Deciphering the Brain–Liver Axis in Cancer-Associated Cachexia

Abstract public domain (NIH RePORTER)

SUMMARY Cancer-associated cachexia (CAC) is a devastating, multifactorial syndrome affecting many advanced cancer patients, particularly those with pancreatic, gastrointestinal, and lung cancers. Characterized by weight loss, muscle wasting, and anorexia, CAC contributes to diminished quality of life, increased treatment toxicity, and ultimately accounts for nearly half of all cancer-related deaths. Despite its prevalence and clinical impact, there are currently no FDA-approved therapies for CAC, and existing interventions remain limited to supportive care with marginal benefit. Thus, there is a critical unmet need to develop effective treatments that both improve patient well-being and extend survival. The team has recently identified vagal hyperactivation as a key driver of CAC through disruption of the brainliver axis. A novel low-frequency vagal block (LFVB) approach has been developed to effectively prevent and reverse cachexia in preclinical cachectic models of pancreatic and lung cancers. LFVB eliminates weight loss, improves appetite, preserves muscle mass, restores hepatic metabolism, reduces inflammation, and significantly extends survival. Importantly, LFVB synergizes with chemotherapy, nearly doubling survival benefit compared to chemotherapy alone. The team has further advanced this technology into a non-invasive, flexible, transcutaneous LFVB (tLFVB) electroceutical patch, which has demonstrated equivalent preclinical efficacy and proven safety in large animal models and early human studies, providing a strong foundation for clinical translation. Building on these findings, this project will evaluate whether tLFVB can halt the progression of cachexia and improve associated phenotypes through a sponsored, randomized controlled clinical trial in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) receiving frontline chemotherapy. In addition, the project will investigate the mechanisms underlying the anti-cachectic effects of tLFVB by examining how the vagus nerve modulates hepatic metabolism and neuroimmune crosstalk via HNF4 -regulated pathways in CAC. Collectively, these studies will position tLFVB as a potential first-in-class therapy for CAC while providing new mechanistic insights into cachexia pathogenesis. If successful, this work could transform the management of CAC, extend survival, and enhance the effectiveness of cancer treatment for patients with pancreatic cancer and other malignancies. There is currently no in vitro or in silico model that can recapitulate the systemic nature of cachexia, including the vagal brain–liver axis and its metabolic and inflammatory effects on the body, hence established animal cachexia models will be used for the mechanistic study.

Public health relevance public domain (NIH RePORTER)

NARRATIVE Cancer-associated cachexia remains a critical unmet need, with no effective therapies to halt its progression or improve patient outcomes. This project will investigate how vagal signaling regulates hepatic metabolism and systemic inflammation, two central mechanisms driving cachexia. It will further evaluate whether vagal blockade can slow or reverse cachectic progression, offering a potential first-in-class therapeutic strategy.