Development of a Gut Microbiome-Based Prognostic Signature Predicting Risk of Hepatocellular Cancer Recurrence After Ablative Therapies
Abstract
The current project is focused on liver cancer, which has been identified by the Congress as one of the FY20 PRCRP Topic Areas. Additionally, this project is focused on better understanding recurrence and thereby improving the quality of life of survivors, which is an Area of Emphasis for FY20 PRCRP. Liver cancer is the fifth most common cause of cancer-related deaths in the United States. Hepatocellular cancer (HCC) is the most common type of liver cancer. Due to high prevalence of the risk factors like hepatitis B and C infection, our military personnel and Veterans bear significant brunt of this formidable disease. For patients with early and localized hepatocellular cancer, surgery or tumor destruction by ablation can be curative. However, most of these patients face a very high risk of cancer coming back. For instance, despite good surgery or ablation, up to 60% of the patients are at risk of their tumor coming back within 5 years. Unfortunately, today, there is no way we can predict which patients will recur, and thus benefit from additional therapy, close surveillance, or even participation in clinical trials of novel therapies. Thus, there is a striking need to identify novel biomarkers that can predict recurrence, and even response to novel treatments. We are surrounded by bacteria. In fact, a large number of bacteria live in our intestines, a niche known as gut microbiome. Not all bacteria are harmful, and many living in our intestines have vital functions and help us live a healthy life. However, our recent studies in animal models of cancer suggest that some of the gut bacteria may actually promote cancer growth and recurrence. These findings have immense clinical significance as our small human study suggests that some patients may harbor cancer-promoting bacteria in their gut microbiome. This may suggest that differences in gut microbiome composition may explain why some patients recur after adequate surgery and chemotherapy, whereas others do not. In the current grant proposal, we are building on our initial studies and evaluating our concepts in patients suffering from localized HCC, which is treatable with surgery or ablation. Based on our preliminary data, we have hypothesized that the composition of gut microbial bacteria helps predict risk of recurrence. In other words, looking at gut microbiome composition can help us predict which patients with localized HCC will or will not recur despite adequate surgery and for whom alternative strategies need to be evaluated. In the second part of the current proposal, using animal studies, we will evaluate whether gut microbiome modulation can help decrease the risk of cancer coming back. For this, we will use a state-of-the-art model human gut microbiome AVATAR mice, where the gut microbiome of patients with HCC will be transplanted into germ-free mice, followed by implantation of the liver cancer cells in them. These AVATAR mice will be used to evaluate whether gut microbiome modulation by antibiotics or prebiotics can decrease tumor growth. Successful execution of these studies will lead to two benefits: (1) proposed studies will lead to generation of a gut microbiome composition signature, where presence of certain bacteria in the gut microbiome will predict the risk of recurrence in patients with HCC. This signature will be identified during the duration of the proposed study (4 years) followed by validation in another 4 years. Thus, within a decade from initiation of this project, this signature could help select appropriate treatment for patients with HCC. (2) The proposed studies will also decipher if gut microbiome can be modulated to decrease the risk of recurrence. The gut microbiome modulation strategies that we will evaluate include, prebiotics, probiotics and poorly absorbable oral antibiotics, which are easily translatable to the clinical realm. With the help of preclinical data generated from these studies, we propose to start a clinical tr
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110649
Entities
People
- Vikas Dudeja
Organizations
- United States Army
- University of Alabama at Birmingham