Each year at the American Pancreas Association (APA) meeting, the conference opens with the Hirshberg Foundation Symposium. This year’s topic, pancreatic cancer cachexia, highlighted an important condition impacting many pancreatic cancer patients. Cachexia is especially common in pancreatic cancer and impacts up to 60-80% of patients. Due to this prevalence and its devastating effects on patients, cachexia is an active area of study in pancreatic cancer; researchers are aiming to uncover the mechanisms by which tumors drive this condition and discover new ways to treat these patients.
Cachexia is loss of muscle mass (muscle wasting) that cannot be reversed with food or nutrition supplementation. This muscle loss can be in combination with fat loss and decreased appetite and affects multiple organ systems leading to overall or systemic dysfunction. While anyone with an underlying disease can develop cachexia, it is commonly seen in cancer patients (25-70% of all types) and can be attributed to 20-40% of cancer-related deaths.
The Symposium began with Christopher Wolfgang MD, PhD, from NYU Langone Health and a 2006 Seed Grant Awardee, noting that, as a new faculty member 20 years ago, his first grant was from the Hirshberg Foundation. That early funding allowed his lab to establish itself and has now trained over 80 post-doctoral fellows, many of whom have stayed in academia and continue to contribute to the pancreatic cancer field. Dr. Wolfgang’s talk, Clinical Insights of Pancreatic Cancer Cachexia, introduced the clinician’s perspective on cachexia, explaining that muscle loss compounds the fact that pancreatic cancer patients are typically older and already frail. This frailty makes treatment of these patients difficult. For patients with resectable tumors, treatment is potentially curative but intense, and cachectic patients may not be able to withstand the chemotherapy/radiation and surgery combination needed to remove their tumors. Therefore, cachexia can be a huge factor limiting patient care.
A key take-away from Dr. Wolfgang’s talk is treatment options for cachexia are a vital need for the community. There are currently no approved therapies for cachexia, although there are a few showing promising results in clinical trials. More details need to be uncovered about the complex mechanisms of how tumor cells initiate the reprogramming of the body into a cachectic state and what other signals and organ systems are involved to begin to develop more therapies for cachexia. This type of research was the focus of the remaining talks of the Hirshberg Symposium as well as other sessions of the meeting.
Ashok Kumar, PhD from the University of Houston; Institute of Muscle Biology and Cachexia, spoke on Molecular and Signaling Mechanisms of Skeletal Muscle Wasting in Pancreatic Cancer Cachexia. The talk detailed his lab’s work to define cellular processes that lead to the breakdown of muscle cells. Using pre-clinical models of pancreatic cancer, Dr. Kumar’s lab discovered a pathway upregulated in muscle cells undergoing atrophy; the IRE1α-XBP1 pathway which is part of the unfolded protein response to stress in the endoplasmic reticulum (ER), where proteins are synthesized. This work suggests targeting of the IRE1α/XBP1 signaling pathway could be therapeutic for cachexia.
Andrew Judge, PhD, from the University of Florida, also focused on the mechanisms driving muscle wasting in his talk entitled Current Updates on Cancer Cachexia Research. Dr. Judge’s lab evaluated samples from cachectic pancreatic ductal adenocarcinoma (PDAC) patients and found increased presence of immune cells, specifically macrophages and neutrophils as well as proteins involved in the complement pathway. The complement system has an important role where activation of it leads to the tagging of cells or pathogens for destruction and then clearance by the immune system. These data help define the complement signaling pathway as an important node for immune cell infiltration into muscles during cachexia and an area for more research.
The final speaker at the Hirsberg Symposium was Min Li MD, PhD, from the University of Oklahoma Health Campus. His talk, Pancreatic Cancer Cachexia: Rethink the Biology, Rebuild the Body, explained that his research found ZIP4 was increased in pancreatic cancer patients and its expression predicted cancer progression or survival. Recent work from Dr. Li’s lab has linked ZIP4 expression in pancreatic tumors to muscle wasting in preclinical models. Dr. Li’s lab found that in tumors that expressed ZIP4, zinc was increased in the cell and increased the function of zinc dependent proteins. Dr. Li’s lab found that in tumors that over-express ZIP4, zinc is accumulated in the cell and increased the function of CREB and the expression of CREB regulated genes such as RAB27A. Increased RAB27A allows for more extracellular vesicles to be released from the tumor and these EVs in turn activate p38 signaling in muscle cells turning on degradation pathways leading to muscle wasting.
Dr. Li emphasized how the interplay between the tumor and other organ systems can control cachexia, which makes it a complex process to understand and to treat. He highlighted recent work from others in the field linking the immune system, the nervous system, and metabolic signaling to cachexia suggesting combination therapies would be necessary to address both cachexia and pancreatic cancer.
Outside the Hirshberg Symposium, Xiling Shen, MD, from MD Anderson Cancer Center, gave a talk on Vagal Modulation of the Brain-Liver Axis to Alleviate Cancer-Associated Cachexia: Mechanistic Insights and Therapeutic Strategies.They described how dysfunction in the nervous system, specifically the vagus nerve, can affect cachexia. In preclinical models, blocking signals from the vagus nerve reversed body weight loss and increased survival, appetite, and muscle function. Dr. Shen and colleagues have developed a wearable device to temporarily and reversibly block the action of the vagus nerve using a low-frequency alternating current of electricity. This low-frequency vagal block has shown an effect on pre-clinical models and healthy volunteers for 30 hours and an initial clinical trial in pancreatic cancer patients will be starting in February of 2026 in combination with the chemotherapy cocktail FOLFIRINOX.
From the University of Oklahoma Health Campus, Zhijun Zhou, MD’s abstract Metabolic Reprogramming Promotes Muscle Wasting and Immune Evasion in Pancreatic Cancer, was honored as one of the Hirshberg Award for Best Abstracts in Pancreatic Cancer. Dr. Zhou’s work explores cachexia as one potential reason for low response to immunotherapy typically seen in pancreatic cancer patients. Dr. Zhou’s work has found that the higher the percentage of macrophages, a type of immune cell, in the tumor correlated with the prevalence of cachexia. In preclinical models, when macrophages were depleted, the cachexia was attenuated; muscle atrophy was reduced and muscle strength was retained. Metabolic stress activates ZIP4 signaling in tumor cells which increases the expression of a protein that attracts and activates macrophages. These macrophages produce a pro-inflammatory protein that signals back to the tumor. The tumor cells then produced a protein called TWEAK that can induce cell death in muscle cells. This signaling reflects a positive feedback loop between macrophages and tumor cells that contributes to muscle atrophy and cachexia and complements the work presented by Drs. Judge, Li, and Shen. Taken together, these presentations all demonstrate the complex and interconnected pathways that drive cachexia and offer starting points for potential therapies that could combine with immunotherapy to address both cachexia and pancreatic cancer.
The talks presented throughout the APA meeting demonstrate how cachexia is an active area of study in pancreatic cancer with researchers trying to uncover the mechanisms by which this condition develops; what signals from the tumor drive the muscle wasting and the resulting multi-organ dysfunction. Cachexia in pancreatic cancer patients can limit treatment options and quality of life, so clinicians and researchers are eager to discover new ways to treat it and potentially extend patients’ lives.
