R01CA255809
Project Grant
Overview
Grant Description
Novel Determinants for Progression of Non-Alcoholic Fatty Liver Disease to Hepatocellular Carcinoma and Other Health Outcomes - Abstract
The incidence rate of hepatocellular carcinoma in the United States has been increasing in the past several decades. Non-alcoholic fatty liver disease has become the most important risk factor for hepatocellular carcinoma. About 25 percent of adults in the United States have non-alcoholic fatty liver disease, which includes a spectrum of liver diseases from simple steatosis, non-alcoholic steatohepatitis to fibrosis and cirrhosis.
Liver fibrosis has been recognized as the key determinant of the risk of long-term health outcome for patients with non-alcoholic fatty liver disease, which will soon be the most common indication for liver transplantation in the United States. Currently, there is no effective treatment or prevention strategy for non-alcoholic fatty liver disease. It is an urgently unmet need to identify novel biological and environmental factors that drive the progression of non-alcoholic fatty liver disease to the development of hepatocellular carcinoma and end-stage liver disease that increasingly require liver transplantation, a significant public health burden in the United States.
The liver is an organ that is constantly exposed to a wide range of immunomodulators, environmental toxins, and gut microbial metabolites through the portal vein. To ensure upkeep of immune tolerance to self and foreign antigens, the liver has a unique immunotolerance mechanism. Heightened immunotolerance or immune permissive microenvironment may create a setting with compromised immunosurveillance that promotes the tumor development and growth in the liver.
The gut microbiota can produce large quantities of metabolites such as secondary bile acids that have genotoxic and tumor-promoting effects. The gut dysbiosis due to obesity and other metabolic diseases, which are underlying conditions for non-alcoholic fatty liver, alters the metabolism, synthesis, and transport of bile acids, resulting in the change of bile acid pool size and characteristics. The altered bile acids profile can elicit inflammation and cause liver injury, leading to fibrosis and cirrhosis, and eventually hepatocellular carcinoma.
We propose prospectively enrolling at least 1000 patients with non-alcoholic fatty liver disease with advanced fibrosis assessed by transient elastography at baseline and once every 6 months. All study participants will be longitudinally followed up for the occurrence of hepatocellular carcinoma and end-stage liver disease for up to five years. The specific aims are to determine if immunosuppressive cytokines, altered bile acid profiles, and the gut dysbiosis have a significant impact on the risk of developing hepatocellular carcinoma and end-stage liver disease.
The findings, if proven our hypotheses, will provide much-needed scientific evidence for the development of an effective strategy for management and surveillance for patients with non-alcoholic fatty liver disease with a goal to lower its progression to hepatocellular carcinoma and other end-stage liver disease.
The incidence rate of hepatocellular carcinoma in the United States has been increasing in the past several decades. Non-alcoholic fatty liver disease has become the most important risk factor for hepatocellular carcinoma. About 25 percent of adults in the United States have non-alcoholic fatty liver disease, which includes a spectrum of liver diseases from simple steatosis, non-alcoholic steatohepatitis to fibrosis and cirrhosis.
Liver fibrosis has been recognized as the key determinant of the risk of long-term health outcome for patients with non-alcoholic fatty liver disease, which will soon be the most common indication for liver transplantation in the United States. Currently, there is no effective treatment or prevention strategy for non-alcoholic fatty liver disease. It is an urgently unmet need to identify novel biological and environmental factors that drive the progression of non-alcoholic fatty liver disease to the development of hepatocellular carcinoma and end-stage liver disease that increasingly require liver transplantation, a significant public health burden in the United States.
The liver is an organ that is constantly exposed to a wide range of immunomodulators, environmental toxins, and gut microbial metabolites through the portal vein. To ensure upkeep of immune tolerance to self and foreign antigens, the liver has a unique immunotolerance mechanism. Heightened immunotolerance or immune permissive microenvironment may create a setting with compromised immunosurveillance that promotes the tumor development and growth in the liver.
The gut microbiota can produce large quantities of metabolites such as secondary bile acids that have genotoxic and tumor-promoting effects. The gut dysbiosis due to obesity and other metabolic diseases, which are underlying conditions for non-alcoholic fatty liver, alters the metabolism, synthesis, and transport of bile acids, resulting in the change of bile acid pool size and characteristics. The altered bile acids profile can elicit inflammation and cause liver injury, leading to fibrosis and cirrhosis, and eventually hepatocellular carcinoma.
We propose prospectively enrolling at least 1000 patients with non-alcoholic fatty liver disease with advanced fibrosis assessed by transient elastography at baseline and once every 6 months. All study participants will be longitudinally followed up for the occurrence of hepatocellular carcinoma and end-stage liver disease for up to five years. The specific aims are to determine if immunosuppressive cytokines, altered bile acid profiles, and the gut dysbiosis have a significant impact on the risk of developing hepatocellular carcinoma and end-stage liver disease.
The findings, if proven our hypotheses, will provide much-needed scientific evidence for the development of an effective strategy for management and surveillance for patients with non-alcoholic fatty liver disease with a goal to lower its progression to hepatocellular carcinoma and other end-stage liver disease.
Funding Goals
TO IDENTIFY CANCER RISKS AND RISK REDUCTION STRATEGIES, TO IDENTIFY FACTORS THAT CAUSE CANCER IN HUMANS, AND TO DISCOVER AND DEVELOP MECHANISMS FOR CANCER PREVENTION AND PREVENTIVE INTERVENTIONS IN HUMANS. RESEARCH PROGRAMS INCLUDE: (1) CHEMICAL, PHYSICAL AND MOLECULAR CARCINOGENESIS, (2) SCREENING, EARLY DETECTION AND RISK ASSESSMENT, INCLUDING BIOMARKER DISCOVERY, DEVELOPMENT AND VALIDATION, (3) EPIDEMIOLOGY, (4) NUTRITION AND BIOACTIVE FOOD COMPONENTS, (5) IMMUNOLOGY AND VACCINES, (6) FIELD STUDIES AND STATISTICS, (7) CANCER CHEMOPREVENTION AND INTERCEPTION, (8) PRE-CLINICAL AND CLINICAL AGENT DEVELOPMENT, (9) ORGAN SITE STUDIES AND CLINICAL TRIALS, (10) HEALTH-RELATED QUALITY OF LIFE AND PATIENT-CENTERED OUTCOMES, AND (11) SUPPORTIVE CARE AND MANAGEMENT OF SYMPTOMS AND TOXICITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO STIMULATE TECHNICAL INNOVATION, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, AND FOSTER PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS.
Grant Program (CFDA)
Awarding / Funding Agency
Place of Performance
Pittsburgh,
Pennsylvania
152133203
United States
Geographic Scope
Single Zip Code
Related Opportunity
Analysis Notes
Amendment Since initial award the total obligations have increased 479% from $634,830 to $3,678,371.
University Of Pittsburgh - Of The Commonwealth System Of Higher Education was awarded
Factors Driving NAFLD Progression to HCC & Outcomes
Project Grant R01CA255809
worth $3,678,371
from National Cancer Institute in September 2021 with work to be completed primarily in Pittsburgh Pennsylvania United States.
The grant
has a duration of 5 years and
was awarded through assistance program 93.393 Cancer Cause and Prevention Research.
The Project Grant was awarded through grant opportunity Epidemiologic Research on Emerging Risk Factors and Liver Cancer Susceptibility (R01 - Clinical Trial Not Allowed).
Status
(Ongoing)
Last Modified 8/20/25
Period of Performance
9/7/21
Start Date
8/31/26
End Date
Funding Split
$3.7M
Federal Obligation
$0.0
Non-Federal Obligation
$3.7M
Total Obligated
Activity Timeline
Transaction History
Modifications to R01CA255809
Additional Detail
Award ID FAIN
R01CA255809
SAI Number
R01CA255809-2607883430
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Other
Awarding Office
75NC00 NIH National Cancer Institute
Funding Office
75NC00 NIH National Cancer Institute
Awardee UEI
MKAGLD59JRL1
Awardee CAGE
1DQV3
Performance District
PA-12
Senators
Robert Casey
John Fetterman
John Fetterman
Budget Funding
Federal Account | Budget Subfunction | Object Class | Total | Percentage |
---|---|---|---|---|
National Cancer Institute, National Institutes of Health, Health and Human Services (075-0849) | Health research and training | Grants, subsidies, and contributions (41.0) | $1,282,523 | 100% |
Modified: 8/20/25