Liver Cancer Program: For Researchers
Liver cancer patients suffer not only from the burden of tumors, but also from the compromised diseased state of the liver. The asymptomatic nature of early liver disease precludes our ability to effectively detect signs of liver cancer before significant disease progression.
Therefore, strategies to identify liver disease status with proclivity towards tumor formation are in dire need. Current efforts include the detection and evaluation of novel biomarkers among patients with chronic liver disease, such as hepatitis viral infection, non-alcoholic fatty liver disease (NASH), alcoholic liver disease.
Additional efforts aim to explore predictive signatures or algorithms for liver cancer initiation.
Patients with liver cancer are currently diagnosed via imaging (ultrasound, CT scan and MRI), but most are at advanced stages of disease with limited treatment options. Liver function tests are also used in diagnosis, but parameters such as alpha-fetoprotein (AFP) are not sensitive or specific. Thus, novel diagnostic tools are highly warranted for liver cancer.
We are currently examining several parameters of tumor biology and the liver microenvironment, including cellular immunity and inflammation factors, metabolic species and the microbiome to identify biomarkers linked to liver cancer.
Approaches include, but are not limited to, exome sequencing of bulk tumors; single cell transcriptome sequencing of tumor core/resection biopsies and circulating tumor cells (CTC) as well as tumor-associated immune cells, tumor organoid culture models, PDX models, 3D-multiplex cell imaging-based technologies and artificial intelligence (AI)-guided multimodality imaging coupled to genomics (radiomics).
Liver cancer is a complex, multifactorial disease, contributing to a significant global health burden. The establishment of patient populations with well-annotated biobanks and well-characterized molecular features is essential to understanding its underlying biology and developing effective strategies for its detection and treatment. To this end, we have successfully established large population-based studies including:
- The Thailand Initiative for Genomics and Expression Research in Liver Cancer (TIGER-LC) consortium aims to recruit 6,000 liver cancer patients in Thailand and matched high risk and population controls.
- The Maryland Liver Cancer Study aims to recruit 2,000 liver cancer patients in the greater Baltimore area in Maryland, U.S.A. at the University of Maryland at Baltimore and the Veterans Affairs (VA) Maryland Healthcare System, along with matched high risk and population controls (https://clinicaltrials.gov; NCT00913757).
These studies aim to identify genomic, genetic, etiological and environmental factors that modify liver cancer risk, susceptibility and progression. Comprehensive and comparative biological and clinical analyses will also promote a greater understanding of heath disparity, environmental and etiological factors contributing to liver cancers across populations of different ethnicity and race.
One of main reasons why survival for patients with liver cancer has not improved in the past twenty years is the lack of approved novel therapies. Multiple phase III studies have failed to demonstrate any survival advantage for patients with liver cancer.
The advent of immunotherapy and biologicals and the implementation of precision cancer management strategy may dramatically shift this situation.
Our capacity to realign the immune response to improve patient response to treatment and outcome is being tested. Current pilot strategies include chimeric antigen receptors (CARs) and antibody conjugates such as Glypican-3 (GPC-3) and other means to enhance adaptive and innate immune responses in patients with HCC.
Expected Interactions and Synergies
The central idea of this proposal is to plant a seed, which allows for crystallization of different research activities in liver cancer research including scientists from NCI, NIH, academic institutions from the Washington area as well selected other extramural sites.
Engagement of Extramural Investigators
One of the central aims of the NCI-CCR-LCP is to foster collaborations between intra-mural and extramural investigators with an interest in liver cancer research. We plan to initiate and support these collaborations at every level.
NCI CLARITY Study
Cancers of the Liver: Accelerating Research of Immunotherapy by a TransdisciplinarY Network The study aims to provide ‘clarity’ on who responds/does not respond to immunotherapy.
Contact us for additional information about our programs.
A Viral Exposure Signature Defines Early Onset of Hepatocellular Carcinoma.
Liu J, Tang W, Budhu A, Forgues M, Hernandez MO, Candia J, Kim Y, Bowman ED, Ambs S, Zhao Y, Tran B, Wu X, Koh C, Surana P, Liang TJ, Guarnera M, Mann D, Rajaure M, Greten TF, Wang Z, Yu H, Wang XW.
Cell. Published online June 10, 2020.
Persistent Polyfunctional Chimeric Antigen Receptor T Cells That Target Glypican 3 Eliminate Orthotopic Hepatocellular Carcinomas in Mice.
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Understanding the Cause and Consequence of Tumor Heterogeneity.
Khatib, S, Yotsawat, P, Hien, D, Wang XW.
Trends in Cancer. Apr;6(4) 267-271, 2020.
Tumor Cell Biodiversity Drives Microenvironmental Reprogramming in Liver Cancer.
Ma L, Hernandez MO, Zhao Y, Mehta M, Tran B, Kelly M, Rae Z, Hernandez JM, Davis JL, Martin SP, Kleiner DE, Hewitt SM, Ylaya K, Wood BJ, Greten TF, Wang XW.
Cancer Cell. Oct 14;36(4):418-430, 2019.
Non-proteolytic ubiquitin modification of PPARγ by Smurf1 protects the liver from steatosis.
Zhu K, Tang Y, Xu X, Dang H, Tang LY, Wang X, Wang XW, Zhang YE.
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Single-cell analysis reveals cancer stem cell heterogeneity in hepatocellular carcinoma.
Zheng H, Pomyen Y, Hernandez MO, Li C, Livak F, Tang W, Dang H, Greten TF, Davis JL, Zhao Y, Mehta M, Levin Y, Shetty J, Tran B, Budhu A, Wang XW.
Hepatology. Jul;68(1):127-140, 2018.
Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells.
Ma C, Han M, Heinrich B, Fu Q, Zhang Q, Sandhu M, Agdashian D, Terabe M, Berzofsky JA, Fako V, Ritz T, Longerich T, Theriot CM, McCulloch JA, Roy S, Yuan W, Thovarai V, Sen SK, Ruchirawat M, Korangy F, Wang XW, Trinchieri G, Greten TF.
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An unbiased in vivo functional genomics screening approach in mice identifies novel tumor cell-based regulators of immune rejection.
Shuptrine CW, Ajina R, Fertig EJ, Jablonski SA, Kim Lyerly H, Hartman ZC, Weiner LM.
Cancer Immunol Immunother. Dec;66(12):1529-1544, 2017.
Common Molecular Subtypes Among Asian Hepatocellular Carcinoma and Cholangiocarcinoma.
Chaisaingmongkol J, Budhu A, Dang H, Rabibhadana S, Pupacdi B, Kwon SM, Forgues M, Pomyen Y, Bhudhisawasdi V, Lertprasertsuke N, Chotirosniramit A, Pairojkul C, Auewarakul CU, Sricharunrat T, Phornphutkul K, Sangrajrang S, Cam M, He P, Hewitt SM, Ylaya K, Wu X, Andersen JB, Thorgeirsson SS, Waterfall JJ, Zhu YJ, Walling J, Stevenson HS, Edelman D, Meltzer PS, Loffredo CA, Hama N, Shibata T, Wiltrout RH, Harris CC, Mahidol C, Ruchirawat M, Wang XW. TIGER-LC Consortium.
Cancer Cell. Jul 0;32(1):57-70.e3, 2017.
Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma.
Cancer Genome Atlas Research Network.
Cell. Jun 15;169(7):1327-1341.e23, 2017.
Mechanisms of hepatic stellate cell activation.
Tsuchida T, Friedman SL.
Nat Rev Gastroenterol Hepatol. Jul;14(7):397-411, 2017.
Transcriptional Induction of Periostin by a Sulfatase 2-TGFβ1-SMAD Signaling Axis Mediates Tumor Angiogenesis in Hepatocellular Carcinoma.
Chen G, Nakamura I, Dhanasekaran R, Iguchi E, Tolosa EJ, Romecin PA, Vera RE, Almada LL, Miamen AG, Chaiteerakij R, Zhou M, Asiedu MK, Moser CD, Han S, Hu C, Banini BA, Oseini AM, Chen Y, Fang Y, Yang D, Shaleh HM, Wang S, Wu D, Song T, Lee JS, Thorgeirsson SS, Chevet E, Shah VH, Fernandez-Zapico ME, Roberts LR.
Cancer Res. Feb 1;77(3):632-645, 2017.
DNAJB1-PRKACA fusion kinase interacts with b-catenin and the liver regenerative response to drive fibrolamellar hepatocellular carcinoma.
Kastenhuber ER, Lalazar G, Houlihan SL, Tschaharganeh DF, Baslan T, Chen CC, Requena D, Tian S, Bosbach B, Wilkinson JE, Simon SM, Lowe SW.
Proc. Natl. Acad. Sci. U.S.A. 114: 13076-13084, 2017.
Analysis of long noncoding RNA expression in hepatocellular carcinoma of different viral etiology.
Zhang Q, Matsuura K, Kleiner DE, Zamboni F, Alter HJ, Farci P.
J Transl Med. Nov 28;14(1):328, 2016.
Telomere Length and Survival of Patients with Hepatocellular Carcinoma in the United States.
Yang B, Shebl FM, Sternberg LR, Warner AC, Kleiner DE, Edelman DC, Gomez A, Dagnall CL, Hicks BD, Altekruse SF, Hernandez BY, Lynch CF, Meltzer PS, McGlynn KA.
PLoS One. Nov 23;11(11):e0166828, 2016.
Distinct Functions of Senescence-Associated Immune Responses in Liver Tumor Surveillance and Tumor Progression.
Eggert T, Wolter K, Ji J, Ma C, Yevsa T, Klotz S, Medina-Echeverz J, Longerich T, Forgues M, Reisinger F, Heikenwalder M, Wang XW, Zender L, Greten TF.
Cancer Cell. Oct 10;30(4):533-547, 2016.
A MYC-aurora kinase A protein complex represents an actionable drug target in p53-altered liver cancer.
Dauch D, Rudalska R, Cossa G, Nault JC, Kang TW, Wuestefeld T, Hohmeyer A, Imbeaud S, Yevsa T, Hoenicke L, Pantsar T, Bozko P, Malek NP, Longerich T, Laufer S, Poso A, Zucman-Rossi J, Eilers M, Zender L.
Nat Med. Jul;22(7):744-53, 2016.
A hepatic stellate cell gene expression signature associated with outcomes in hepatitis C cirrhosis and hepatocellular carcinoma after curative resection.
Zhang DY, Goossens N, Guo J, Tsai MC, Chou HI, Altunkaynak C, Sangiovanni A, Iavarone M, Colombo M, Kobayashi M, Kumada H, Villanueva A, Llovet JM, Hoshida Y, Friedman SL.
Gut. Oct;65(10):1754-64, 2016.
Liver kinase B1 regulates hepatocellular tight junction distribution and function in vivo.
Porat-Shliom N, Tietgens AJ, Van Itallie CM, Vitale-Cross L, Jarnik M, Harding OJ, Anderson JM, Gutkind JS, Weigert R, Arias IM.
Hepatology. Oct;64(4):1317-29, 2016.
p53-dependent Nestin regulation links tumor suppression to cellular plasticity in liver cancer.
Tschaharganeh DF, Xue W, Calvisi DF, Evert M, Michurina TV, Dow LE, Banito A, Katz SF, Kastenhuber ER, Weissmueller S, Huang CH, Lechel A, Andersen JB, Capper D, Zender L, Longerich T, Enikolopov G, Lowe SW.
Cell. Jul 31;158(3):579-92, 2014. Erratum in: Cell. Jun 2;165(6):1546-154, 2016.
Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signaling and protein synthesis.
Gao W, Tang Z, Zhang YF, Feng M, Qian M, Dimitrov DS, Ho M.
Nat Commun. Mar 11; 6:6536, 2015.
c-Abl modulates tumor cell sensitivity to antibody-dependent cellular cytotoxicity.
Murray JC, Aldeghaither D, Wang S, Nasto RE, Jablonski SA, Tang Y, Weiner LM.
Cancer Immunol Res. Dec;2(12):1186-98, 2014.
Therapeutically targeting glypican-3 via a conformation-specific single-domain antibody in hepatocellular carcinoma.
Feng M, Gao W, Wang R, Chen W, Man YG, Figg WD, Wang XW, Dimitrov DS, Ho M.
Proc Natl Acad Sci U S A. Mar 19;110(12):E1083-91, 2013.
Senescence surveillance of pre-malignant hepatocytes limits liver cancer development.
Kang TW, Yevsa T, Woller N, Hoenicke L, Wuestefeld T, Dauch D, Hohmeyer A, Gereke M, Rudalska R, Potapova A, Iken M, Vucur M, Weiss S, Heikenwalder M, Khan S, Gil J, Bruder D, Manns M, Schirmacher P, Tacke F, Ott M, Luedde T, Longerich T, Kubicka S, Zender L.
Nature. Nov 9;479(7374):547-51, 2011.
Selective killing of tumor neovasculature paradoxically improves chemotherapy delivery to tumors.
Escorcia FE, Henke E, McDevitt MR, Villa CH, Smith-Jones P, Blasberg RG, Benezra R, Scheinberg DA.
Cancer Res. Nov 15;70(22):9277-86, 2010.
The expression of phospho-AKT, phospho-mTOR, and PTEN in extrahepatic cholangiocarcinoma.
Chung JY, Hong SM, Choi BY, Cho H, Yu E, Hewitt SM.
Clin Cancer Res. Jan 15;15(2):660-7, 2009.
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