Program Official

Principal Investigator

Yujin
Hoshida
Awardee Organization

Ut Southwestern Medical Center
United States

Fiscal Year
2024
Activity Code
U01
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Therapeutic modulation of a proteomic HCC risk signature with statins in patients with liver cirrhosis

Hepatocellular carcinoma (HCC) is a major cirrhosis complication producing an alarming rise in mortality. The prognosis for HCC is poor due to extremely high recurrence rate even after curative-intent surgical therapies and limited efficacy of available medical therapies. Given its refractory nature, prevention of HCC in cirrhosis patients will be the most impactful strategy to improve its poor prognosis; however, effective HCC prevention remains a major unmet need. Retrospective and pre-clinical studies have suggested that statins are a viable form of HCC chemoprevention, with a differential effect between lipophilic and hydrophilic statins. Further evidence suggests that statins may modulate HCC risk through Hedgehog and Hippo signaling pathways. However, the clinical validation of statins has been hampered by the requirement for large and lengthy clinical trials to define their clinical utility. To overcome these challenges, we have developed a serum-based HCC risk biomarker, the Prognostic Liver Secretome signature (PLSec). Of note, PLSec is therapeutically modifiable and the magnitude of PLSec modulation is associated with future HCC incidence as demonstrated by our previous and preliminary studies. In a retrospective case-control series, PLSec-based HCC risk level was lower in cirrhosis patients on statins compared to non-users. Based on these observations, PLSec is now being tested as a surrogate endpoint in HCC chemoprevention trials of atorvastatin (TORCH trial). To achieve the goal of establishing statins as viable HCC chemoprevention with PLSec as a surrogate endpoint, we have assembled a team of cirrhosis and HCC experts to analyze serum samples from three nation-wide multi-center prospective cohorts (Liver Cirrhosis Network, Southern Liver Health Study, and Mass General Brigham cohorts) and two randomized controlled trials (TORCH and LCN RESCU trials). Aim 1. Validate lower biomarker-based HCC risk level in cirrhosis patients on statins compared to non-users. We will validate our preliminary finding in prospective case-control series of cirrhosis patients form the three cohorts. We will explore patient characteristics and types of statins associated with the PLSec-based HCC risk level, along with mechanistic markers of Hedgehog/Hippo signaling. Aim 2. Determine magnitude of biomarker-based HCC risk modulation after starting or stopping statins. We will conduct target trial emulation mimicking single-arm clinical trials with statins to determine the magnitude of PLSec modulation in patients who start or stop statins from three cohorts. We will explore patient characteristics and types of statins associated with PLSec-based HCC risk modulation, along with mechanistic markers. Aim 3. Compare biomarker-based HCC risk modulation between lipophilic and hydrophilic statins. We will compare the magnitude of placebo-adjusted PLSec modulation between lipophilic (atorvastatin) and hydrophilic (rosuvastatin) statins by analyzing serum samples from two parallel randomized clinical trials. We will explore patient characteristics associated with differential PLSec modulation, along with mechanistic markers. Our strategy showcases a novel approach to substantially advance clinical translation of HCC chemoprevention therapies.
  • Macias RIR, Kanzaki H, Berasain C, Avila MA, Marin JJG, Hoshida Y. The Search for Risk, Diagnostic, and Prognostic Biomarkers of Cholangiocarcinoma and Their Biological and Clinicopathologic Significance. The American journal of pathology. 2025 Mar;195(3):422-436. Epub 2024 Aug 3. PMID: 39103092
  • Ge X, Subramaniyam N, Song Z, Desert R, Han H, Das S, Komakula SSB, Wang C, Lantvit D, Ge Z, Hoshida Y, Nieto N. Post-translational modifications drive the effects of HMGB1 in alcohol-associated liver disease. Hepatology communications. 2024 Oct 17;8. (11). doi: 10.1097/HC9.0000000000000549. eCollection 2024 Nov 1. PMID: 39760999
  • Kanzaki H, Hoshida Y. Transcriptomic signature in advanced hepatocellular carcinoma tissue to predict combination immunotherapy response: Editorial on "Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: Insights from the IMbrave150 trial". Clinical and molecular hepatology. 2025 Jan;31(1):308-310. Epub 2024 Aug 30. PMID: 39218442
  • Kanzaki H, Hoshida Y. Reply to correspondence on "Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: Insights from the IMbrave150 trial". Clinical and molecular hepatology. 2025 Jan;31(1):e121-e122. Epub 2024 Oct 11. PMID: 39391909
  • Suzuki H, Mishra S, Paul S, Hoshida Y. Molecular and immune landscape of hepatocellular carcinoma for therapeutic development. Journal of liver cancer. 2024 Dec 6. Epub 2024 Dec 6. PMID: 39639434
  • Tanabe KK, Zahrieh D, Strand CA, Hoshida Y, Flotte TJ, Della'Zanna G, Umar A, Chavin KD, Cleary S, Kubota N, Llovet JM, Patel T, Siegel C, Limburg PJ. Epidermal Growth Factor Receptor Inhibition With Erlotinib in Liver: Dose De-Escalation Pilot Trial as an Initial Step in a Chemoprevention Strategy. Gastro hep advances. 2024 Jan 29;3(3):426-439. doi: 10.1016/j.gastha.2024.01.009. eCollection 2024. PMID: 39131140
  • Wang H, Chen X. Hydrodynamic Injection for Developing NASH Model. Methods in molecular biology (Clifton, N.J.). 2022;2455:31-39. PMID: 35212983
  • Macdonald JK, Taylor HB, Wang M, Delacourt A, Edge C, Lewin DN, Kubota N, Fujiwara N, Rasha F, Marquez CA, Ono A, Oka S, Chayama K, Lewis S, Taouli B, Schwartz M, Fiel MI, Drake RR, Hoshida Y, Mehta AS, Angel PM. The Spatial Extracellular Proteomic Tumor Microenvironment Distinguishes Molecular Subtypes of Hepatocellular Carcinoma. Journal of proteome research. 2024 Sep 6;23(9):3791-3805. Epub 2024 Jul 9. PMID: 38980715
  • Mukherji A, Jühling F, Simanjuntak Y, Crouchet E, Del Zompo F, Teraoka Y, Haller A, Baltzinger P, Paritala S, Rasha F, Fujiwara N, Gadenne C, Slovic N, Oudot MA, Durand SC, Ponsolles C, Schuster C, Zhuang X, Holmes J, Yeh ML, Abe-Chayama H, Heikenwälder M, Sangiovanni A, Iavarone M, Colombo M, Foung SKH, McKeating JA, Davidson I, Yu ML, Chung RT, Hoshida Y, Chayama K, Lupberger J, Baumert TF. An atlas of the human liver diurnal transcriptome and its perturbation by hepatitis C virus infection. Nature communications. 2024 Aug 29;15(1):7486. PMID: 39209804
  • Rezaee-Zavareh MS, Koltsova EK, Hoshida Y, Yang JD. Primary liver cancer spectrum: current knowledge and the next steps. Hepatobiliary surgery and nutrition. 2024 Feb 1;13(1):157-160. Epub 2024 Jan 15. PMID: 38322221
  • Zhu S, Kubota N, Wang S, Wang T, Xiao G, Hoshida Y. STIE: Single-cell level deconvolution, convolution, and clustering in in situ capturing-based spatial transcriptomics. Nature communications. 2024 Aug 30;15(1):7559. PMID: 39214995
  • Wang H, Zhang S, Zhang Y, Jia J, Wang J, Liu X, Zhang J, Song X, Ribback S, Cigliano A, Evert M, Liang B, Wu H, Calvisi DF, Zeng Y, Chen X. TAZ is indispensable for c-MYC-induced hepatocarcinogenesis. Journal of hepatology. 2022 Jan;76(1):123-134. Epub 2021 Aug 28. PMID: 34464659
  • Lu C, Pankaj A, Raabe M, Nawrocki C, Liu A, Xu N, Patel BK, Emmett MJ, Coley AK, Ferrone CR, Deshpande V, Bhan I, Hoshida Y, Ting DT, Aryee MJ, Franses JW. HCC spatial transcriptomic profiling reveals significant and potentially targetable cancer-endothelial interactions. Hepatology communications. 2024 Sep 27;8. (10). doi: 10.1097/HC9.0000000000000533. eCollection 2024 Oct 1. PMID: 39330965
  • Roca Suarez AA, Jühling F, Moehlin J, Mailly L, Virzì A, Brignon N, Durand SC, Oudot MA, Schaeffer E, Martin R, Meiss-Heydmann L, Bach C, Boulahtouf Z, Girard L, Osswald E, Jamey C, Brumaru D, Dali-Youcef N, Mukherji A, Saez-Palma M, Testoni B, Zoulim F, Koneru B, Fujiwara N, Hoshida Y, Felli E, Pessaux P, Tremblay ML, Parent R, Schuster C, Baumert TF, Lupberger J. Protein tyrosine phosphatase delta is a STAT3-phosphatase and suppressor of metabolic liver disease. eGastroenterology. 2025 Jan 27;3(1):e100159. doi: 10.1136/egastro-2024-100159. eCollection 2025 Jan. PMID: 40124988
  • Wang H, Zhou Y, Xu H, Wang X, Zhang Y, Shang R, O'Farrell M, Roessler S, Sticht C, Stahl A, Evert M, Calvisi DF, Zeng Y, Chen X. Therapeutic efficacy of FASN inhibition in preclinical models of HCC. Hepatology (Baltimore, Md.). 2022 Oct;76(4):951-966. Epub 2022 Feb 16. PMID: 35076948
  • Hsiehchen D, Beg MS, Kainthla R, Lohrey J, Kazmi SM, Khosama L, Maxwell MC, Kline H, Katz C, Hassan A, Kubota N, Siglinsky E, Pillai AK, Youssoufian H, Mockbee C, Culm K, Uhlik M, Benjamin L, Brekken RA, Ahn C, Singal AG, Zhu H, Hoshida Y, Yopp AC. The phosphatidylserine targeting antibody bavituximab plus pembrolizumab in unresectable hepatocellular carcinoma: a phase 2 trial. Nature communications. 2024 Mar 11;15(1):2178. PMID: 38467639
  • Wang M, Grauzam S, Bayram MF, Dressman J, DelaCourt A, Blaschke C, Liang H, Scott D, Huffman G, Black A, Ochoa-Rios S, Lewin D, Angel PM, Drake RR, Ball L, Bethard J, Castellino S, Kono Y, Kubota N, Hoshida Y, Quirk L, Yopp A, Gopal P, Singal A, Mehta AS. Spatial omics-based machine learning algorithms for the early detection of hepatocellular carcinoma. Communications medicine. 2024 Dec 3;4(1):258. PMID: 39627514
  • Song X, Xu H, Wang P, Wang J, Affo S, Wang H, Xu M, Liang B, Che L, Qiu W, Schwabe RF, Chang TT, Vogl M, Pes GM, Ribback S, Evert M, Chen X, Calvisi DF. Focal adhesion kinase (FAK) promotes cholangiocarcinoma development and progression via YAP activation. Journal of hepatology. 2021 Oct;75(4):888-899. Epub 2021 May 28. PMID: 34052254
  • Kao SZ, Sangha K, Fujiwara N, Hoshida Y, Parikh ND, Singal AG. Cost-effectiveness of a precision hepatocellular carcinoma surveillance strategy in patients with cirrhosis. EClinicalMedicine. 2024 Aug 13;75:102755. doi: 10.1016/j.eclinm.2024.102755. eCollection 2024 Sep. PMID: 39234558
  • Singal AG, Quirk L, Boike J, Chernyak V, Feng Z, Giamarqo G, Kanwal F, Ioannou GN, Manes S, Marrero JA, Mehta N, Pillai A, Shaheen NJ, Shaukat A, Sirlin CB, Verna E, Wani S, Wilson Woods A, Yang JD, Parikh ND. Value of HCC surveillance in a landscape of emerging surveillance options: Perspectives of a multi-stakeholder modified Delphi panel. Hepatology (Baltimore, Md.). 2024 Dec 18. Epub 2024 Dec 18. PMID: 39699563
  • Almazan E, Chung RT. Association of Statin, Metformin, and Aspirin Use With Hepatocellular Carcinoma in the All of Us Research Program. Gastro hep advances. 2024 Aug 24;4(1):100535. doi: 10.1016/j.gastha.2024.08.014. eCollection 2025. PMID: 39758847