Muscle Wasting In Cancer Patients Research Articles

Oncostatin M signaling drives cancer-associated skeletal muscle wasting

Progressive weakness and muscle loss are associated with multiple chronic conditions, including muscular dystrophy and cancer. Cancer-associated cachexia, characterized by dramatic weight loss and fatigue, leads to reduced quality of life and poor survival. Inflammatory cytokines have been implicated in muscle atrophy; however, available anticytokine therapies failed to prevent muscle wasting in cancer patients. Here, we show that oncostatin M (OSM) is a potent inducer of muscle atrophy. OSM triggers cellular atrophy in primary myotubes using the JAK/STAT3 pathway. Identification of OSM targets by RNA sequencing reveals the induction of various muscle atrophy-related genes, including Atrogin1. OSM overexpression in mice causes muscle wasting, whereas muscle-specific deletion of the OSM receptor (OSMR) and the neutralization of circulating OSM preserves muscle mass and function in tumor-bearing mice. Our results indicate that activated OSM/OSMR signaling drives muscle atrophy, and the therapeutic targeting of this pathway may be useful in preventing muscle wasting.

Skeletal muscle analysis of cancer patients reveals a potential role for carnosine in muscle wasting.

Muscle wasting during cancer cachexia is mediated by protein degradation via autophagy and ubiquitin-linked proteolysis. These processes are sensitive to changes in intracellular pH ([pH]i ) and reactive oxygen species, which in skeletal muscle are partly regulated by histidyl dipeptides, such as carnosine. These dipeptides, synthesized by the enzyme carnosine synthase (CARNS), remove lipid peroxidation-derived aldehydes, and buffer [pH]i . Nevertheless, their role in muscle wasting has not been studied. Histidyl dipeptides in the rectus abdominis (RA) muscle and red blood cells (RBCs) of male and female controls (n=37), weight stable (WS: n=35), and weight losing (WL; n=30) upper gastrointestinal cancer (UGIC) patients, were profiled by LC-MS/MS. Expression of enzymes and amino acid transporters, involved in carnosine homeostasis, was measured by Western blotting and RT-PCR. Skeletal muscle myotubes were treated with Lewis lung carcinoma conditioned medium (LLC CM), and β-alanine to study the effects of enhancing carnosine production on muscle wasting. Carnosine was the predominant dipeptide present in the RA muscle. In controls, carnosine levels were higher in men (7.87±1.98nmol/mg tissue) compared with women (4.73±1.26nmol/mg tissue; P=0.002). In men, carnosine was significantly reduced in both the WS (5.92±2.04nmol/mg tissue, P=0.009) and WL (6.15±1.90nmol/mg tissue; P=0.030) UGIC patients, compared with controls. In women, carnosine was decreased in the WL UGIC (3.42±1.33nmol/mg tissue; P=0.050), compared with WS UGIC patients (4.58±1.57nmol/mg tissue), and controls (P=0.025). Carnosine was significantly reduced in the combined WL UGIC patients (5.12±2.15nmol/mg tissue) compared with controls (6.21±2.24nmol/mg tissue; P=0.045). Carnosine was also significantly reduced in the RBCs of WL UGIC patients (0.32±0.24pmol/mg protein), compared with controls (0.49±0.31pmol/mg protein, P=0.037) and WS UGIC patients (0.51±0.40pmol/mg protein, P=0.042). Depletion of carnosine diminished the aldehyde-removing ability in the muscle of WL UGIC patients. Carnosine levels were positively associated with decreases in skeletal muscle index in the WL UGIC patients. CARNS expression was decreased in the muscle of WL UGIC patients and myotubes treated with LLC-CM. Treatment with β-alanine, a carnosine precursor, enhanced endogenous carnosine production and decreased ubiquitin-linked protein degradation in LLC-CM treated myotubes. Depletion of carnosine could contribute to muscle wasting in cancer patients by lowering the aldehyde quenching abilities. Synthesis of carnosine by CARNS in myotubes is particularly affected by tumour derived factors and could contribute to carnosine depletion in WL UGIC patients. Increasing carnosine in skeletal muscle may be an effective therapeutic intervention to prevent muscle wasting in cancer patients.

The role of microRNA in cancer cachexia and muscle wasting: A review article.

Almost half of cancer patients experience cachexia syndrome. Cachexic patients are at risk of increased side effects of chemotherapy, reduced tolerance to chemotherapy drugs, longer duration of treatment period, and decreased quality of life. Cancer cachexia is a multifactorial syndrome. Micro ribonucleic acid (miRNA), a “non-coding RNA”, is considered to be a risk factor of cachexia and muscle wasting in cancer patients. miRNA has a role in affecting protein regulation, associated with different inflammatory and disease pathways. miRNA can also affect cytokines or directly change the regulation of metabolism that lead to cachexia. In this review, we want to focus on the pathophysiology to give a better understanding about the role of miRNA in the development of cancer cachexia. Based on various pathways of miRNA in cancer cachexia, it can be a potential target for therapeutic strategies. Improved knowledge about miRNA can give the opportunity to develop new treatment in the management of cancer cachexia.

Novel molecular targets of muscle wasting in cancer patients.

Cancer-associated muscle wasting affects many patients and leads to reduced patient function, decreased quality of life and poor responses to surgical and oncological treatments. Despite advancements in the understanding of its pathophysiology, no current treatment or accepted strategy for successful management exists. In this review, we provide an update on potential novel therapeutic targets in cancer cachexia. Recent research has focused on molecular mechanisms underlying cancer-associated muscle wasting, allowing identification of potential therapeutic targets and the development of several promising drugs. However, due to the multifactorial and patient-specific pathogenesis of cachexia, the demonstration of a measurable and meaningful clinical effect in randomized controlled trials has proven difficult. Potential novel targets such as circulating macrophage inhibitory cytokine 1/growth differentiation factor 15 and ZRT/IRT-like protein 14 have shown relevance in animal models, but their therapeutic manipulation has yet to be translated to patients. Increasing evidence has suggested that a single therapy may not be successful and a targeted, multimodal approach is required. The management of cancer-associated muscle wasting is complex. Future clinical trials should focus on early multimodal therapeutic interventions involving targeted therapies, with careful deliberation of chosen nutritional and functional outcomes.

Moderate Exercise Improves Experimental Cancer Cachexia by Modulating the Redox Homeostasis.

Cachexia is a debilitating syndrome that complicates the management of cancer patients. Muscle wasting, one of the main features of cachexia, is associated with hyper-activation of protein degradative pathways and altered mitochondrial function that could both result from impaired redox homeostasis. This study aimed to investigate the contribution of oxidative stress to cancer-induced cachexia in the presence or in the absence of moderate exercise training. Mice bearing the colon C26 carcinoma, either sedentary or exercised, were used. The former showed muscle wasting and redox imbalance, with the activation of an antioxidant response and with upregulation of markers of proteasome-dependent protein degradation and autophagy. Moderate exercise was able to relieve muscle wasting and prevented the loss of muscle strength; such a pattern was associated with reduced levels of Reactive Oxygen Species (ROS), carbonylated proteins and markers of autophagy and with improved antioxidant capacity. The muscle of sedentary tumor hosts also showed increased levels of molecular markers of mitophagy and reduced mitochondrial mass. Conversely, exercise in the C26 hosts led to increased mitochondrial mass. In conclusion, moderate exercise could be an effective non-pharmacological approach to prevent muscle wasting in cancer patients, decreasing muscle protein catabolism and oxidative stress and preserving mitochondria.

ED06.04 Biology and Management of Tumor Cachexia

ED06.04 Biology and Management of Tumor Cachexia

Cancer cachexia-when proteasomal inhibition is not enough.

Cachexia is a life threatening syndrome associated with several diseases, such as end‐stage heart failure, end‐stage renal disease, chronic obstructive pulmonary disease, chronic inflammation (i.e. rheumatoid arthritis), acquired immune deficiency syndrome, and cancer.1, 2 Cachexia is found in 31–87% of cancer patients especially in advanced disease stages.3 It is characterized by progressive weight loss, metabolic alterations, fatigue, and persistent reduction of body cell mass in response to a malignant tumour.2, 4, 5, 6 The incidence of cachexia in cancer patients is dependent on the type and site of the tumour. While patients with non‐Hodgkin's lymphoma, breast cancer, and sarcomas show low incidences, rates up to 83% in pancreatic cancer patients, and over 85% in patients with gastric cancer have been found. Additionally, around 60% of small‐cell and non‐small‐cell lung cancer patients develop cachexia.7, 8, 9 Cancer cachexia affects the function of several organs such as muscle, adipose tissue, liver, brain, immune system, and heart, collectively decreasing patients' quality of life and worsening their prognosis. Therefore, cachexia must be considered as a true multi‐organ syndrome.10 Because cancer cachexia leads to a decrease in physical performance and quality of life,11 and is associated with poor survival (accounting for more than 20% of cancer deaths,7, 12, 13, 14, 15) it is of major clinical relevance. Even more so since cachectic patients show lower response rates to chemotherapy7 and a reduced tolerance to anticancer treatment.16 Despite its importance, weight loss in cancer patients is rarely recognized, assessed,17 or treated actively.18, 19 Thus, cancer cachexia represents an important underappreciated clinical syndrome.

Study Design and Rationale for the Phase 3 Clinical Development Program of Enobosarm, a Selective Androgen Receptor Modulator, for the Prevention and Treatment of Muscle Wasting in Cancer Patients (POWER Trials).

Muscle wasting in cancer is a common and often occult condition that can occur prior to overt signs of weight loss and before a clinical diagnosis of cachexia can be made. Muscle wasting in cancer is an important and independent predictor of progressive functional impairment, decreased quality of life, and increased mortality. Although several therapeutic agents are currently in development for the treatment of muscle wasting or cachexia in cancer, the majority of these agents do not directly inhibit muscle loss. Selective androgen receptor modulators (SARMs) have the potential to increase lean body mass (LBM) and hence muscle mass, without the untoward side effects seen with traditional anabolic agents. Enobosarm, a nonsteroidal SARM, is an agent in clinical development for prevention and treatment of muscle wasting in patients with cancer (POWER 1 and 2 trials). The POWER trials are two identically designed randomized, double-blind, placebo-controlled, multicenter, and multinational phase 3 trials to assess the efficacy of enobosarm for the prevention and treatment of muscle wasting in subjects initiating first-line chemotherapy for non-small-cell lung cancer (NSCLC). To assess enobosarm’s effect on both prevention and treatment of muscle wasting, no minimum weight loss is required. These pivotal trials have pioneered the methodological and regulatory fields exploring a therapeutic agent for cancer-associated muscle wasting, a process hereby described. In each POWER trial, subjects will receive placebo (n = 150) or enobosarm 3 mg (n = 150) orally once daily for 147 days. Physical function, assessed as stair climb power (SCP), and LBM, assessed by dual-energy X-ray absorptiometry (DXA), are the co-primary efficacy endpoints in both trials assessed at day 84. Based on extensive feedback from the US Food and Drug Administration (FDA), the co-primary endpoints will be analyzed as a responder analysis. To be considered a physical function responder, a subject must have ≥10 % improvement in physical function compared to baseline. To meet the definition of response on LBM, a subject must have demonstrated no loss of LBM compared with baseline. Secondary endpoints include durability of response assessed at day 147 in those responding at day 84. A combined overall survival analysis for both studies is considered a key secondary safety endpoint. The POWER trials design was established with extensive clinical input and collaboration with regulatory agencies. The efficacy endpoints are a result of this feedback and discussion of the threshold for clinical benefit in patients at risk for muscle wasting. Full results from these studies will soon be published and will further guide the development of future anabolic trials. Clinical Trial ID: NCT01355484. https://clinicaltrials.gov/ct2/show/NCT01355484, NCT01355497. https://clinicaltrials.gov/ct2/show/NCT01355497?term=g300505&rank=1.

Skeletal muscle regeneration in cancer cachexia.

Muscle wasting is the most important phenotypic and clinical feature of cancer cachexia, and the principal cause of impaired physical function, fatigue, and respiratory complications. Muscle loss has been attributed to a variable combination of reduced nutritional intake and an imbalance between anabolic and catabolic processes. It has been suggested that defective skeletal muscle regeneration may also contribute to muscle wasting in cancer patients. However, there is little in vitro or in vivo data available, in either animals or in humans, regarding skeletal muscle regeneration in cancer wasting. The aim of the present review is to define the role of skeletal muscle regeneration in the muscle wasting of cancer patients and to determine possible therapeutic implications.

Muscle wasting in cancer patients treated with anamorelin

Muscle wasting in cancer patients treated with anamorelin

Selective androgen receptor modulators for the prevention and treatment of muscle wasting associated with cancer

This review highlights selective androgen receptor modulators (SARMs) as emerging agents in late-stage clinical development for the prevention and treatment of muscle wasting associated with cancer. Muscle wasting, including a loss of skeletal muscle, is a cancer-related symptom that begins early in the progression of cancer and affects a patient's quality of life, ability to tolerate chemotherapy, and survival. SARMs increase muscle mass and improve physical function in healthy and diseased individuals, and potentially may provide a new therapy for muscle wasting and cancer cachexia. SARMs modulate the same anabolic pathways targeted with classical steroidal androgens, but within the dose range in which expected effects on muscle mass and function are seen androgenic side-effects on prostate, skin, and hair have not been observed. Unlike testosterone, SARMs are orally active, nonaromatizable, nonvirilizing, and tissue-selective anabolic agents. Recent clinical efficacy data for LGD-4033, MK-0773, MK-3984, and enobosarm (GTx-024, ostarine, and S-22) are reviewed. Enobosarm, a nonsteroidal SARM, is the most well characterized clinically, and has consistently demonstrated increases in lean body mass and better physical function across several populations along with a lower hazard ratio for survival in cancer patients. Completed in May 2013, results for the Phase III clinical trials entitled Prevention and treatment Of muscle Wasting in patiEnts with Cancer1 (POWER1) and POWER2 evaluating enobosarm for the prevention and treatment of muscle wasting in patients with nonsmall cell lung cancer will be available soon, and will potentially establish a SARM, enobosarm, as the first drug for the prevention and treatment of muscle wasting in cancer patients.

Effect of enobosarm on physical function in cancer patients with < or ≥ 5% weight loss in a phase IIb trial.

e19585 Background: Although cachexia has been defined as >5% weight loss, limited data exists on the prevention and treatment of muscle wasting prior to a patient becoming cachectic. Cancer induced muscle wasting can begin early in the course of a patient’s malignancy resulting in decline in physical function and other detrimental clinical consequences including less tolerability to chemotherapy, worse outcomes, and shorter survival - underscoring the importance of diagnosing and treating this condition at an early stage. Methods: We conducted a randomized, double blind, placebo controlled, multi-center study to evaluate the effect of enobosarm on physical function and muscle wasting in cancer patients. Subjects (n=159) were randomized to oral enobosarm or placebo for 16 weeks. Subjects were males >45y and postmenopausal females, with ≥2% weight loss in the 6 months prior to randomization and diagnosed with NSCLC, colorectal cancer, non-Hodgkin’s lymphoma, chronic lymphocytic leukemia or breast cancer. We report on changes in physical function based on weight loss of < or ≥5%in the 6 months prior to randomization. Results: 103 subjects (MITT) had physical function assessed by stair climb at baseline and week 16 with 24% losing <5% weight in the previous 6 months. Distribution of weight loss was similar across genders, however subjects with <5% weight loss were more likely to be ECOG=0 (<5% loss: 46.2%; ≥5% loss: 35.8%). Subjects with ≥5% weight loss had worse physical function at baseline compared to those with <5% loss (p=0.048). A significant improvement in physical function was observed in subjects that received enobosarm regardless of baseline weight loss (<5% loss, p=0.041, ≥5% loss, p<0.001) while subjects that received placebo failed to improve. Conclusions: Enobosarm was generally well tolerated and showed a statistically significant improvement in physical function in cancer subjects regardless of baseline weight loss. These data provide evidence that enobosarm may play an important role in the management of cancer patients by not only treating, but also preventing further decline in physical function and muscle wasting before a patient becomes cachectic.

Skeletal muscle of gastric cancer patients expresses genes involved in muscle regeneration

Experimental studies have suggested that defective skeletal muscle regeneration could contribute to muscle wasting in cancer patients. However, data in humans are still lacking. In this study we aimed to assess the expression of the genes involved in muscle regeneration in gastric cancer patients. The RNA expression of the genes involved in muscle regeneration was assessed in the rectus abdominis muscle of patients with gastric cancer (n=30) and in age-matched control subjects (n=8). The Pax7 expression was significantly increased in the muscle of gastric cancer patients, either in the first stages of the disease or in stages IIIA and B. The increased expression was present both in stages IA and B and in stages II and III. The MyoD espression was also higher in the cancer patients than in the controls. However, the increased MyoD expression was present only in stages IA and B and not in the more advanced stages of the disease. The Myf5 expression, as well as that of the neonatal isoform of Myosin Heavy Chain (nMHC) did not differ significantly between the cancer patients and the controls. The necdin expression was negligible in healthy adult muscles and was significantly up-regulated in the muscle of gastric cancer patients. Its expression was highly increased in stages IA and B while it was similar to the control in stages II and III. The results of the present study show that in the skeletal muscle of gastric cancer patients, the expression of the genes involved in muscle regeneration is increased with respect to the controls.

Cancer cachexia-anorexia syndrome and skeletal muscle wasting

Cancer cachexia-anorexia syndrome and skeletal muscle wastingBackground. Cachexia-anorexia syndrome is a common and important indicator of cancer. It occurs in 30% to 80% of cancer patients. Cachexia means "bad condition" and may be present in the early stages of tumor growth, before any signs of malignancy. Cancer cachexia is a syndrome of progressive body wasting, characterized by loss of adipose tissue and skeletal muscle mass. In most cancer patients, cachexia is characterized by anorexia, which implies a failure of food intake, regulated through a complex system of hormones and neuropeptides. A decline in food intake relative to energy expenditure is a fundamental physiologic derangement leading to cancer associated weight loss. The weight loss in patients with cachexia-anorexia syndrome differs from that in caloric starvation or anorexia nervosa. The pathophysiology of cancer cachexia is not fully understood; however, studies have shown that cytokines are important in the alteration of the carbohydrate, lipid and protein metabolism. Cancer, prolonged bed rest, HIV infection and aging are conditions in which muscle wasting is a common feature. An intervention that may potentially attenuate the progression of muscle wasting in cancer patients is resistance exercise training, defined as multiple repetitions of static or dynamic muscular contractions

Attenuation of skeletal muscle atrophy in cancer cachexia by d-myo-inositol 1,2,6-triphosphate

To determine the effectiveness of the polyanionic, metal binding agent D-myo-inositol-1,2,6-triphosphate (alpha trinositol, AT), and its hexanoyl ester (HAT), in tissue wasting in cancer cachexia. The anti-cachexic effect was evaluated in the MAC16 tumour model. Both AT and HAT attenuated the loss of body weight through an increase in the nonfat carcass mass due to an increase in protein synthesis and a decrease in protein degradation in skeletal muscle. The decrease in protein degradation was associated with a decrease in activity of the ubiquitin-proteasome proteolytic pathway and caspase-3 and -8. Protein synthesis was increased due to attenuation of the elevated autophosphorylation of double-stranded RNA-dependent protein kinase, and of eukaryotic initiation factor 2alpha together with hyperphosphorylation of eIF4E-binding protein 1 and decreased phosphorylation of eukaryotic elongation factor 2. In vitro, AT completely attenuated the protein degradation in murine myotubes induced by both proteolysis-inducing factor and angiotensin II. These results show that AT is a novel therapeutic agent with the potential to alleviate muscle wasting in cancer patients.

Increased expression of phosphorylated forms of RNA-dependent protein kinase and eukaryotic initiation factor 2α may signal skeletal muscle atrophy in weight-losing cancer patients

Previous studies suggest that the activation (autophosphorylation) of dsRNA-dependent protein kinase (PKR) can stimulate protein degradation, and depress protein synthesis in skeletal muscle through phosphorylation of the translation initiation factor 2 (eIF2) on the α-subunit. To understand whether these mediators are important in muscle wasting in cancer patients, levels of the phospho forms of PKR and eIF2α have been determined in rectus abdominus muscle of weight losing patients with oesophago-gastric cancer, in comparison with healthy controls. Levels of both phospho PKR and phospho eIF2α were significantly enhanced in muscle of cancer patients with weight loss irrespective of the amount and there was a linear relationship between phosphorylation of PKR and phosphorylation of eIF2α (correlation coefficient 0.76, P=0.005). This suggests that phosphorylation of PKR led to phosphorylation of eIF2α. Myosin levels decreased as the weight loss increased, and there was a linear relationship between myosin expression and the extent of phosphorylation of eIF2α (correlation coefficient 0.77, P=0.004). These results suggest that phosphorylation of PKR may be an important initiator of muscle wasting in cancer patients.

247. Expressing Full-Length Dystrophin in 50% Cardiomyocytes Corrects Cardiomyopathy in the Mdx Mouse Model for Duchenne Muscular Dystrophy

Muscle wasting, a syndrome characterized by the disproportional loss of skeletal muscle, is a frequent complication in patients with cancer or other chronic diseases. Recent studies in vitro and in vivo have demonstrated that tumor cells produce and secrete cytokines such as TNF- α that are responsible for inhibition of differentiation of myoblast cells into multinucleated myotubes and thereby may prevent muscle repair in cancer patients. Activation of NF-κB triggered by TNF-α interaction with its receptor on muscle cells, is considered a major pathway through which cytokines lead to muscle wasting in cancer patients. Gene therapy offers a potential solution by modulating downstream events within muscle cells. In vitro models of muscle wasting can provide an important resource to understand which pathways to modulate and to test potential therapies. In our In vitro studies, we found that application of TNF-α results in apoptosis of primary C57 mouse myoblast cells at 3 days after treatment. IFN-γ, IL-1β and IL-6 do not lead to apoptosis of myoblast cells, but result in inhibition of myoblast differentiation at 20 ng/ml. In addition, the conditioned media from human prostate cancer cell lines (PC-3 and DU145P) and a human melanoma cell line (Mel) significantly inhibit the differentiation of myoblast cells. NF-κB activity was activated in treated myoblast cells compared to untreated or 293 cell culture supernatant-treated myoblast cells. However we found that myoblasts stably transfected with IKBSR, a mutant IKBα, or cellular FLICE/Caspase-8-inhibitory protein, cFLIP, inhibited NF-κB activation after treatment of myoblast cells with cytokines (TNF-α, IFN-γ, IL-1β or IL-6) or tumor cell conditioned media (PC-3, DU145P or Mel). Inhibition of NF-κB activation was associated with amelioration of the inhibition of muscle cell differentiation. To our knowledge, this is the first report that cFLIP, an important caspase-8-inhibitory protein is capable of inhibiting NF-κB activation and reducing inhibition of myoblast cell differentiation treated with PC-3, DU145P and Mel tumor media. The results encourage us to generate gene transfer virus vectors expressing IKBSR or cFLIP or both, and to determine whether IKBSR or cFLIP or both can ameliorate muscle wasting.

The 'cancer cachectic factor'.

The object of this study was to summarize information on catabolic factors produced by tumours which lead to tissue catabolism in cancer cachexia and to use this information for the development of effective therapy. The study population was made up of patients with cancer cachexia and weight loss greater than 1 kg month(-1). They had a varied range of carcinomas, particularly pancreatic, but also of the breast, ovary, lung, colon and rectum. Cachectic factors were isolated by standard biochemical methods, and the mechanism of tissue catabolism was evaluated in vitro and in vivo. We isolated a 24-kDa sulphated glycoprotein produced by cachexia-inducing murine and human tumours, which induces catabolism of myofibrillar proteins in skeletal muscle and for this reason has been named proteolysis-inducing factor (PIF). PIF was shown to be present in a diverse range of carcinomas in patients whose rate of weight loss exceeded 1.0 kg month(-1). Administration of PIF to normal mice produced a rapid decrease in body weight, which arose primarily from a loss of skeletal muscle, accompanied by increased mRNA levels for ubiquitin, the ubiquitin-carrier protein (E2(14k)), and proteasome subunits. This suggests that PIF induces protein catabolism through an increased expression of the key components of the ATP-ubiquitin-dependent proteolytic pathway. The action of PIF was attenuated both in vitro and in vivo by eicosapentaenoic acid (EPA). Oral EPA has been found to stabilize the body weight of patients with advanced pancreatic cancer and, when combined with an energy- and protein-rich nutritional supplement, to produce weight gain arising solely from an increase in lean body mass. Nutritional supplementation alone is unable to reverse the process of muscle wasting in cancer patients, since this arises from activation of the ubiquitin proteasome pathway by PIF, which is independent of nutrient intake. EPA is able to down-regulate the increased expression of this pathway and prevents muscle wasting in cancer patients.