Cachexia Research Articles

IL36G-producing neutrophil-like monocytes promote cachexia in cancer

Most patients with advanced cancer develop cachexia, a multifactorial syndrome characterized by progressive skeletal muscle wasting. Despite its catastrophic impact on survival, the critical mediators responsible for cancer cachexia development remain poorly defined. Here, we show that a distinct subset of neutrophil-like monocytes, which we term cachexia-inducible monocytes (CiMs), emerges in the advanced cancer milieu and promotes skeletal muscle loss. Unbiased transcriptome analysis reveals that interleukin 36 gamma (IL36G)-producing CD38+ CiMs are induced in chronic monocytic blood cancer characterized by prominent cachexia. Notably, the emergence of CiMs and the activation of CiM-related gene signatures in monocytes are confirmed in various advanced solid cancers. Stimuli of toll-like receptor 4 signaling are responsible for the induction of CiMs. Genetic inhibition of IL36G-mediated signaling attenuates skeletal muscle loss and rescues cachexia phenotypes in advanced cancer models. These findings indicate that the IL36G-producing subset of neutrophil-like monocytes could be a potential therapeutic target in cancer cachexia.

Tumor immune microenvironment promotes cachexia in pancreatic cancer.

Tumor immune microenvironment promotes cachexia in pancreatic cancer.

SP4.9 - Relationship Between Classifications for Cancer Cachexia and Overall Survival in Patients with Oesophagogastric Cancer

Abstract Aim Classifications for cancer cachexia remain heterogenous within the existing literature. The aim of this study is to compare prognostication using three established descriptors: the Fearon et al. consensus definition, Martin et al.’s weight loss grading system and the Global Leadership Initiative on Malnutrition (GLIM) criteria, in patients with oesophagogastric cancer. Methods Consecutive patients with newly diagnosed oesophagogastric cancer between 2019-2020 were identified from a prospectively maintained regional database. Data were retrieved regarding involuntary weight loss, body mass index, CT body composition analyses and neutrophil-lymphocyte-ratio at the time of clinical staging. This allowed comparison based on Fearon, Martin and GLIM classifications. The primary outcome of interest was overall survival. Results Overall, 465 patients (66.9% male, median 71 years) were diagnosed with oesophageal (72.0%) or gastric cancer (28.0%). Greater proportions of advanced stage disease were associated with Fearon (p=0.019), Martin (p=0.004) and GLIM (p<0.001) defined cachexia. Patients who met the GLIM criteria were also older and had poorer ECOG performance status (both p<0001). Each cachexia classifier was associated with worsened overall survival (all p<0.001). Following adjustment for clinicopathological confounders, Fearon (aHR: 1.54 (95%CI:1.24-1.92) and GLIM defined cachexia (aHR: 1.74 (95%CI:1.40-2.17) were both adversely associated with overall survival. Grade 4 weight-loss, as per Martin et al., had the greatest prognostic effect (aHR: 2.11 (95%CI:1.52-2.93). Conclusion Cancer cachexia is strongly associated with poorer survival in oesophagogastric cancer. The GLIM criteria and high Martin et al. weight loss grade appear to have the greatest prognostic value.

MOY 2 - ‘Cachexia Index’ for Prognostication in Surgical Patients with Locally Advanced Oesophageal or Gastric Cancer: A Multicentre Cohort Study

Abstract Background Features of cancer cachexia are known to adversely influence patient outcomes, yet few currently inform clinical decision-making. This study assessed the value of ‘cachexia index’ (CXI), a novel prognostic marker, in patients planned for curative multimodal therapy (neoadjuvant chemotherapy (NAC) and surgery) for oesophagogastric cancer. Methods Consecutive patients newly diagnosed with locally advanced (T3/4 or ≥N1) oesophagogastric cancer were identified through the West of Scotland and South-East Scotland Cancer Networks. CXI was calculated as (L3 skeletal muscle index) x (serum albumin) / (neutrophil-lymphocyte-ratio). Sex-stratified cut-off values were determined based on area under the curve (AUC), and patients were divided into low and normal CXI groups. Primary outcomes of interest were disease progression during NAC and overall survival (≥5-years follow-up). Results Overall, 385 patients (72% male, median 66 years) were treated with NAC for oesophageal (n=274) or gastric (n=111) cancer across the study period. While patients with a low CXI (males: <52 [AUC: 0.691] and females: <41 [AUC: 0.759]) were older and more comorbid, disease characteristics were comparable to those with a normal CXI. Rates of disease progression during neoadjuvant chemotherapy, leading to inoperability, were higher in patients with low CXI (28% vs. 12%, aOR: 3.07 (95% CI: 1.67-5.64), p<0.001). Moreover, low CXI was associated with worsened post-operative mortality (p=0.019) and decreased overall survival (median: 14.9 vs. 56.9 months, aHR: 1.85 (95% CI: 1.42-2.42), p<0.001). Conclusion CXI represents a valuable marker of ‘host stage’, and a potential adjunct to routine tumour staging. This could improve prognostication and decision-making in patients with locally advanced oesophagogastric cancer.

FP1.1 - The relationship between tumour necrosis, the tumour microenvironment, systemic inflammation, body composition and survival in patients with operable colon cancer. Does tumour necrosis drive systemic inflammation and cachexia?

Abstract Introduction The prognostic value of the systemic inflammatory response and its incorporation into the definition of cancer cachexia (GLIM) is now established. However, the basis of the relationship between the tumour, its environment and the systemic inflammatory response is not clear. The aim of the present study is to examine this hypothesis in greater detail. Methods A total of 473 patients were included. Host and tumour characteristics were assessed including tumour cell signaling pathways, CT derived body composition and systemic inflammation (as assessed by SIG). Categorical variables were analysed using χ2 test for linear-by-linear association, or χ2 test for 2 by 2 tables. Survival analysis was carried out using univariate Cox regression. Results Tumour necrosis was associated with age (p<0.01), tumour location (p<0.01), T-stage (p<0.001), margin involvement (p<0.05), SIG (p<0.001), SMI (Martin, p<0.01), SMI (Dolan, p<0.01), SMD (Dolan, p<0.05) and 5-year survival (p<0.001). No association was found between tumour necrosis and signalling markers of the IL-6/JAK/ STAT and NF-KB pathways. On univariate survival analysis age (p<0.001), ASA (p<0.001), T-stage (p<0.001), N-stage (p<0.001), tumour budding (p<0.05), venous invasion (p<0.01), adjuvant therapy (p<0.01), margin involvement (p<0.001), necrosis (p<0.01), SIG (p<0.001), MUST (p<0.001), BMI (p<0.05), sub cutaneous obesity (p<0.001), visceral obesity (p<0.05), Sarcopenia (Martin, p<0.05), Sarcopenia (Dolan, p<0.01), Myosteatosis (Dolan, p<0.05) GMS (p<0.001), Ki67 (p<0.01) and TSP (p<0.01) were independently associated with overall survival. Conclusion There is a clear association between tumour necrosis, the SIR and body composition in patients with colon cancer. These results are consistent with the hypothesis that tumour necrosis and the subsequent inflammatory response results in profound changes in body composition.

Supplementation with Fish Oil and Selenium Protects Lipolytic and Thermogenic Depletion of Adipose in Cachectic Mice Treated with an EGFR Inhibitor.

Lung cancer and cachexia are the leading causes of cancer-related deaths worldwide. Cachexia is manifested by weight loss and white adipose tissue (WAT) atrophy. Limited nutritional supplements are conducive to lung cancer patients, whereas the underlying mechanisms are poorly understood. In this study, we used a murine cancer cachexia model to investigate the effects of a nutritional formula (NuF) rich in fish oil and selenium yeast as an adjuvant to enhance the drug efficacy of an EGFR inhibitor (Tarceva). In contrast to the healthy control, tumor-bearing mice exhibited severe cachexia symptoms, including tissue wasting, hypoalbuminemia, and a lower food efficiency ratio. Experimentally, Tarceva reduced pEGFR and HIF-1α expression. NuF decreased the expression of pEGFR and HIF-2α, suggesting that Tarceva and NuF act differently in prohibiting tumor growth and subsequent metastasis. NuF blocked LLC tumor-induced PTHrP and expression of thermogenic factor UCP1 and lipolytic enzymes (ATGL and HSL) in WAT. NuF attenuated tumor progression, inhibited PTHrP-induced adipose tissue browning, and maintained adipose tissue integrity by modulating heat shock protein (HSP) 72. Added together, Tarceva in synergy with NuF favorably improves cancer cachexia as well as drug efficacy.

Increased Myocardial MAO-A, Atrogin-1, and IL-1β Expression in Transgenic Mice with Pancreatic Carcinoma-Benefit of MAO-A Inhibition for Cardiac Cachexia.

Cancer cachexia (CC) continues to challenge clinicians by massively impairing patients' prognosis, mobility, and quality of life through skeletal muscle wasting. CC also includes cardiac cachexia as characterized by atrophy, compromised metabolism, innervation and function of the myocardium through factors awaiting clarification for therapeutic targeting. Because monoamine oxidase-A (MAO-A) is a myocardial source of H2O2 and implicated in myofibrillar protein catabolism and heart failure, we presently studied myocardial MAO-A expression, inflammatory cells, and capillarization together with transcripts of pro-inflammatory, -angiogenic, -apoptotic, and -proteolytic signals (by qRT-PCR) in a 3x-transgenic (LSL-KrasG12D/+; LSL-TrP53R172H/+; Pdx1-Cre) mouse model of orthotopic pancreatic ductal adenoarcinoma (PDAC) compared to wild-type (WT) mice. Moreover, we evaluated the effect of MAO-A inhibition by application of harmine hydrochloride (HH, 8 weeks, i.p., no sham control) on PDAC-related myocardial alterations. Myocardial MAO-A protein content was significantly increased (1.69-fold) in PDAC compared to WT mice. PDAC was associated with an increased percentage of atrogin-1+ (p < 0.001), IL-1β+ (p < 0.01), COX2+ (p < 0.001), and CD68+ (p > 0.05) cells and enhanced transcripts of pro-inflammatory IL-1β (2.47-fold), COX2 (1.53-fold), TNF (1.87-fold), and SOCS3 (1.64-fold). Moreover, PDAC was associated with a reduction in capillary density (-17%, p < 0.05) and transcripts of KDR (0.46-fold) but not of VEGFA, Notch1, or Notch3. Importantly, HH treatment largely reversed the PDAC-related increases in atrogin-1+, IL-1β+, and TNF+ cell fraction as well as in COX2, IL-1β, TNF, and SOCS3 transcripts, whereas capillary density and KDR transcripts failed to improve. In mice with PDAC, increased myocardial pro-atrophic/-inflammatory signals are attributable to increased expression of MAO-A, because they are significantly improved with MAO-A inhibition as a potential novel therapeutic option. The PDAC-related loss in myocardial capillary density may be due to other mechanisms awaiting evaluation with consideration of cardiomyocyte size, cardiac function and physical activity.

Challenges in Targeting the “Crosstalks” in Cancer Cachexia

AbstractCancer cachexia syndrome is characterized by involuntary weight loss which usually occurs in advanced malignancies. The pathogenicity of this syndrome is multifactorial, due to a complex interaction of tumor and host factors. The syndrome is closely related to the prognostication of malignancies. Several research works are in progress to target the major effectors of cancer cachexia syndrome. This letter is a nutshell on the current status of the cancer cachexia syndrome—the crosstalks and potential therapeutic targets.

Efficacy and safety of pharmacotherapy for cancer cachexia: A systematic review and network meta-analysis.

Cancer cachexia affects more than half of all cancer patients, reducing survival rates. Evidence-based approaches are urgently needed to optimize treatment. A systematic review and network meta-analysis were conducted to assess the effectiveness and safety of different pharmacotherapies for cancer cachexia. Three databases (PubMed, Cochrane Library, and Web of Science) were searched for the period from January 1, 2000, to March 20, 2024. The netmeta package in R software was used to calculate the pooled effect, employing a random effects model. Seven placebo-controlled randomized trials involving 1421 patients were analyzed. Pairwise analysis showed that body weight increases were 4.6 kg (95% confidence interval [CI] 0.83-8.37 kg) for olanzapine, 3.82 kg (95% CI 0.73-6.91 kg) for espindolol (20 mg), 2.36 kg (95% CI 1.84-2.89 kg) for anamorelin (100 mg), and 1.31 kg (95% CI 0.42-2.19 kg) for anamorelin (50 mg). In terms of safety profiles, olanzapine demonstrated the lowest odds ratio when compared to placebo, at 0.26 (95% CI 0.07-0.94), followed by anamorelin (50 mg) at 0.86 (95% CI 0.30-2.48), and anamorelin (100 mg) at 0.89 (95% CI 0.42-1.88). However, network meta-analysis could not confirm the superiority of olanzapine over anamorelin in terms of efficacy and safety. Both olanzapine and anamorelin are useful in improving body weight in patients with cancer cachexia. Personalization may be helpful for different patients.

526. COMPARISON OF CANCER CACHEXIA DEFINITIONS AND THEIR ASSOCIATION WITH OVERALL SURVIVAL IN PATIENTS WITH INCURABLE OESOPHAGOGASTRIC CANCER

Abstract Background Cancer cachexia is highly prevalent in oesophagogastric cancer, particularly amongst patients with advanced stage disease. However, classifications for cachexia remain heterogenous within the existing literature. The aim of this study is to compare prognostication using the Fearon et al. consensus definition to the Global Leadership Initiative on Malnutrition (GLIM) criteria, in patients with incurable oesophagogastric cancer. Methods Consecutive patients with newly diagnosed incurable oesophagogastric cancer between 2019-2020 were identified from a prospectively maintained regional database. Data were collected regarding demographics, clinicopathological details, patient-reported involuntary weight loss and body mass index. CT body composition analysis was performed using staging scans and neutrophil-lymphocyte-ratio was retrieved as a marker of inflammation at the time of diagnosis. These data allowed comparison based on Fearon and GLIM classifications for cachexia. The primary outcome of interest was overall survival. Results Overall, 330 patients (66.9% male, median 74 years) were diagnosed with incurable oesophageal (70.6%) or gastric cancer (29.4%) during the study period. Of these 65.5% (n=216) met the Fearon definition of cachexia at diagnosis, while 64.8% (n=214) could be diagnosed based on the GLIM criteria. Both diagnostic criteria were met by 148 patients (47.9%). Clinicopathological characteristics were all broadly comparable between cachectic and non-cachectic groups based on both classifications. Worse overall survival was seen in cachectic patients using Fearon (median: 118 vs. 228 days) and GLIM (median: 114 vs. 245 days) diagnostic criteria (both p&amp;lt;0.001). Following adjustment for known confounders, cachexia diagnosed based on the GLIM criteria (HR 1.60 (95%CI: 1.25-2.05), p&amp;lt;0.001) was more strongly associated with adverse survival than that diagnosed using the Fearon criteria (HR: 1.44 (95%CI: 1.13-1.84), p=0.003)). Conclusion Cancer cachexia is strongly associated with worse survival in patients with incurable oesophagogastric cancer. Diagnosis based on the GLIM criteria appears to have the greatest prognostic effect.

EDA2R-NIK signaling in cancer cachexia.

Cachexia is a debilitating condition causing weight loss and skeletal muscle wasting that negatively influences treatment and survival of cancer patients. The objective of this review is to describe recent discoveries on the role of a novel signaling pathway involving ectodysplasin A2 receptor (EDA2R) and nuclear factor κB (NFκB)-inducing kinase (NIK) in muscle atrophy. Studies identified tumor-induced upregulation of EDA2R expression in muscle tissues in pre-clinical cachexia models and patients with various cancers. Activation of EDA2R by its ligand promoted atrophy in cultured myotubes and muscle tissue, which depended on NIK activity. The non-canonical NFκB pathway via NIK also stimulated muscle atrophy. Mice lacking EDA2R or NIK were protected from muscle loss due to tumors. Tumor-induced cytokine oncostatin M (OSM) upregulated EDA2R expression in muscles whereas OSM receptor-deficient mice were resistant to muscle wasting. Recent discoveries revealed a mechanism involving EDA2R-NIK signaling and OSM that drives cancer-associated muscle loss, opening up new directions for designing anti-cachexia treatments. The therapeutic potential of targeting this mechanism to prevent muscle loss should be further investigated. Future research should also explore broader implications of the EDA2R-NIK pathway in other muscle wasting diseases and overall muscle health.

Anabolic deficits and divergent unfolded protein response underlie skeletal and cardiac muscle growth impairments in the Yoshida hepatoma tumor model of cancer cachexia.

Cancer cachexia manifests as whole body wasting, however, the precise mechanisms governing the alterations in skeletal muscle and cardiac anabolism have yet to be fully elucidated. In this study, we explored changes in anabolic processes in both skeletal and cardiac muscles in the Yoshida AH-130 ascites hepatoma model of cancer cachexia. AH-130 tumor-bearing rats experienced significant losses in body weight, skeletal muscle, and heart mass. Skeletal and cardiac muscle loss was associated with decreased ribosomal (r)RNA, and hypophosphorylation of the eukaryotic factor 4E binding protein 1. Endoplasmic reticulum stress was evident by higher activating transcription factor mRNA in skeletal muscle and growth arrest and DNA damage-inducible protein (GADD)34 mRNA in both skeletal and cardiac muscles. Tumors provoked an increase in tissue expression of interferon-γ in the heart, while an increase in interleukin-1β mRNA was apparent in both skeletal and cardiac muscles. We conclude that compromised skeletal muscle and heart mass in the Yoshida AH-130 ascites hepatoma model involves a marked reduction translational capacity and efficiency. Furthermore, our observations suggest that endoplasmic reticulum stress and tissue production of pro-inflammatory factors may play a role in the development of skeletal and cardiac muscle wasting.

LBA82 Efficacy and safety of ponsegromab, a first-in-class, monoclonal antibody inhibitor of growth differentiation factor 15, in patients with cancer cachexia: A randomized, placebo-controlled, phase II study

LBA82 Efficacy and safety of ponsegromab, a first-in-class, monoclonal antibody inhibitor of growth differentiation factor 15, in patients with cancer cachexia: A randomized, placebo-controlled, phase II study

240. CACHEXIA INDEX AS A POTENTIAL BIOMARKER FOR SENSITIVITY OF NEOADJUVANT THERAPY AND PROGNOSIS IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Abstract Background Cancer cachexia has a negative impact on the clinical outcome of patients with esophageal squamous cell carcinoma (ESCC). The cachexia index (CXI) is a potential biomarker for cancer cachexia, whereas its implications for ESCC prognosis and treatment outcomes have not been investigated. Methods In our study, 454 ESCC patients who had neoadjuvant therapy followed by surgery were included. Based on the exclusion criteria, a total of 224 patients were finally enrolled in this study. The CXI was determined as the serum albumin/neutrophil-lymphocyte ratio × the skeletal muscle index (based on CT image), which was classified as L3-CXI or pectoralis muscles-CXI depending upon the type of muscle involved. The patients were divided into high- and low-CXI groups using sex-specific medians as cutoff values for CXI. Results Tumor regression grade = 0,1 (sensitive to treatment) to neoadjuvant therapy was obtained in 61.6% and 46.4% of patients in the high-pretreatment L3-CXI and low-pretreatment L3-CXI groups, respectively (P = 0.023). ESCC patients with △L3-CXI &amp;lt;0 (L3-CXI decreased during treatment) had significantly shorter overall survival (P = 0.006) and disease-free survival (P = 0.002) than those with △L3-CXI ≥0. Multivariable analysis showed that △L3-CXI &amp;lt;0 was an independent negative prognostic factor for overall survival and disease-free survival. Conclusions In patients with ESCC, pretreatment CXI is a biomarker for treatment response, and △CXI can predict postoperative complications and survival outcomes. Patients could be clearly stratified by pretreatment CXI and △CXI categories, which provides a new nutritional assessment tool for clinical decision-making for patients with ESCC.

Central neural mechanisms of cancer cachexia.

Cachexia is a devasting syndrome which impacts a large number of patients with cancer. This review aims to provide a comprehensive overview of the central mechanisms of cancer cachexia. In particular, it focuses on the role of the central nervous system (CNS), the melanocortin system, circulating hormones and molecules which are produced by and act on the CNS and the psychological symptoms of cancer cachexia. A growing body of evidence suggests that a central mechanism of action underpins this multi-system disorder. Recent research has focused on the role of neuroinflammation that drives the sickness behaviour seen in cancer cachexia, with emphasis on the role of the hypothalamus. Melanocortin receptor antagonists are showing promise in preclinical studies. There are also new pharmacological developments to overcome the short half-life of ghrelin. GDF-15 has been identified as a core target and trials of compounds that interfere with its signalling or its central receptor are underway. Understanding the central mechanisms of cancer cachexia is pivotal for enhancing treatment outcomes in patients. While emerging pharmacological interventions targeting these pathways have shown promise, further research is essential.

1335P The relationship between nivolumab pharmacokinetics and cancer cachexia biomarkers in patients with metastatic non-small cell lung cancer (NSCLC)

1335P The relationship between nivolumab pharmacokinetics and cancer cachexia biomarkers in patients with metastatic non-small cell lung cancer (NSCLC)

Determination of anamorelin concentration in human plasma using a simple high-performance liquid chromatography-ultraviolet detection method.

Anamorelin, a non-peptide ghrelin analog and growth hormone secretagogue, is a novel oral drug used to treat cancer cachexia. Patients with cancer cachexia frequently use several drugs and anamorelin is a substrate of cytochrome P450 (CYP) 3A4; therefore, drug-drug interactions with CYP3A4 inhibitors and inducers pose a clinical problem. In this study, we aimed to determine the concentration of anamorelin in human plasma using a simple high-performance liquid chromatography-ultraviolet (HPLC-UV)-based method. The analysis involved extracting a 200-μL plasma sample and protein precipitation using solid-phase extraction. Anamorelin was isocratically separated using a mobile phase consisting of 0.5% potassium dihydrogen phosphate (pH 4.5) and acetonitrile (61:39, v/v) on a Capcell Pack C18 MG II column (250 mm × 4.6 mm) at a flow rate of 1.0 mL/min and monitored at a detection wavelength of 220 nm. The calibration curve was linear within a plasma concentration range of 12.5-1,500 ng/mL, with a coefficient of determination of 0.9999. The intra- and inter-day coefficients of variation were 0.37-6.71% and 2.05-4.77%, respectively. The accuracy of the assay and recovery were 85.25-112.94% and > 86.58%, respectively. This proposed HPLC-UV method is simple and can be applied in clinical settings.

Potential value and advances in research on bone mineral density (BMD) measurement in the auxiliary clinical assessment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer death worldwide and its prognosis is highly heterogeneous, being related not only to underlying chronic liver disease but also to the severity of cancer cachexia. Nutritional factors play a crucial role in influencing the prognosis of HCC. Despite musculoskeletal imbalance being consistently reported as a predictor of perioperative mortality in patients with HCC, this condition is often overlooked in clinical management. Bone mineral density (BMD), which serves as a marker of nutritional status, can be assessed through CT by measuring the pixel density of the vertebral bone. Recent clinical studies have indicated that BMD serves not only as a significant risk factor for development of HCC in cirrhotic patients but also potentially functions as an independent prognostic indicator for post-treatment outcomes in patients with HCC. Preoperative abdominal CT scans provide a convenient and cost-effective method to measure BMD, offering significant assistance in prognostic evaluation of patients with HCC. A thorough grasp of the liver-bone connection, along with the conduct of higher-quality studies and the establishment of standardized methods and cutoff values for BMD measurement, could enhance approaches to manage HCC.

Salivary Interleukin-13 and Transforming Growth Factor Beta as Potential Biomarkers of Cancer Cachexia.

serum and saliva specimens were obtained from 78 patients. Forty-six patients were non-cachectic, and 32 patients were cachectic (per SCRINIO group criteria), all with metastatic solid tumors. Commercial ELISA kits were used to determine the salivary and serum concentrations of interleukin 13 (IL-13) and transforming growth factor beta (TGF-β) in two patient groups and healthy controls. Laboratory values were obtained from the hospital information system, and weight and height were measured at the time of sampling. A statistically significant difference was observed between the groups in saliva IL-13 concentrations but no difference in serum concentrations. Statistically significant differences were also observed between the groups in saliva and serum concentrations of TGF-β. Logistic regression analysis has identified salivary IL-13 and TGF-β as independent factors for cancer cachexia. We demonstrated saliva as a valuable specimen for cachexia investigation and established IL-13 and TGF-β as potential cancer cachexia biomarkers. Further research is needed to evaluate these findings.

Nutritional Mechanisms of Cancer Cachexia.

Cancer cachexia is a complex systemic wasting syndrome. Nutritional mechanisms that span energy intake, nutrient metabolism, body composition, and energy balance may be impacted by, and may contribute to, the development of cachexia. To date, clinical management of cachexia remains elusive. Leaning on discoveries and novel methodologies from other fields of research may bolster new breakthroughs that improve nutritional management and clinical outcomes. Characteristics that compare and contrast cachexia and obesity may reveal opportunities for cachexia research to adopt methodology from the well-established field of obesity research. This review outlines the known nutritional mechanisms and gaps in the knowledge surrounding cancer cachexia. In parallel, we present how obesity may be a different side of the same coin and how obesity research has tackled similar research questions. We present insights into how cachexia research may utilize nutritional methodology to expand our understanding of cachexia to improve definitions and clinical care in future directions for the field.