Congratulations to the Pilot and Feasibility Awardees for the 2020-2021 cycle:

Individual Awards

Andres Duarte-Rojo, MD, MS, DSc

Andres Duarte-Rojo, MD, DSc – Associate Professor, Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition

“Cardiopulmonary exercise testing for cardiac risk and frailty assessment in liver transplant candidates”

Patients undergoing liver transplantation (LT) have a high risk for cardiovascular disease, including coronary artery disease and cirrhotic cardiomyopathy – a form of heart failure specific to cirrhosis. Frailty is a frequent condition among LT candidates. Together, cardiac disease and frailty are major causes of morbidity and mortality before and after LT. Conventional methods to diagnose and predict cardiovascular disease in LT candidates lack sensitivity and clinically relevant application. However, cardiopulmonary exercise testing (CPET) can assess coronary artery disease, cardiomyopathy, and frailty. Such versatility of CPET has caused it to become the standard of care in many transplant centers outside of the United States. In preliminary work that will be used to fund a more definitive study (RO1), we plan to investigate coronary artery disease, cirrhotic cardiomyopathy, and frailty in LT candidates, both by existing standard of care methods and CPET. LT candidates will be invited to participate, and CPET will be performed on a recumbent cycle ergometer, taking patients to maximal exercise. Respiratory rate, oxygen consumption, carbon dioxide production, heart rate, blood pressure and electrocardiogram will be continuously monitored during the test. We will compare agreement between tests used to diagnose coronary artery disease (CPET vs. cardiac stress testing), cirrhotic cardiomyopathy (CPET vs. dobutamine stress echocardiogram), and frailty (CPET vs. liver frailty index and 6-minute walk tests). We plan on including 75 LT candidates. We expect our results to improve our capacity to assess and prognosticate cardiovascular disease and frailty in LT, ultimately changing practice.

Akshata Moghe, MD, PhD

Akshata Moghe, MD, PhD – Chief Gastroenterology Fellow, Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition

“The role of mTOR inhibition in β-catenin-mutated hepatocellular carcinoma”

Hepatocellular carcinoma (HCC) is currently the most rapidly-rising cause of cancer-related mortality in the Unites States. The 5-year survival rate of HCC is extremely poor at ~18%. We still lack effective medical therapeutic options in HCC; and the surgical options of liver transplantation or resection are the only curative strategies. However, surgical options are frequently not offered as a majority of the patients tend to present at late stages of the disease. Hence, there is an urgent need for the development and discovery of novel, efficacious medical therapies in HCC.
β-catenin-activating CTNNB1(Catenin beta1) mutations are encountered in ~1/3rd of all HCCs. To recapitulate this genetic scenario, we previously developed a Met- β-catenin-activated mouse model of HCC, which displays activation of β-catenin and Met, and develops liver tumors in 5-6 weeks. Recent data in this mouse model demonstrated that β-catenin-activated tumors are addicted to mTOR for survival via a robust Wnt-β-catenin-glutamine synthetase (GS)-mTORC1 axis. Further, disruption of this axis using rapamycin, an mTOR inhibitor, led to impressive growth inhibition in the tumors. It is known that mTOR activation plays a critical role in HCC pathogenesis. In spite of this, everolimus, an mTORC1 inhibitor, showed no significant survival benefit over placebo in the Everolimus for Liver Cancer Evaluation (EVOLVE-1) trial, a randomized, double-blind, phase 3 study in HCC patients who had failed first-line therapy (Sorafenib). It was theorized that the lack of benefit stemmed from the fact that the recruited HCC patients were ‘all-comers’, and had not been selected for mTOR-activated tumors. These data, and our preliminary results with rapamycin in β-catenin-activated HCC, suggest that the benefit of mTOR inhibition in HCC is selective to certain classes of HCC, i.e. those that activate mTOR as part of their cancer pathogenesis. Our overall hypothesis is that β-catenin activation can serve as a biomarker for responsiveness to mTOR inhibition in HCC. Our studies are ultimately directed towards the goal of precision medicine, aiming for individualization of therapy to maximize positive outcomes.

Dr. Samer Tohme

Samer Tohme, Complex General Surgical Oncology and HPB Fellow, Department of Surgery

“The Role of Neutrophil Extracellular Traps in Promoting the Progression of Metastases after Liver Ischemia-Reperfusion”

More than a quarter of people worldwide will ultimately be affected by cancer with metastases as the most feared
presentation. Although developing metastases is a devastating cause of mortality worldwide, when feasible, resection of metastatic disease can provide a chance of cure and improve survival. The liver represents a major site of metastatic disease. Resection of hepatic metastases is performed with a curative intent; however, cancer recurs in most patients and is the major cause of treatment failure. The local and systemic inflammatory changes resulting from surgery may promote tumor growth through a complex set of incompletely understood pathways. No intervention to date is used in the perioperative period to help prevent tumor recurrence. This work will define the unique roles of neutrophils and neutrophil extracellular traps (NETs) in promoting growth of metastases after surgery, thus opening the potential NETs as a therapeutic target in the immediate postoperative period. To identify relevant pathways, we utilized our established murine model of liver ischemiareperfusion (I/R) and liver metastases. Liver I/R is a strong inducer of NET formation and significantly increases the growth of liver metastases. The effect of liver I/R on tumor growth was significantly inhibited in mice genetically incapable of forming NETs (PAD4KO mice) or mice treated with DNAse, an inhibitor of NETs. Similarly, in patients undergoing resection of hepatic colorectal metastases, high NET formation in the immediate postoperative period correlated with a 4x increase risk of cancer recurrence.
This grant proposal will address how surgery-induced NETs can affect tumor growth by 1) inducing an immunosuppressive microenvironment allowing cancer cells’ immune escape and 2) directly interacting with cancer cells to help them meet the metabolic demands of tumor growth and gain survival advantage via the process of mitochondrial biogenesis.

Bokai Zhu, PhD

Bokai Zhu, PhD – Assistant Professor, Department of Medicine, Division of Endocrinology and Metabolism

“Hepatic 12h-to-24h reprogramming drives NAFLD”

In addition to the circadian rhythms (~24h oscillation), genes cycling with a 12h period were also prevalently found in multiple species ranging from circatidal marine animals, to nematode C. elegans and mammals like mouse and baboon. Our group recently discovered a mammalian 12h-clock that is evolutionarily conserved, cell-autonomous and established independently from the circadian clock but dependent on the unfolded protein response transcription factor XBP1s. Liver-specific deletion of XBP1s globally impairs the murine 12h transcriptome, but not circadian rhythms in vivo. XBP1s-dependent hepatic 12h transcriptome preferentially peaks at dawn and dusk, and is remarkably enriched in pathways regulating innate immune functions and endoplasmic reticulum (ER) and the Golgi apparatus homeostasis, including translation regulation, protein processing and sorting in ER and Golgi, protein quality control and sphingolipid and glycerolipid metabolism.
These pathways are often dysregulated during NAFLD progression. It is well-established that nutritional challenge such as high fat diet (HFD) can lead to NAFLD. Very intriguingly, preliminary data revealed a very robust global reprogramming of 12h-cycling transcriptome and metabolome to 24h circadian rhythms under high fat diet condition in mouse liver. This HFD-induced 12h-to-24h hepatic reprogramming is further associated with a conversion of 12h hepatic XBP1s oscillation to 24h circadian oscillation. Based upon these findings, we hypothesize that hepatic 12h-to-24h (circadian) reprogramming drives NAFLD. This proposal is aimed to study whether this 12h-to-24h reprogramming is casually linked to the NAFLD development.

Team Award

Carla Ng, PhD Stacy Wendell, PhD

Carla Ng, PhD – Assistant Professor, Civil and Environmental Engineering
Stacy Wendell, PhD – Assistant Professor, Pharmacology and Chemical Biology

“Investigating the impacts of an emerging PFAS contaminant, Nafion-BP2, on liver metabolism”

Non-alcoholic fatty liver disease (NAFLD) affects 20-30% of the population in Western countries and is the number one cause of liver disease in children. In addition to contributors such as obesity and metabolic syndrome there is growing concern that chronic exposure to environmental toxicants such as per- and polyfluorinated alkyl acids (PFAA) contribute to liver disease. PFAA are highly persistent toxicants that have been detected in more than 99% of the US population and have been associated with markers of liver injury in exposed populations. Due to the growing concern for their long half-lives and association with a variety of disease pathologies, long chain PFAA, such as perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) have been replaced by a variety of per- and polyfluorinated alkyl ethers (PFAEs). Although intended to be safe replacements, there is now a growing body of evidence that these less studied compounds are also toxic and bioaccumulative. The co-PIs will combine their expertise in the biological fate and toxicokinetics of perfluorinated substances and on lipidomic and metabolomic analysis of toxicant impact to investigate whether PFAE replacements of long-chain PFAAs promote similar types and extent of liver injury. This proposal will focus on a particular PFAE, Nafion By-Product 2 (NBP2), recently discovered in the blood of residents living near a facility where it was used to replace long-chain PFAAs in fluoropolymer synthesis. We believe that NBP2 will be just as deleterious as PFOS, a PFAA of similar fluorinated chain length, in contributing to liver injury. We will test this hypothesis through complementary aims that will provide both discovery data sets and mechanistic insight into NBP2 signaling actions. Completion of this project will provide critical insight into the toxicological implications of ongoing exposure to NBP2. More broadly, our results will provide insight into the biological actions of PFAE with a goal of establishing structure-based modes of action for diverse PFAA and PFAE structures related to liver disease.