler, Donald E; Pang, Junfeng et al. (2014) Therapeutic inducers of the HSP70/HSP110 protect mice against traumatic brain injury. J Neurochem 130:626-41

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