Principal Investigator

Amit
Singal
Awardee Organization

Ut Southwestern Medical Center
United States

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

Clinical Validation Center for Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the fastest-growing cause of cancer death in the U.S. and it is projected to be the 3rd leading cause of cancer death in the U.S. by 2040 given the poor effectiveness of current HCC risk stratification and early detection strategies. Specifically, HCC screening is recommended in all patients with cirrhosis, despite annual HCC risk varying between 1-4%/year, highlighting a need for risk stratification biomarkers. HCC screening is performed using abdominal ultrasound and the serum biomarker alpha fetoprotein (AFP); however, this strategy misses over one-third of HCCs at an early stage and results in screening harms in many patients. The goal of our Clinical Validation Center for HCC (CVC-HCC) is to validate novel blood and imaging biomarkers in phase I-III studies to improve HCC risk stratification and early detection. Translation of HCC biomarkers to practice has been hampered by a dearth of high-quality sample sets including both stored blood and imaging. Existing sample sets also primarily include patients with cirrhosis from active viral hepatitis, with limited applicability to contemporary populations who primarily have cured viral hepatitis or non-viral causes of liver disease. Our CVC will create a contemporary resource with blood and imaging data to allow for rapid validation of promising biomarkers for HCC risk-stratification and early detection in phase I-III studies. A specific population in need of better biomarkers is patients with indeterminate liver nodules (ILNs) on diagnostic CT or MRI, which are observed in over one-fourth of patients undergoing HCC screening and have a high, yet variable, risk for developing into HCC (annual risk ~6-10%/year). Our group has validated a novel bloodbased biomarker, PLSec, for risk stratification and a biomarker panel, GALAD, for early HCC detection in patients with cirrhosis and herein propose to perform a phase II-III biomarker study to evaluate them in patients with ILNs. Our team includes national leaders in HCC screening, imaging, and biomarker validation. We are leading efforts to evaluate HCC biomarkers including the EDRN-funded Hepatocellular Early Detection Strategy (HEDS) Study, NCI-funded Translational Liver Cancer (TLC) Consortium, and CPRIT-funded Texas HCC Consortium. We will leverage existing infrastructure across five health systems to create two novel resources not offered by the current sample sets including (1) a biorepository with both blood and imaging data from patients, with and without HCC, representing contemporary etiologies of liver disease for Phase II studies and (2) a prospective cohort of patients with ILNs to evaluate HCC risk stratification and early detection biomarkers in Phase III studies using a prospective-specimen-collection, retrospective-blinded-evaluation (PRoBE) design. We will work with the BCCs and DMCC to evaluate novel biomarkers, facilitating contributions to trans-network projects. Overall, our CVCHCC will lead to significant advances in phase I-III validation of novel biomarkers for HCC risk stratification and early detection, areas of need that will facilitate development of well-designed phase IV clinical utility trials.
  • Park J, Lee YT, Agopian VG, Liu JS, Koltsova EK, You S, Zhu Y, Tseng HR, Yang JD. Liquid biopsy in hepatocellular carcinoma: Challenges, advances, and clinical implications. Clinical and molecular hepatology. 2025 Feb;31(Suppl):S255-S284. Epub 2024 Nov 28. PMID: 39604328
  • Murphy CC, Tavakkoli A, Wani S, Singal AG. Pandemic-Related Changes in Incidence and Mortality Rates of Gastrointestinal Cancers During 2020. The American journal of gastroenterology. 2024 Feb 1;119(2):382-387. Epub 2023 Oct 27. PMID: 37791616
  • Singal AG, Yang JD, Parikh ND. Blood-Based Biomarkers for HCC Surveillance: Ready for the Center Stage? The American journal of gastroenterology. 2024 Nov 1;119(11):2147-2150. Epub 2023 Oct 5. PMID: 37795908
  • Singal AG, Sanduzzi-Zamparelli M, Nahon P, Ronot M, Hoshida Y, Rich N, Reig M, Vilgrain V, Marrero J, Llovet JM, Parikh ND, Villanueva A. International Liver Cancer Association (ILCA) white paper on hepatocellular carcinoma risk stratification and surveillance. Journal of hepatology. 2023 Jul;79(1):226-239. Epub 2023 Feb 26. PMID: 36854345
  • Shaikh A, Goli K, Lee TH, Rich NE, Benhammou JN, Keeling S, Kim D, Ahmed A, Goss J, Rana A, Singal AG, Kanwal F, Cholankeril G. Reduction in Racial and Ethnic Disparity in Survival Following Liver Transplant for Hepatocellular Carcinoma in the Direct-acting Antiviral Era. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2023 Aug;21(9):2288-2297.e4. Epub 2022 Dec 12. PMID: 36521738
  • Shaikh A, Lee TH, Rich NE, Benhammou JN, Lymberopoulos P, Agopian VG, Kim D, Ahmed A, Hernaez R, Berg CL, Goss J, Rana A, Kanwal F, Cholankeril G. Survival following liver transplantation for hepatocellular carcinoma after implementation of MMaT-3 policy. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2023 Oct 1;29(10):1138-1142. Epub 2023 May 3. PMID: 37129867
  • Singal AG, Parikh ND, Shetty K, Han SH, Xie C, Ning J, Rinaudo JA, Arvind A, Lok AS, Kanwal F, Translational Liver Cancer Investigators. Natural History of Indeterminate Liver Nodules in Patients With Advanced Liver Disease: A Multicenter Retrospective Cohort Study. The American journal of gastroenterology. 2024 Nov 1;119(11):2251-2258. Epub 2024 Apr 30. PMID: 38686922
  • Tan Y, Zhu J, Gutierrez Reyes CD, Lin Y, Tan Z, Wu Z, Zhang J, Cano A, Verschleisser S, Mechref Y, Singal AG, Parikh ND, Lubman DM. Discovery of Core-Fucosylated Glycopeptides as Diagnostic Biomarkers for Early HCC in Patients with NASH Cirrhosis Using LC-HCD-PRM-MS/MS. ACS omega. 2023 Mar 21;8(13):12467-12480. doi: 10.1021/acsomega.3c00519. eCollection 2023 Apr 4. PMID: 37033807
  • Cholankeril G, Kramer JR, Chu J, Yu X, Balakrishnan M, Li L, El-Serag HB, Kanwal F. Longitudinal changes in fibrosis markers are associated with risk of cirrhosis and hepatocellular carcinoma in non-alcoholic fatty liver disease. Journal of hepatology. 2023 Mar;78(3):493-500. Epub 2022 Nov 17. PMID: 36402450
  • Patel AA, Tapper EB, Kanwal F, Woodrell CD, Hansen L, Lai JC, Rogal S, McDermott C, Rakoski M, Ufere NN. Targets and study design for symptom-focused trials aimed at patients with cirrhosis: An expert consensus. Hepatology communications. 2023 Jun 2;7. (6). doi: 10.1097/HC9.0000000000000135. eCollection 2023 Jun 1. PMID: 37267219
  • Antwi SO, Siaw ADJ, Armasu SM, Frank JA, Yan IK, Ahmed FY, Izquierdo-Sanchez L, Boix L, Rojasti A, Banales JM, Reig M, Stål P, Romero Gómez M, Wangensteen KJ, Singal AG, Roberts LR, Patel T. Genome-wide DNA methylation markers associated with metabolic liver cancer. medRxiv : the preprint server for health sciences. 2024 Nov 15. PMID: 39606355
  • Singal AG, Parikh ND, Kanwal F, Marrero JA, Deodhar S, Page-Lester S, Lopez C, Feng Z, Tayob N. National Liver Cancer Screening Trial (TRACER) study protocol. Hepatology communications. 2024 Nov 4;8. (11). doi: 10.1097/HC9.0000000000000565. eCollection 2024 Nov 1. PMID: 39495136
  • Abedrabbo N, Lerner E, Lam E, Kadi D, Dawit H, van der Pol C, Salameh JP, Naringrekar H, Adamo R, Alabousi M, Levis B, Tang A, Alhasan A, Arvind A, Singal A, Allen B, Bartnik K, Podgórska J, Furlan A, Cannella R, Dioguardi Burgio M, Cerny M, Choi SH, Clarke C, Jing X, Kierans A, Ronot M, Rosiak G, Jiang H, Song JS, Reiner CC, Joo I, Kwon H, Wang W, Rao SX, Diaz Telli F, Piñero F, Seo N, Kang HJ, Wang J, Min JH, Costa A, McInnes M, Bashir M. Is concurrent LR-5 associated with a higher rate of hepatocellular carcinoma in LR-3 or LR-4 observations? An individual participant data meta-analysis. Abdominal radiology (New York). 2025 Apr;50(4):1533-1546. Epub 2024 Sep 27. PMID: 39333410
  • Seif El Dahan K, Yokoo T, Mendiratta-Lala M, Fetzer D, Davenport M, Daher D, Rich NE, Yang E, Parikh ND, Singal AG. Exam quality of ultrasound and dynamic contrast-enhanced abbreviated MRI and impact on early-stage HCC detection. Abdominal radiology (New York). 2024 Nov 15. Epub 2024 Nov 15. PMID: 39542949
  • Bhatnagar A, Prakash S, Lymberopoulos P, Goff C, Shaikh A, Kim D, Ahmed A, Berg C, Naggie S, Kanwal F, Cholankeril G, Lee TH. Transplanting hepatitis B surface antigen-positive livers in the United States: Outcomes and opportunities. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2023 Aug;23(8):1221-1226. Epub 2023 Apr 26. PMID: 37116583
  • Zheng Y, Wagner PD, Singal AG, Hanash SM, Srivastava S, Huang Y, Zhao YQ, Chari ST, Marquez G, Etizioni R, Marsh TL, Feng Z. Designing Rigorous and Efficient Clinical Utility Studies for Early Detection Biomarkers. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2024 Sep 3;33(9):1150-1157. PMID: 39223980
  • Wang M, Singal AG, Parikh N, Kono Y, Marrero J, Mehta A. A Biomarker Panel Based upon AFP, Fucosylated Kininogen and PEG-Precipitated IgG Is Highly Accurate for the Early Detection Hepatocellular Carcinoma in Patients with Cirrhosis in Phase II and Phase III Biomarker Evaluation. Cancers. 2022 Dec 2;14. (23). PMID: 36497452
  • Marsh TL, Parikh ND, Roberts LR, Schwartz ME, Nguyen MH, Befeler A, Page-Lester S, Tayob N, Srivastava S, Rinaudo JA, Singal AG, Reddy KR, Marrero JA. A Phase 3 Biomarker Validation of GALAD for the Detection of Hepatocellular Carcinoma in Cirrhosis. Gastroenterology. 2025 Feb;168(2):316-326.e6. Epub 2024 Sep 16. PMID: 39293548
  • Antwi SO, Heckman M, White L, Yan I, Sarangi V, Lauer KP, Reddy J, Ahmed F, Veliginti S, Mejías Febres ED, Hatia RI, Chang P, Izquierdo-Sanchez L, Boix L, Rojas A, Banales JM, Reig M, Stål P, Gómez MR, Singal AG, Li D, Hassan MM, Roberts LR, Patel T. Metabolic liver cancer: associations of rare and common germline variants in one-carbon metabolism and DNA methylation genes. Human molecular genetics. 2023 Aug 7;32(16):2646-2655. PMID: 37369012
  • Kanwal F, Neuschwander-Tetri BA, Loomba R, Rinella ME. Metabolic dysfunction-associated steatotic liver disease: Update and impact of new nomenclature on the American Association for the Study of Liver Diseases practice guidance on nonalcoholic fatty liver disease. Hepatology (Baltimore, Md.). 2024 May 1;79(5):1212-1219. Epub 2023 Nov 9. PMID: 38445559
  • McMahon B, Cohen C, Brown RS Jr, El-Serag H, Ioannou GN, Lok AS, Roberts LR, Singal AG, Block T. Opportunities to address gaps in early detection and improve outcomes of liver cancer. JNCI cancer spectrum. 2023 May 2;7. (3). PMID: 37144952
  • Mendiratta-Lala M, Fetzer D, Kamaya A, Parikh ND, Singal AG. The Future Role of Abdominal US in Hepatocellular Carcinoma Surveillance. Radiology. 2024 May;311(2):e232624. PMID: 38742973
  • El-Serag HB, Jin Q, Tayob N, Salem E, Luster M, Alsarraj A, Khaderi S, Singal AG, Marrero JA, Asrani SK, Kanwal F. HES V2.0 outperforms GALAD for detection of HCC: A phase 3 biomarker study in the United States. Hepatology (Baltimore, Md.). 2025 Feb 1;81(2):465-475. Epub 2024 Jun 19. PMID: 38899967
  • Zhao C, Wang Z, Kim H, Kong H, Lee J, Yang JZ, Wang A, Zhang RY, Ju Y, Kim J, Feng B, Liu D, Zhang Y, Wang Z, Zhang Y, Guo S, Gao D, Tomlinson JS, Pei R, Wan J, Pandol SJ, Sim MS, You S, Ma D, Lu S, Sun N, Tseng HR, Zhu Y. Identification of Tumor-Specific Surface Proteins Enables Quantification of Extracellular Vesicle Subtypes for Early Detection of Pancreatic Ductal Adenocarcinoma. Advanced science (Weinheim, Baden-Wurttemberg, Germany). 2025 Mar 25: e2414982. Epub 2025 Mar 25. PMID: 40130819
  • 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