Hepatocellular carcinoma (HCC) appears to consist of several poorly-defined phenotypes, with several distinct poor prognostic factors, such as high alpha-fetoprotein (AFP) and presence of portal vein thrombosis (PVT). Recently, systemic inflammation has been identified as a major independent poor prognosis factor, based on the Glasgow score that utilizes serum C-reactive protein (CRP) and albumin levels. This implicated the tumor microenvironment (inflammation) in prognosis and thus as an influence on the biology of the tumor itself.
Our over-all aims are to: A, identify distinct clinical HCC profiles/phenotypes; to B, study the effects of inflammatory mediator influence on HCC growth and invasion in vitro; and C, to continue our previous studies on multikinase drug resistance in HCC cells and to learn how to enhance the effects of these agents on HCC growth inhibition.
We have collaborated with a group of 15 Turkish institutions that treat HCC, to assemble a 1700 HCC patient database for phenotype analysis. We have published one paper (in Oncology) with 3 more in press, to show that Turkish HCC, which is predominantly HBV based- and thus similar to Chinese but not Western HCC in this respect- is broadly similar to western HCC, with regard to presence of PVT, importance of AFP and our identification of the characteristics of that 50% of patients that do not have elevated AFP levels. Interestingly, HCC in different regions of Turkey may have marked variations, such as the high incidence of HDV infection in HCC patients in the Diyabakir region.
We have worked on the significance of albumin and C-reactive protein (CRP) on HCC biology. We reasoned that to have such important clinical prognostic significance (high CRP and low albumin predict poor outcomes). These 2 proteins must have effects. Directly or indirectly on HCC biology. In 2017 we published 2 papers to show that low albumin levels were associated with more aggressive tumor parameters of larger tumors and more portal vein invasion, that could explain the poor prognosis 8by contrast, higher serum albumin levels were associated with smaller tumors). We followed this up, by showing that pure albumin in tissue culture could slow HCC cell line growth a limit invasiveness. This sets the scene for future experiments to test these ideas in animals. We have recently shown that high CRP levels are associated with larger and more aggressive tumors in Turkish HCC patients (in press) and we are beginning to study the actions of pure CRP on and in (CRP is synthesized by cells of liver origin) HCC cells in culture.
In collaboration with the labs of Profs Nese Atabey and Esra Erdal, we are working in the development of Regorafenib-resistant and double Regorafenib/Sorafenib resistant HCC cell lines, to examine both the peculiarities of their cell signaling compared to the parental cells and also to identify possible mechanisms of limiting their resistance to drug growth-inhibitory actions. Furthermore, since both Sorafenib and Regorafenib are FDA-approved for treating HCC patients, they are quite toxic (multiple side-effects) and thus we are examining ways to enhance the effects on HCC cells of both drugs when used at low concentrations.
|PUBLICATIONS (from Pubmed)
Full list and citations: Google Scholar: Brian Carr
• Carr BI, Guerra V, Steel JL, Lin SN. A comparison of patients with hepatitis B- or hepatitis C-based advanced stage hepatocellular carcinoma. Seminars in Oncology 2015; 42: 309-315.
• Pancoska P, Skala L, Nesetril J, Carr BI. Evaluation of total HCC lifespan, including both clinically evident and pre-clinical development, using combined Network Phenotyping Strategy and Fisher information analysis. Seminars in Oncology 2015; 42: 339-346
• Carr BI Viruses and Cancer: Guest Editorial Seminars in Oncology 2015; 42: 189-90
• D’Alessandro R, Refolo MG, Lippolis C, Giannuzzi G, Carella N, Messa C, Cavallini A, Carr BI. Modulation of Regorafenib effects on HCC cell lines by epidermal growth factor. Cancer Chemotherapy and Pharmacology 2015; APRIL 24 EPUB
• Facciorusso A, Licinio R, Carr BI, Di Leo A, Barone M. MEK 1/2 inhibitors in the treatment of hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol. 2015 Apr 27:1-11
• D’Alessandro R, Messa C, Refolo MG, Carr BI. Modulation of sensitivity and resistance to multikinase inhibitors by microenvironmental platelet factors in HCC. Expert Opinion on Pharmacotherapy. 2015; 16: 2773-2780
• Lippolis C, Refolo MG, D’Alessandro R, Carella N, Messa C, Cavallini A, Carr BI. Resistance to multikinase inhibitor actions mediated by insulin like growth factor-1. J Exp Clin Cancer Res. 2015; 34 (1):90. PMID: 26329608
• Pančoška P, Skála L, Nešetřil J, Carr BI. Validation of the Concept of a Common Typical Time of Disease Duration for Hepatocellular Carcinoma Patients Using the Fisher Information Processing of Tumor Imaging Results Combined With Network Phenotyping Strategy Quantification of Individual Patient Clinical Profile Patterns. Semin Oncol. 2015;42:672-8. PMID: 26320070
• Carr BI and Guerra V. Low alpha-fetoprotein levels are associated with improved survival in hepatocellular carcinoma patients with portal vein thrombosis. Dig. Dis. Sciences 2016; 61:937-947
• Carr BI and Guerra V. HCC extrahepatic metastasis in relation to tumor size and ALKP levels. Oncology 2016; 90:136-142
• Carr BI and Guerra V. A Hepatocellular Carcinoma Aggressiveness Index and its relationship to liver enzyme levels. Oncology 2016; 90:215-220
• Modulation of doxorubicin actions in hepatocellular carcinoma cells by Insulin-like Growth Factor-I. Biochemistry & Analytical Biochemistry 2016;5: 256. doi:10.4172/2161- 1009.1000256
• Yilmaz Y, Erdal Y, Atabey N, Carr BI. Platelets, microenvironment and hepatocellular carcinoma: a review. Biochemistry and Analytical Biochemistry 2016;5;2. doi:10.4172/2161-1009.1000281
• Mazzocca A, Ferraro G, Misciagna G, Carr BI. A systemic evolutionary approach to cancer: hepatocarcinogenesis as paradigm. Medical Hypotheses 2016; 93: 132-137
• Carr BI, Guerra V, Giannini EO et al. An HCC Aggressiveness Index and blood GTP, bilirubin and platelet levels. J. Integrative Oncology 2016; 5:172. doi:10.4172/2329-6771.1000172
• Pinato DJ et al. The ALBI grade provides objective hepatic reserve phenotyping across each BCLC stage of hepatocellular carcinoma. J. Hepatology 2017; 66: 338-346
• Rozen R, Menachem Y, Carr BI, Shibolet O. Liver Transplantation for a Patient with Hepatocellular Carcinoma with Vascular Invasion and Exceeding Milan Criteria-Happy End Despite it all. J Gastrointest Cancer. 2016 Nov 11. [Epub ahead of print] • Carr BI, Guerra V, Giannini EG et al A Liver Index and its relationship to indices of HCC Aggressiveness. J. Integrative Oncology 2016; 5:3 DOI: 10.4172/2329-6771.1000178
• Marino IR, Carr BI. New Developments in Orthotopic Liver Transplant for Hepatocellular Carcinoma. Exp Clin Transplant. 2017 Mar;15 (Suppl 2):1-6
• Bağırsakçı E, Sahin E, Atabey N , Erdal E, Carr BI. Role of Albumin in growth inhibition in Hepatocellular Carcinoma. Oncology May 2017; 93: 136-142
• Carr BI, Guerra V. Validation of a Liver Index and its Significance for HCC Aggressiveness. J. Gastrointestinal Cancer 2017; June 20; doi: 10.1007/s12029-017-9971-4. EPub
• Carr BI, Guerra V. Serum albumin levels in relation to tumor parameters in hepatocellular carcinoma patients. Int J. Biol Markers 2017; 32: e391-e396
• Akkiz H, Carr BI, Yalcun K, Guerra V et at. Characteristics of hepatocellular carcinoma aggressiveness factors in Turkish patients. Oncology 2017|; Dec 6. doi: 10.1159/000484564. [Epub ahead of print]. PMID: 29207378
• Carr BI, Akkiz, H, Uskudar O, Yalcin K et al. HCC with low- and normal- alphafetoprotein levels. Clinical Practice 2018 (in press)
• D’Alessandro R, Refolo MG, Lippolis C, Carella N, Messa C, Cavallini A, Carr BI. Strong enhancement by an IGF1-R antagonist of migration inhibition due to Sorafenib, vitamin K1 or both in hepatocellular carcinoma cell lines. Cellular Oncology 2018 (in press)