For Researchers



Focus Areas


Early Detection

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.

Diagnosis

scan image

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).

Population Studies

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:

  1. 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.
  2. 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.

Treatment

Medical illustration showing liver cancer cell loss

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.

Liver cancer cells

Collaborations


Doctors in consultationExpected 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.

Walter Reed National Military Medical Center

Patient exchange between the Walter Reed National Military Medical Center John P. Murtha Cancer Center and the GI-Malignancy Section at CCR. Weekly phone conferences will be held to discuss patients. This interaction will support and take advantage of the Tri-Federal Cancer Initiative to optimize federal cancer resources, enhance cancer research and discoveries, decrease duplication, leverage technologies, enhance intellectual capital and increase educational and training opportunities within two government funded medical institutions within close proximity. Dr. Greten has already initiated a collaboration with Dr. Fishbein and Kroemer from the Transplantation Center at Georgetown and an MTA is in place, which allows exchange liver tissue for research studies.

Georgetown University Lombardi Cancer Center

Foster research collaborations between the Georgetown University Lombardi Cancer Center and CCR. Georgetown University has one of the largest liver transplant centers in the United States. Every year more than 100 patients undergo liver transplantation at Georgetown. Patients with chronic liver disease, enrolled on NIDDK clinical protocols and currently undergoing surveillance programs for liver cancer with newly diagnosed liver cancer will be referred to the Liver Transplant Program at Georgetown University. Fresh clinical specimen obtained from patients with liver cancer undergoing liver transplantation at Georgetown will be send to CCR and used for ongoing basic and preclinical research protocols.

Health Disparities

Options for health disparities. Poor patients are relatively more frequently affected. We will provide the opportunity for patients with low income to receive a state of the art diagnosis including genetic testing, imaging etc.

Publications


Zhu K, Tang Y, Xu X, Dang H, Tang LY, Wang X, Wang XW, Zhang YE. Non-proteolytic ubiquitin modification of PPARγ by Smurf1 protects the liver from steatosis. PLoS Biol. 2018 Dec 19;16(12): e3000091. doi: 10.1371/journal.pbio.3000091. [Epub ahead of print] PubMed PMID: 30566427.

 

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. Single-cell analysis reveals cancer stem cell heterogeneity in hepatocellular carcinoma. Hepatology. 2018 Jul;68(1):127-140. doi: 0.1002/hep.29778. Epub 2018 May 9. PubMed PMID: 29315726; PubMed Central PMCID: PMC6033650.

 

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. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science. 2018 May 25;360(6391). pii: eaan5931. doi: 10.1126/science.aan5931. PubMed PMID: 29798856.

 

Greer YE, Porat-Shliom N, Nagashima K, Stuelten C, Crooks D, Koparde VN, Gilbert SF, Islam C, Ubaldini A, Ji Y, Gattinoni L, Soheilian F, Wang X, Hafner M, Shetty J, Tran B, Jailwala P, Cam M, Lang M, Voeller D, Reinhold WC, Rajapakse V, Pommier Y, Weigert R, Linehan WM, Lipkowitz S. ONC201 kills breast cancer cells in vitro by targeting mitochondria. Oncotarget. 2018 Apr 6;9(26):18454-18479. doi: 10.18632/oncotarget.24862. eCollection 2018 Apr 6. PubMed PMID: 29719618; PubMed Central PMCID: PMC5915085.

 

Escorcia FE, Steckler JM, Abdel-Atti D, Price EW, Carlin SD, Scholz WW, Lewis JS, Houghton JL. Tumor-Specific Zr-89 Immuno-PET Imaging in a Human Bladder Cancer Model. Mol Imaging Biol. 2018 Mar 5. doi: 10.1007/s11307-018-1177-z. [Epub ahead of print] PubMed PMID: 29508263.

 

Shuptrine CW, Ajina R, Fertig EJ, Jablonski SA, Kim Lyerly H, Hartman ZC, Weiner LM. An unbiased in vivo functional genomics screening approach in mice identifies novel tumor cell-based regulators of immune rejection. Cancer Immunol Immunother. 2017 Dec;66(12):1529-1544. doi: 10.1007/s00262-017-2047-2. Epub 2017 Aug 2. PubMed PMID: 28770278; PubMed Central PMCID: PMC5854209.

 

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. Common Molecular Subtypes Among Asian Hepatocellular Carcinoma and Cholangiocarcinoma. Cancer Cell. 2017 Jul 0;32(1):57-70.e3. doi: 10.1016/j.ccell.2017.05.009. Epub 2017 Jun 22. PubMed PMID: 28648284; PubMed Central PMCID: PMC5524207.

 

Cancer Genome Atlas Research Network. Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma. Cell. 2017 Jun 15;169(7):1327-1341.e23. doi: 10.1016/j.cell.2017.05.046. PubMed PMID: 28622513; PubMed Central PMCID: PMC5680778.

 

Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol. 2017 Jul;14(7):397-411. doi: 10.1038/nrgastro.2017.38. Epub 2017 May 10. Review. PubMed PMID: 28487545.

 

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. Transcriptional Induction of Periostin by a Sulfatase 2-TGFβ1-SMAD Signaling Axis Mediates Tumor Angiogenesis in Hepatocellular Carcinoma. Cancer Res. 2017 Feb 1;77(3):632-645. doi: 10.1158/0008-5472.CAN-15-2556. Epub 2016 Nov 21. PubMed PMID: 27872089; PubMed Central PMCID: PMC5429157.

 

Kastenhuber, ER, Lalazar, G, Houlihan, SL, Tschaharganeh, DF, Baslan, T, Chen, CC, Requena, D, Tian, S, Bosbach, B, Wilkinson, JE, Simon, SM, and Lowe, SW (2017). DNAJB1-PRKACA fusion kinase interacts with b-catenin and the liver regenerative response to drive fibrolamellar hepatocellular carcinoma. Proc. Natl. Acad. Sci. U.S.A. 114: 13076-13084. PMID: 29162699.

 

Zhang Q, Matsuura K, Kleiner DE, Zamboni F, Alter HJ, Farci P. Analysis of long noncoding RNA expression in hepatocellular carcinoma of different viral etiology. J Transl Med. 2016 Nov 28;14(1):328. PubMed PMID: 27894309; PubMed Central PMCID: PMC5125040.

 

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. Telomere Length and Survival of Patients with Hepatocellular Carcinoma in the United States. PLoS One. 2016 Nov 23;11(11):e0166828. doi: 10.1371/journal.pone.0166828. eCollection 2016. PubMed PMID: 27880792; PubMed Central PMCID: PMC5120796.

 

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. Distinct Functions of Senescence-Associated Immune Responses in Liver Tumor Surveillance and Tumor Progression. Cancer Cell. 2016 Oct 10;30(4):533-547. doi: 10.1016/j.ccell.2016.09.003. PubMed PMID: 27728804.

 

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. A MYC-aurora kinase A protein complex represents an actionable drug target in p53-altered liver cancer. Nat Med. 2016 Jul;22(7):744-53. doi: 10.1038/nm.4107. Epub 2016 May 23. PubMed PMID: 27213815.

 

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. A hepatic stellate cell gene expression signature associated with outcomes in hepatitis C cirrhosis and hepatocellular carcinoma after curative resection. Gut. 2016 Oct;65(10):1754-64. doi: 10.1136/gutjnl-2015-309655. Epub 2015 Jun 4. PubMed PMID: 26045137; PubMed Central PMCID: PMC4848165.

 

Porat-Shliom N, Tietgens AJ, Van Itallie CM, Vitale-Cross L, Jarnik M, Harding OJ, Anderson JM, Gutkind JS, Weigert R, Arias IM. Liver kinase B1 regulates hepatocellular tight junction distribution and function in vivo. Hepatology. 2016 Oct;64(4):1317-29. doi: 10.1002/hep.28724. Epub 2016 Jul 28. PubMed PMID: 27396550; PubMed Central PMCID: PMC5033699.

 

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. p53-dependent Nestin regulation links tumor suppression to cellular plasticity in liver cancer. Cell. 2014 Jul 31;158(3):579-92. doi: 10.1016/j.cell.2014.05.051. Erratum in: Cell. 2016 Jun 2;165(6):1546-1547. PubMed PMID: 25083869; PubMed Central PMCID: PMC4221237.

 

Gao W, Tang Z, Zhang YF, Feng M, Qian M, Dimitrov DS, Ho M. Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signaling and protein synthesis. Nat Commun. 2015 Mar 11; 6:6536. doi: 10.1038/ncomms7536. PubMed PMID: 25758784; PubMed Central PMCID: PMC4357278.

 

Murray JC, Aldeghaither D, Wang S, Nasto RE, Jablonski SA, Tang Y, Weiner LM. c-Abl modulates tumor cell sensitivity to antibody-dependent cellular cytotoxicity. Cancer Immunol Res. 2014 Dec;2(12):1186-98. doi: 10.1158/2326-6066.CIR-14-0083. Epub 2014 Oct 9. PubMed PMID: 25300860; PubMed Central PMCID: PMC4258447.

 

Feng M, Gao W, Wang R, Chen W, Man YG, Figg WD, Wang XW, Dimitrov DS, Ho M. Therapeutically targeting glypican-3 via a conformation-specific single-domain antibody in hepatocellular carcinoma. Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):E1083-91. doi: 10.1073/pnas.1217868110. Epub 2013 Mar 5. PubMed PMID: 23471984; PubMed Central PMCID: PMC3607002.

 

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. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature. 2011 Nov 9;479(7374):547-51. doi: 10.1038/nature10599. PubMed PMID: 22080947.

 

Escorcia FE, Henke E, McDevitt MR, Villa CH, Smith-Jones P, Blasberg RG, Benezra R, Scheinberg DA. Selective killing of tumor neovasculature paradoxically improves chemotherapy delivery to tumors. Cancer Res. 2010 Nov 15;70(22):9277-86. doi: 10.1158/0008-5472.CAN-10-2029. Epub 2010 Nov 2. PubMed PMID: 21045141; PubMed Central PMCID: PMC3058681.

 

Chung JY, Hong SM, Choi BY, Cho H, Yu E, Hewitt SM. The expression of phospho-AKT, phospho-mTOR, and PTEN in extrahepatic cholangiocarcinoma. Clin Cancer Res. 2009 Jan 15;15(2):660-7. doi: 10.1158/1078-0432.CCR-08-1084. PubMed PMID: 19147772.


Meetings & Seminars


  • 21 FEB
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  • 22 FEB
    Conference Day 2 Lorem ipsum dolor sit amet, consectetur adipiscing elit. Maecenas at purus pretium, finibus ex a, scelerisque velit. Pellentesque habitant morbi tristique senectus et netus et malesuada fames ac turpis egestas.