Confronting Cachexia - A Disease within a Disease

Cancer-associated cachexia is a syndrome that is clinically defined by weight loss. The current definition is useful in that it predicts chemotherapy toxicity, complications from cancer surgery, and mortality across many tumor types. However, it lacks the appropriate specificity required for routine clinical care and clinical trial enrollment. Many physiologic processes can lead to weight loss and it is unlikely that one therapy will benefit all conditions. Data from our and other cancer cachexia clinics suggest that there are subtypes of cachexia that uniquely benefit from existing interventions. In the first half of this talk, I will review our algorithm for clinical cachexia management. In the second half, I will discuss pre-clinical data that support the need for a multi-modal approach to treating cachexia.

Cancer cachexia is a multifactorial energy‐wasting syndrome reducing the efficiency of anti‐cancer therapies, quality of life, and survival of cancer patients. It is becoming increasingly evident that both tumor- and host-derived signalling molecules mediate tissue wasting. Tissue crosstalk therefore is an important aspect of cachexia development and progression.

Using secretome analyses, we have identified novel tumor-secreted proteins driving organ dysfunction and catabolism. These may serve as biomarkers for the early disease detection, and represent potential new mechanisms for intervention. In addition, we are addressing the knowledge gap regarding bioactive lipids in cachexia, which exists despite ample evidence of altered lipid metabolism in metabolic organs such as adipose tissue. Circulating bioactive lipids are important endocrine mediators regulating inflammation, metabolism, and energy expenditure, playing central roles in metabolic disease.

We have measured the lipid profile in plasma of multiple different mouse models of cachexia and weight-losing cancer patients. We identified 8 lipid species consistently and significantly altered in all mice and patients with cachexia, and correlating with weight loss. Altered lipid metabolism in the liver was key to altered lipid levels. With the identification of specific signalling lipids and underlying mechanisms, we have come closer to understanding the complexity of multi-organ dysfunction in metabolic wasting.

Cancer cachexia is a complex multi-organ syndrome characterized by weight loss, muscle atrophy, fat mass loss, anorexia and inflammation. With a prevalence of 1 million people in Europe and only limited therapeutic options, there is a high medical need for new approaches to treat cachexia. In this context, we started a few years ago studying the therapeutic interest of modulating the gut microbiota in the context of cancer cachexia.

We discovered not only that the gut microbiota composition and function were deeply altered in cancer cachexia but also that the gut function itself was altered at several levels (gut immunity, gut barrier, epithelium renewal, intestinal morphology), independently of any chemotherapeutic intervention. Furthermore, our experimental results establish that nutritional modulation of the gut microbiota could constitute an interesting adjuvant therapeutic tool for cancer and associated cachexia. Among the mechanisms involved in these beneficial effects, we can pinpoint some nutritionally derived microbial metabolites being able to influence cancer progression outside the gastrointestinal tract. In addition, our recent findings support a therapeutic interest for modulating the gut microbiota to target the gut dysfunction as well as a role for microbial metabolites in the regulation of the hepatic inflammation associated with cancer development.

Cachexia is a debilitating syndrome that results in severe, involuntary weight loss due to the depletion of skeletal muscle mass. Currently, no effective therapy exists to combat this malignant disorder. For pancreatic cancer, 85% of patients lose on average 14% of their pre-illness weight, and cachexia dramatically limits their ability to tolerate surgery, chemo- or radiotherapy. New therapies will likely evolve from an enhanced understanding of the mechanisms leading to muscle wasting and tumor development. Our laboratory has been examining the role of the NF-kB signaling pathway in tumorigenesis for several decades and that interest led us to discover the connection between NF-kB and muscle wasting in cancer cachexia. We view the pathway as playing an important function in cancer-induced cachexia. We have found that during cancer progression, skeletal muscle undergoes a type of injury response leading to the activation of resident stem cells to engage in a regeneration program. NF-kB is activated in these stem cells and functions to inhibit regeneration, which contributes to the overall wasting process in cachexia. New data reveal that NF-kB activity in progenitor cells also regulates a local muscle inflammatory environment that might also contribute to skeletal muscle catabolism. The mechanism of this regulation will be discussed in more details and is consistent with the notion that NF-kB functions in cancer cachexia by acting in muscle stem cells to block muscle repair.

We have shown that muscle depletion and weakness occur as a direct consequence of anticancer treatments (i.e., chemotherapy), mainly by affecting mitochondrial homeostasis and energy metabolism. We sought to investigate whether preservation of muscle mitochondria may prevent muscle loss and neurodegeneration following chemotherapy. Here, we showed that chemotherapy drives loss of muscle mass and strength, accompanied by neurodegeneration and changes in electrophysiological parameters (e.g., MUNE, SMUP). C2C12 cultures overexpressing OPA1, a regulator of mitochondrial fusion, maintained their myotube size when exposed to chemotherapy, whereas administration of the mitochondria-targeted antioxidant MitoQ to C2C12 cultures in combination with Folfiri was able to preserve myotube size, also consistent with improved OPA1 expression. Similarly, cisplatin-treated mice infected with AAV-OPA1 showed preserved plantar flexion force and innervation. Interestingly, 18- month-old transgenic mice overexpressing the regulator of mitochondrial biogenesis PGC1alpha in their skeletal muscle were protected from cisplatin-induced loss of muscle mass and weakness and presented preservation of MUNE and SMUP, unlike young animals. Our results suggest that preserving mitochondria may be a novel therapeutic strategy to counteract chemotherapy-induced muscle toxicities. Hence, prospective multi-modal therapies including mitochondria-targeted agents in combination with chemotherapy are warranted.

Cancer patients experience cachexia which is characterized by extensive skeletal muscle wasting that worsens the quality of life and increases mortality. Currently, there are no approved treatments that can effectively counteract cancer cachexia. Vascular endothelial cells (ECs) are essential for maintaining tissue perfusion, nutrient supply and preventing inappropriate transmigration of immune cells into the tissue. However, little is known about the role of the muscle vasculature in cancer cachexia. We hypothesized that endothelial dysfunction in the skeletal muscle mediates cancer cachexia. Using genetically modified KPCpancreatic ductal adenocarcinoma (PDAC) mice and a tissue clearing and high-resolution 3Dtissue imaging approach, we found that the loss of skeletal muscle vascular density precedes the loss of muscle mass. Circulating Activin-A released by the tumor suppresses expression of the transcriptional co-activator PGC1α in the muscle endothelium of cachexic mice, thus disrupting junctional integrity in the vasculature and increasing vascular leak. Furthermore, an EC-specific inducible PGC1α deletion (ECΔPGC1α) mouse phenocopied the decreased vascular density and muscle loss observed in tumor-bearing mice. Our study suggests that EC-PGC1α is essential for maintaining the integrity of the skeletal muscle vascular barrier and that restoring muscle endothelial dysfunction could be a novel therapeutic approach to prevent or reverse cancer cachexia.

Cancer cachexia is a complex condition from both a biological and clinical perspective resulting in a major area of unmet medical need.  The current lack of effective interventions have limited guideline recommendations and resulted in lack of recognition of the disorder and under-management.  Clinical trials have provided important insights into patient outcomes, both in the control and treatment groups.  However, a limited number of agents under study, combined with lack of agreement on major endpoints and limited regulatory guidance have all been barriers to the success of clinical trials.  Fortunately, with the scientific advances in the preclinical study of cancer cachexia, many pathways and potential targets have emerged with several new promising agents in development.  The recent approval of anamorelin for the treatment of cachexia in cancer patients in Japan is an exciting step forward that will hopefully help provide guidance for regulatory authorities, as well as clinical investigators involved with clinical trial design, leading to an expansion of clinical research in this field in the years ahead.

Cachexia is a disease associated with malnutrition, with severe loss of skeletal muscle mass. Optimizing nutritional status is one of the unmet needs in optimal disease care. For example, in the cancer context, International oncology societies now recognize that nutrition is part of the comprehensive management of cancer care, which should be initiated early in the disease trajectory.

Patients with cachexia have anabolic potential. Importantly, the quality and quantity of nutrients is essential to prevent and reverse muscle loss. Although targeted nutrition care goals and expected outcomes are different among precachexia, cachexia and refractory cachexia, they provide a framework for the role of nutrition support in the context of multimodal interventions. The latter is considered the way of the future to optimize outcomes in cachexia.