Program Official

Principal Investigator

Raymond T
Awardee Organization

Massachusetts General Hospital
United States

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

Trial of Statins for Chemoprevention in Hepatocellular Carcinoma

Worldwide, hepatocellular carcinoma (HCC) represents the fifth most common cancer and the second-leading cause of cancer-related mortality. In the U.S., both the HCC incidence and mortality are increasing at an alarming pace. Despite these concerning trends, treatment options for HCC remain limited, and the prognosis is grim, with a 5-year survival rate of just 15%. Thus, identifying effective strategies to prevent the development of incident HCC represents a critical public health need. A growing body of preclinical and population-based observational data now demonstrate that lipophilic statins, and in particular atorvastatin, reduces hepatic inflammation, cellular proliferation and cancer cell invasion, and reduces the incidence of HCC, in part by acting on relevant pathways, including the Hippo-YAP signaling pathway. However, despite these promising data, well-designed randomized controlled trials (RCTs) of atorvastatin for HCC prevention have not yet been reported. Historically, the feasibility of an HCC prevention trial has been limited by large sample size and long lengths of follow-up required to assess target endpoints. Recently, however, our group has derived and validated a 186-gene expression Prognostic Liver Signature (PLS), that represents an accurate, reproducible and highly reliable surrogate biomarker for HCC risk in multiple international cohorts of all major viral and non-viral etiologies of cirrhosis. Further, we have demonstrated that therapeutic modulation of the PLS accurately recapitulates future risk of developing incident HCC tumors, both in vivo and in confirmatory human studies. Finally, we and others have demonstrated in human liver tissue samples that atorvastatin modulates the PLS in part by acting on the Hippo-YAP pathway. Thus, the PLS represents a novel and highly tractable surrogate biomarker endpoint for an RCT of atorvastatin for the reduction of incident HCC risk. In this proposal, we will conduct a phase II RCT in 60 patients with compensated cirrhosis, designed to test the efficacy, safety and tolerability of 48 weeks of atorvastatin for the reduction of HCC risk, defined by our validated PLS profile. All subjects will have a high-risk PLS defined at screening liver biopsy, and subjects will be randomly assigned to 1 of 2 study arms for the 48-week study period: atorvastatin 20mg/day or placebo, with appropriate monitoring for the 48-week period, followed by a repeat biopsy at week 48 to assess for improvement in the PLS profile. We will also confirm whether atorvastatin has adequately engaged its targets by evaluating pharmacokinetics/pharmacodynamics, pre/neoplastic markers, and alteration in the Hippo-YAP pathway. We hypothesize that PLS-based HCC risk level decreases in the atorvastatin arm at the end of 48-week treatment. If atorvastatin treatment is effective, safe and well-tolerated, it could become the first chemopreventive agent designed to prevent the development of HCC, guided by PLS, in the growing population of patients in the U.S. who are affected by cirrhosis and are at high risk for this devastating complication.


  • Singal AG, Zhang E, Narasimman M, Rich NE, Waljee AK, Hoshida Y, Yang JD, Reig M, Cabibbo G, Nahon P, Parikh ND, Marrero JA. HCC surveillance improves early detection, curative treatment receipt, and survival in patients with cirrhosis: A meta-analysis. Journal of hepatology. 2022 Jul;77(1):128-139. Epub 2022 Feb 6. PMID: 35139400
  • Rocha C, Doyle EH, Bowman CA, Fiel MI, Stueck AE, Goossens N, Bichoupan K, Patel N, Crismale JF, Makkar J, Lewis S, Perumalswami PV, Schiano TD, Hoshida Y, Schwartz M, Branch AD. Hepatocellular carcinoma in patients cured of chronic hepatitis C: Minimal steatosis. Cancer medicine. 2023 May;12(9):10175-10186. Epub 2023 Apr 20. PMID: 37078924
  • Lee YT, Fujiwara N, Yang JD, Hoshida Y. Risk stratification and early detection biomarkers for precision HCC screening. Hepatology (Baltimore, Md.). 2023 Jul 1;78(1):319-362. Epub 2022 Oct 11. PMID: 36082510
  • Mender I, Siteni S, Barron S, Flusche AM, Kubota N, Yu C, Cornelius C, Tedone E, Maziveyi M, Grichuk A, Venkateswaran N, Conacci-Sorrell M, Hoshida Y, Kang R, Tang D, Gryaznov S, Shay JW. Activating an Adaptive Immune Response with a Telomerase-Mediated Telomere Targeting Therapeutic in Hepatocellular Carcinoma. Molecular cancer therapeutics. 2023 Jun 1;22(6):737-750. PMID: 37070671
  • Saito Y, Yin D, Kubota N, Wang X, Filliol A, Remotti H, Nair A, Fazlollahi L, Hoshida Y, Tabas I, Wangensteen KJ, Schwabe RF. A Therapeutically Targetable TAZ-TEAD2 Pathway Drives the Growth of Hepatocellular Carcinoma via ANLN and KIF23. Gastroenterology. 2023 Jun;164(7):1279-1292. Epub 2023 Mar 7. PMID: 36894036
  • Zhu S, Kubota N, Wang S, Wang T, Xiao G, Hoshida Y. Single-cell level deconvolution, convolution, and clustering in spatial transcriptomics by aligning spot level transcriptome to nuclear morphology. bioRxiv : the preprint server for biology. 2023 Dec 18. PMID: 38187541
  • Suzuki H, Iwamoto H, Tanaka T, Sakaue T, Imamura Y, Masuda A, Nakamura T, Koga H, Hoshida Y, Kawaguchi T. Fibroblast growth factor inhibition by molecular-targeted agents mitigates immunosuppressive tissue microenvironment in hepatocellular carcinoma. Hepatology international. 2024 Apr;18(2):610-622. Epub 2023 Oct 21. PMID: 37864726
  • Wang X, He Q, Zhou C, Xu Y, Liu D, Fujiwara N, Kubota N, Click A, Henderson P, Vancil J, Marquez CA, Gunasekaran G, Schwartz ME, Tabrizian P, Sarpel U, Fiel MI, Diao Y, Sun B, Hoshida Y, Liang S, Zhong Z. Prolonged hypernutrition impairs TREM2-dependent efferocytosis to license chronic liver inflammation and NASH development. Immunity. 2023 Jan 10;56(1):58-77.e11. Epub 2022 Dec 14. PMID: 36521495
  • Fujiwara N, Kubota N, Zhu S, Nakagawa S, Baba H, Hoshida Y. Disseminative Recurrence Signature for Hepatocellular Carcinoma From Nonalcoholic Fatty Liver Disease. Gastro hep advances. 2023;2(5):681-683. Epub 2023 Mar 20. PMID: 37621719
  • Dhanasekaran R, Suzuki H, Lemaitre L, Kubota N, Hoshida Y. Molecular and immune landscape of hepatocellular carcinoma to guide therapeutic decision-making. Hepatology (Baltimore, Md.). 2023 Jun 12. Epub 2023 Jun 12. PMID: 37300379
  • Wen Z, Lin YH, Wang S, Fujiwara N, Rong R, Jin KW, Yang DM, Yao B, Yang S, Wang T, Xie Y, Hoshida Y, Zhu H, Xiao G. Deep-Learning-Based Hepatic Ploidy Quantification Using H&E Histopathology Images. Genes. 2023 Apr 16;14. (4). PMID: 37107679
  • Kanzaki H, Katz C, Hoshida Y. Matrisomic characterization of HCC to inform individualized patient management. Hepatology (Baltimore, Md.). 2023 Sep 1;78(3):691-693. Epub 2023 May 11. PMID: 37163234
  • Crouchet E, Li S, Sojoodi M, Bandiera S, Fujiwara N, El Saghire H, Zhu S, Qian T, Rasha FA, Del Zompo F, Barrett SC, Schaeffer E, Oudot MA, Ponsolles C, Durand SC, Ghoshal S, Arora G, Giannone F, Chung RT, Slovic N, Van Renne N, Felli E, Pessaux P, Lupberger J, Pochet N, Schuster C, Tanabe KK, Hoshida Y, Fuchs BC, Baumert TF. Hepatocellular carcinoma chemoprevention by targeting the angiotensin-converting enzyme and EGFR transactivation. JCI insight. 2022 Jul 8;7. (13). PMID: 35801591
  • Arvind A, Joshi S, Zaki T, Burkholder D, Parikh ND, Singal AG, North American Liver Cancer (NALC) Consortium, Yekkaluri S, Yokoo T, Fetzer D, Browning T, Rich NE, Khatri G, Zhu H, Hoshida Y, Marrero JA, Yopp AC, Gopal P, Manwaring C. Risk of Hepatocellular Carcinoma in Patients With Indeterminate (LI-RADS 3) Liver Observations. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2023 Apr;21(4):1091-1093.e3. Epub 2021 Dec 10. PMID: 34902571
  • Kim MH, Kim MY, Salloum S, Qian T, Wong LP, Xu M, Lee Y, Shroff SG, Sadreyev RI, Corey KE, Baumert TF, Hoshida Y, Chung RT. Atorvastatin favorably modulates a clinical hepatocellular carcinoma risk gene signature. Hepatology communications. 2022 Sep;6(9):2581-2593. Epub 2022 Jun 16. PMID: 35712812
  • 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
  • Rasha F, Paul S, Simon TG, Hoshida Y. Hepatocellular Carcinoma Chemoprevention with Generic Agents. Seminars in liver disease. 2022 Nov;42(4):501-513. Epub 2022 Sep 14. PMID: 36104114
  • Fujiwara N, Kubota N, Crouchet E, Koneru B, Marquez CA, Jajoriya AK, Panda G, Qian T, Zhu S, Goossens N, Wang X, Liang S, Zhong Z, Lewis S, Taouli B, Schwartz ME, Fiel MI, Singal AG, Marrero JA, Fobar AJ, Parikh ND, Raman I, Li QZ, Taguri M, Ono A, Aikata H, Nakahara T, Nakagawa H, Matsushita Y, Tateishi R, Koike K, Kobayashi M, Higashi T, Nakagawa S, Yamashita YI, Beppu T, Baba H, Kumada H, Chayama K, Baumert TF, Hoshida Y. Molecular signatures of long-term hepatocellular carcinoma risk in nonalcoholic fatty liver disease. Science translational medicine. 2022 Jun 22;14(650):eabo4474. Epub 2022 Jun 22. PMID: 35731891
  • 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 Z, Zhu S, Jia Y, Wang Y, Kubota N, Fujiwara N, Gordillo R, Lewis C, Zhu M, Sharma T, Li L, Zeng Q, Lin YH, Hsieh MH, Gopal P, Wang T, Hoare M, Campbell P, Hoshida Y, Zhu H. Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease. Cell. 2023 Apr 27;186(9):1968-1984.e20. Epub 2023 Apr 10. PMID: 37040760
  • Qian T, Fujiwara N, Koneru B, Ono A, Kubota N, Jajoriya AK, Tung MG, Crouchet E, Song WM, Marquez CA, Panda G, Hoshida A, Raman I, Li QZ, Lewis C, Yopp A, Rich NE, Singal AG, Nakagawa S, Goossens N, Higashi T, Koh AP, Bian CB, Hoshida H, Tabrizian P, Gunasekaran G, Florman S, Schwarz ME, Hiotis SP, Nakahara T, Aikata H, Murakami E, Beppu T, Baba H, Rew Warren, Bhatia S, Kobayashi M, Kumada H, Fobar AJ, Parikh ND, Marrero JA, Rwema SH, Nair V, Patel M, Kim-Schulze S, Corey K, O'Leary JG, Klintmalm GB, Thomas DL, Dibas M, Rodriguez G, Zhang B, Friedman SL, Baumert TF, Fuchs BC, Chayama K, Zhu S, Chung RT, Hoshida Y. Molecular Signature Predictive of Long-Term Liver Fibrosis Progression to Inform Antifibrotic Drug Development. Gastroenterology. 2022 Apr;162(4):1210-1225. Epub 2021 Dec 22. PMID: 34951993
  • Simon TG, Wilechansky RM, Stoyanova S, Grossman A, Dichtel LE, Lauer GM, Miller KK, Hoshida Y, Corey KE, Loomba R, Chung RT, Chan AT. Aspirin for Metabolic Dysfunction-Associated Steatotic Liver Disease Without Cirrhosis: A Randomized Clinical Trial. JAMA. 2024 Mar 19;331(11):920-929. PMID: 38502074
  • Verrier ER, Ligat G, Heydmann L, Doernbrack K, Miller J, Maglott-Roth A, Jühling F, El Saghire H, Heuschkel MJ, Fujiwara N, Hsieh SY, Hoshida Y, Root DE, Felli E, Pessaux P, Mukherji A, Mailly L, Schuster C, Brino L, Nassal M, Baumert TF. Cell-based cccDNA reporter assay combined with functional genomics identifies YBX1 as HBV cccDNA host factor and antiviral candidate target. Gut. 2022 Dec 9;72(9):1745-57. Epub 2022 Dec 9. PMID: 36591611