Investigational drugs for the treatment of cancer cachexia: a focus on phase I and phase II clinical trials

Introduction: Cachexia is frequent in chronic diseases and especially during cancer development. Multiple definitions of cachexia have been proposed; it may be considered a multifactorial complex syndrome that presents with progressive unintentional weight loss and wasting of muscle mass and adipose tissue.

Area covered: This article covers phase-I and phase-II clinical trials of investigational drugs for cancer cachexia. We performed a search on PubMed with keywords as cancer cachexia, phase-I/phase-II trial, drug, identifying articles relevant to this review. Studies were conducted using compounds, including anabolic agents such as ghrelin analogs, selective androgen receptor modulators, as well as anti-inflammatory drugs such as thalidomide, OHR, anti-interleukin antibody, cannabinoids, and omega-3 supplements. We also describe the mechanisms of action of these molecules and their phase-I and phase-II study design. The major outcomes were appetite stimulation, weight gain, improvement of muscle mass and function, modulation of inflammation, and quality of life.

Expert opinion: The molecules discussed act on molecular pathways involved in cancer cachexia; they modulate appetite, anabolic effects, inflammation and direct interaction with muscle. Considering the multifactorial aspects of the cachexia syndrome, the combination of these drugs with metabolic and nutritional interventions may represent the most promising therapeutic approach to cancer cachexia.     

Novel investigational drugs mimicking exercise for the treatment of cachexia

Introduction: Cachexia is a syndrome characterized by body weight loss, muscle wasting and metabolic abnormalities, that frequently complicates the management of people affected by chronic diseases. No effective therapy is actually available, although several drugs are under clinical evaluation. Altered energy metabolism markedly contributes to the pathogenesis of cachexia; it can be improved by exercise, which is able to both induce anabolism and inhibit catabolism.

Areas covered: This review focuses on exercise mimetics and their potential inclusion in combined protocols to treat cachexia. The authors pay with particular reference to the cancer-associated cachexia.

Expert opinion: Even though exercise improves muscle phenotype, most patients retain sedentary habits which are quite difficult to disrupt. Moreover, they frequently present with chronic fatigue and comorbidities that reduce exercise tolerance. For these reasons, drugs mimicking exercise could be beneficial to those who are unable to comply with the practice of physical activity. Since some exercise mimetics may exert serious side effects, further investigations should focus on treatments which maintain their effectiveness on muscle phenotype while remaining tolerable at the same time.     

The use of melanocortin antagonists in cachexia of chronic disease

Cachexia is a wasting syndrome that frequently develops in the setting of chronic diseases including cancer, congestive heart failure, chronic obstructive pulmonary disease, AIDS, renal failure and liver failure. Loss of lean body mass is believed to be a significant factor contributing to morbidity and mortality in these chronic diseases; however, there are currently no treatments available that have proven to be effective in reversing the progressive loss of lean body mass in cachectic patients. Evidence from animal models suggests a compelling link between inflammation, the central melanocortin system and cachexia. This review summarises the current evidence supporting the role of the melanocortin 4 (MC4) receptor subtype in cachexia, and discusses the development and use of small-molecule MC4 antagonists, which have proved to be effective in preventing the loss of lean body mass in animal models of cachexia. MC4 antagonists represent an attractive therapeutic approach for cachexia that may attenuate the loss of lean body mass in cachectic patients.     

The use of melanocortin antagonists in cachexia of chronic disease

Cachexia is a wasting syndrome that frequently develops in the setting of chronic diseases including cancer, congestive heart failure, chronic obstructive pulmonary disease, AIDS, renal failure and liver failure. Loss of lean body mass is believed to be a significant factor contributing to morbidity and mortality in these chronic diseases; however, there are currently no treatments available that have proven to be effective in reversing the progressive loss of lean body mass in cachectic patients. Evidence from animal models suggests a compelling link between inflammation, the central melanocortin system and cachexia. This review summarises the current evidence supporting the role of the melanocortin 4 (MC4) receptor subtype in cachexia, and discusses the development and use of small-molecule MC4 antagonists, which have proved to be effective in preventing the loss of lean body mass in animal models of cachexia. MC4 antagonists represent an attractive therapeutic approach for cachexia that may attenuate the loss of lean body mass in cachectic patients.     

Advances in pharmacologic strategies for cancer cachexia

Introduction: Cancer cachexia is a severe inflammatory metabolic syndrome accounting for fatigue, an impairment of normal activities and, eventually, death. The loss of muscle mass associated with body weight loss is the main feature of this syndrome.

Areas covered: The present review aims to describe the advances in the pharmacological approaches for cancer cachexia, highlighting the impact on weight loss, muscle wasting and related outcomes.

Expert opinion: Among the pharmacological agents, attention should yet be given to the currently most widely studied drugs, such as progestogens and NSAIDs. Emerging drugs, such as ghrelin and selective androgen receptor modulators, have obtained promising results in recent randomized clinical trials. Larger sample sizes and more robust data on the effectiveness of anti-cytokine agents are needed. Any pharmacological approach to counteract cancer cachexia should always be associated with an adequate caloric intake, obtained by diet or through enteral or parenteral supplementation, if indicated. Finally, we can currently state that a combined approach that simultaneously targets the fundamental pathways involved in the pathogenesis of cancer cachexia is likely to be the most effective in terms of improvements in body weight as well as muscle wasting, function, physical performance and quality of life.     

Phase II drugs that are currently in development for the treatment of cachexia

Introduction: Cachexia is a syndrome presenting with progressive unintentional weight loss and wasting and weakness of skeletal muscle. Cachexia is prevalent in cancer and in chronic diseases including chronic obstructive pulmonary disease (COPD).

Areas covered: The authors searched trial registers for current Phase II clinical trials on cachexia. Twelve studies were found with 11 compounds, including the anti-inflammatory drugs thalidomide, OHR/AVR118, celecoxib, VT-122, omega-3 supplements, and anabolic agents such as ghrelin analogues, MT-102, BYM338 and ruxolotinib. The authors note that one of the studies related to COPD while the others were related to different cancers. Herein, the authors describe the mechanisms of action and their Phase II study design.

Expert opinion: The compounds under study affect several pathways involved in cachexia by modulating inflammatory activity, anabolic potential, digestion and direct interaction with the muscle. Due to the multifactorial aspects of cachexia syndrome, combinations of these new drugs with nutritional intervention is probably the most promising approach. Furthermore, future studies should include interventions in pre-cachetic patients, as this stage might be more responsive to treatment. Future studies will benefit from well-defined end points and improved measures of cachexia, providing new insight into the disease. This insight, in combination with the elucidation of cachexia’s underlying mechanism, will yield new treatment strategies in the near future.     

Update on emerging drugs for cancer cachexia

Cancer cachexia is a complex syndrome that describes the progressive muscle wasting and weakness in many cancer patients. Muscle wasting reduces the ability of affected patients to perform the tasks of daily living and causes severe fatigue, leading to a reduction in quality of life. Cancer cachexia reduces patient response to anti-neoplastic treatments, increases the risk of postoperative complications and accounts for > 20% of cancer-related deaths. The pathogenesis of cancer cachexia is multifactorial and includes anorexia, inflammation, metabolic disturbances and enhanced muscle proteolysis, and each of these presents as a potential therapeutic target for ameliorating cancer cachexia. Objective: This review provides an update on some of the emerging drugs for cancer cachexia. Methods: This is a review of the current status of emerging therapies for cancer cachexia. Results: An increasing number of studies are focused on the development of novel therapies for cancer cachexia. Initial studies concentrated on the treatment of anorexia, but now aim to attenuate inflammation or muscle proteolysis, or to use different drugs in combination so as to treat several aspects of cachexia simultaneously. Conclusions: There are several existing and emerging drugs with the potential to ameliorate cancer cachexia, but the most efficacious treatment will probably come from combined drug therapies.     

Novel C-C chemokine receptor 2 antagonists in metabolic disease: a review of recent developments

Introduction: C-C chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein-1, and its receptor, C-C chemokine receptor 2 (CCR2), play important roles in various inflammatory diseases. Recently, it has been reported that the CCL2/CCR2 pathway also has an important role in the pathogenesis of metabolic syndrome through its association with obesity and related systemic complications.

Areas covered: This review focuses on the roles of CCR2 in the pathogenesis of adipose tissue inflammation and other organ damage associated with metabolic syndrome, which is still a matter of debate in many studies. It also covers the use of novel CCR2 antagonists as therapies in such conditions.

Expert opinion: There is abundant experimental evidence that the CCL2/CCR2 pathway may be involved in chronic low-grade inflammation of adipose tissue in obesity and related metabolic diseases. Although animal models of diabetes and obesity, as well as human trials, have produced controversial results, there is continued interest in the roles of CCR2 inhibition in metabolic disease. Further identification of the mechanisms for recruitment and activation of phagocytes and determination of the roles of other chemokines are needed. Future study of these fundamental questions will provide a clearer understanding of adipose tissue biology and potential therapeutic targets for treatment of obesity-related metabolic disease, including diabetic nephropathy.     

New developments in investigational HDAC inhibitors for the potential multimodal treatment of cachexia

Introduction: Cachexia is a frequent feature of chronic diseases. This syndrome includes loss of body weight, depletion of skeletal muscle mass and altered metabolic homeostasis. Acceleration of protein and energy metabolism, impaired myogenesis, and systemic inflammation contribute to cachexia. Its occurrence impinges on treatment tolerance and on the quality of life of the patient, however, no effective therapy is available yet.

Areas covered: This review focuses on the use of histone deacetylase inhibitors as pharmacological tools to prevent or delay cachexia, with reference to muscle wasting.

Expert opinion: Novel histone deacetylase inhibitors could be considered as exercise mimetics and this supports their use as a treatment for muscle-wasting associated diseases, such as cachexia. The ability of some of these inhibitors to modulate the release of extracellular vesicles from tumor cells is a potential tool for restricting the development of cancer-induced muscle protein depletion. There are few clinical trials that are testing histone deacetylase inhibitors as a treatment for cachexia; this reflects the lack of robust experimental evidence of effectiveness. The determination of the pathogenic mechanisms of muscle wasting and the identification of suitable histone deacetylase inhibitors that target such mechanisms are necessary.     

Resolvin inflammation with pain

Background: Inflammation and pain coexist in conditions such as arthritis, inflammatory bowel disease and lower back pain. The drugs currently used to treat the combination of inflammation and pain all have disadvantages. Thus, new drugs and new approaches are needed to treat inflammation with pain. Resolvins are considered to be part of the natural resolving mechanism for inflammation and have been shown to prevent inflammation in animal models.

Objectives/methods: To evaluate a paper suggesting that the resolvins RvE1 and RvD1 attenuate inflammatory pain in animal models.

Results: RvE1 has been shown to attenuate inflammation and, to a lesser extent, pain in animal models. Limited results are presented of the effectiveness of RvD1 against inflammatory pain.

Conclusion: Drugs that mimic or potentiate the effects of the resolvins may be useful for the treatment of some inflammation with pain.     

Animal models for acute radiation syndrome drug discovery

Introduction: Although significant scientific advances have been made over the past six decades in developing safe, nontoxic and effective radiation/medical countermeasures (MCMs) for acute radiation syndrome (ARS), no drug has been approved by the US FDA. The availability of adequate animal models is a prime requisite under the criteria established by the FDA ‘animal rule’ for the development of novel MCMs for ARS and the discovery of biomarkers for radiation exposure.

Areas covered: This article reviews the developments of MCMs to combat ARS, with particular reference to the various animal models (rodents: mouse and rat; canine: beagle; minipigs and nonhuman primates [NHPs]) utilized for the in-depth evaluation. The objective, pathways and challenges of the FDA Animal Efficacy Rule are also discussed.

Expert opinion: There are a number of well-defined animal models, the mouse, canine and NHP, that are being used for the development of MCMs. Additional animal models, such as the minipig, are under development to further assist in the identification, efficacy testing and approval of MCMs under the FDA Animal Efficacy Rule.     

Animal models of skin disease for drug discovery

Introduction: Discovery of novel drugs, treatments, and testing of consumer products in the field of dermatology is a multi-billion dollar business. Due to the distressing nature of many dermatological diseases, and the enormous consumer demand for products to reverse the effects of skin photodamage, aging, and hair loss, this is a very active field.

Areas covered: In this paper, we will cover the use of animal models that have been reported to recapitulate to a greater or lesser extent the features of human dermatological disease. There has been a remarkable increase in the number and variety of transgenic mouse models in recent years, and the basic strategy for constructing them is outlined.

Expert opinion: Inflammatory and autoimmune skin diseases are all represented by a range of mouse models both transgenic and normal. Skin cancer is mainly studied in mice and fish. Wound healing is studied in a wider range of animal species, and skin infections such as acne and leprosy also have been studied in animal models. Moving to the more consumer-oriented area of dermatology, there are models for studying the harmful effect of sunlight on the skin, and testing of sunscreens, and several different animal models of hair loss or alopecia.     

New dimensions in the use of rodent behavioral tests for novel drug discovery and development

ABSTRACT

Introduction: Dimensional models of psychopathology describe mental illness in terms of natural variance along certain phenotypic dimensions that are continuous with normal. Vulnerability to psychopathology might arise when certain adaptive psychophysiological processes, conserved between humans and non-human animals, function outside of their “normal” range. Therefore, an in-depth understanding of the neurobiology and neurochemistry underlying these processes could identify possible novel drug targets.

Areas covered: Psychophysiological processes that might be related to anxiety disorders and depression are proposed and discussed. Those processes relevant to depressive disorders include: hedonic responsiveness, biases in the processing of stimuli, and sleep architecture. Those relevant to anxiety disorders include: startle reactivity, CO₂ sensitivity, and fear generalization. Rodent behavioral tests for assessing the function of these processes and investigating their neurobiology are described. A psychophysiological process strategy for translational research is proposed, which focusses on understanding the neurobiology and neurochemistry underlying key psychophysiological processes that, when their activity deviates from normal, are associated with neuropsychiatric symptoms. This strategy emphasizes the use of analogous tests and measures in both preclinical and clinical studies, while de-emphasizing the use of preclinical animal models that attempt to replicate features of the neuropsychiatric disorder through experimental manipulations.

Expert opinion: Investigating the neurobiology of key psychophysiological processes in rodents should enhance our understanding of the pathophysiology of neuropsychiatric disorders. New drug development could be directed toward developing pharmacological strategies that would normalize the function of these psychophysiological processes.     

A novel animal model of metabolic syndrome with non-alcoholic fatty liver disease and skin inflammation

Abstract

Context: Metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) are the emerging co-morbidities of skin inflammation. Occurrence of skin inflammation such as psoriasis is substantially higher in NAFLD patients than normal. Currently, there are no animal models to study the interaction between these co-morbidities.

Objective: The present study seeks to develop a simple mouse model of NAFLD-enhanced skin inflammation and to study the effect of NAFLD on different parameters of skin inflammation.

Materials and method: Metabolic syndrome and NAFLD were induced in C57BL/6 mice by feeding high-fat diet (HFD, 60% kcal) and high fructose liquid (HFL, 40% kcal) in drinking water. Skin inflammation was induced by repeated application of oxazolone (1% sensitization and repeated 0.5% challenge) in both normal and NAFLD mice and various parameters of skin inflammation and NAFLD were measured.

Results: HFD and HFL diet induced obesity, hyperglycemia, hyperinsulinemia, and histological features of NAFLD in mice. Oxazolone challenge significantly increased ear thickness, ear weight, MPO activity, NF-κB activity, and histological features of skin inflammation in NAFLD mice as compared with normal mice. Overall, induction of oxazolone-induced skin inflammation was more prominent in NAFLD mice than normal mice. Hence, HFD and HFL diet followed by topical oxazolone application develops metabolic syndrome, NAFLD, and enhanced skin inflammation in mice.

Discussion and conclusion: This simple model can be utilized to evaluate a therapeutic strategy for the treatment of metabolic syndrome and NAFLD with skin inflammation and also to understand the nexus between these co-morbidities.     

Heparan sulfate inhibitors and their therapeutic implications in inflammatory illnesses

Introduction: Heparan sulfate (HS) is a polysaccharide that is ubiquitously expressed on the cell surface and in the extracellular matrix and interacts with a wide variety of proteins to mediate numerous biological and pathological functions, including inflammation.

Areas covered: The structural diversity and the multiple biological roles of HS in inflammation are discussed. HS is involved in the recruitment and attachment of leukocytes to the inflamed epithelium, the activation of chemokines and the transmigration of leukocytes to the underlying target tissue. The endoglycosidase heparanase plays a key role in the above processes via the degradation of HS. HS mimetics that inhibit heparanase and block HS-binding proteins have been shown to inhibit inflammation in multiple animal models.

Expert opinion: HS plays important roles in many stages of the inflammation process, in particular the regulation of leukocyte extravasation. Compounds that can inhibit HS–protein interactions thus have considerable potential as anti-inflammatory therapeutics capable of simultaneously interfering with multiple steps of the inflammation process. There are a number of such compounds in various stages of clinical development for cancer, which should also find applications in inflammatory illnesses.     

Progress in the development of animal models of acute kidney injury and its impact on drug discovery

Introduction: Acute kidney injury (AKI) is a clinical syndrome characterized by the acute loss of kidney function. AKI is increasingly frequent and is associated with impaired survival and chronic kidney disease progression. Experimental AKI models have contributed to a better understanding of pathophysiological mechanisms but they have not yet resulted in routine clinical application of novel therapeutic approaches.

Areas covered: The authors present the advances in experimental AKI models over the last decade. Furthermore, the authors review their current and expected impact on novel drug discovery.

Expert opinion: New AKI models have been developed in rodents and non-rodents. Non-rodents allow the evaluation of specific aspects of AKI in both bigger animals and simpler organisms such as drosophila and zebrafish. New rodent models have recently reproduced described clinical entities, such as aristolochic and warfarin nephropathies, and have also provided better models for old entities such as thrombotic microangiopathy-induced AKI. Several therapies identified in animal models are now undergoing clinical trials in human AKI, including p53 RNAi and bone-marrow derived mesenchymal stem cells. It is conceivable that further refinement of animal models in combination with ongoing trials and novel trials based on already identified potential targets will eventually yield effective therapies for clinical AKI.     

Caspase-3 as a therapeutic target for heart failure

Introduction: Heart failure is a condition with significant morbidity and high mortality. It is likely to become unmanageable in the rapidly increasing aging population, due mainly to lack of effective treatment. Apoptosis is one of the major mechanisms causing cardiomyocyte loss in the failing hearts of both human patients and animal models. Thus, anti-apoptosis has been proposed as a provocative new concept for preventive and therapeutic strategies for heart failure.

Areas covered: This review summarizes evidence that apoptotic cells in heart are not completely committed to death. They are likely to be targeted for reversing the cardiac dysfunction. Drugs that inhibit the progression of apoptosis help restore systolic function, reverse remodeling or even prevent heart failure. Inhibitors of caspase-3, the major executors of apoptosis, have been shown to hold great promises for apoptosis interruption in heart tissues.

Expert opinion: Although the underlying cause and the pathophysiological role of apoptosis remain elusive, antiapoptotic therapy has emerged as an enigma for heart failure. Caspases promote the progressive loss of contractile function in heart failure by facilitating the degradation of myofibrillar proteins. Selective inhibition of the proteolytic functions of caspase-3 may represent an attractive approach to attenuate or reverse heart failure.     

Fibroblast growth factor 19-targeted therapies for the treatment of metabolic disease

Introduction: Fibroblast growth factors (FGFs) belong to the FGF superfamily with diverse biological functions, including proliferation, cellular differentiation, wound repair, angiogenesis and tumorigenesis. The ability to reduce liver fat content and concentrations of triglycerides, total cholesterol and plasma glucose, and to improve sensitivity and limit pro-lipogenic properties of insulin, makes FGF19 a promising therapeutic target for the treatment of metabolic syndrome. FGF19 regulates bile acid biosynthesis in the bile duct, glucose metabolism and vitamin D and phosphate homeostasis, raises the metabolic rate, reduces body weight, and ameliorates diabetes in mice. The therapeutic potential of FGF19 to treat metabolic disorders has been widely studied in animal models, but currently there are no reports concerning its use in humans.

Areas covered: The following article highlights the metabolic effects and mechanism of action of FGF19. It also discusses the potential therapies that target FGF19.

Expert opinion: FGF19 is emerging as a new target for the therapy of metabolic disorders, including diabetes. The results obtained from animal models are promising. However, there is still much to be done before the translation of these effects into practice will be possible.     

Animal models of anorexia and cachexia

Background: Cachexia is a devastating syndrome of body wasting that worsens quality of life and survival for patients suffering from diseases such as cancer, chronic kidney disease and chronic heart failure. Successful treatments have been elusive in humans, leaving a clear need for the development of new treatment compounds. Animal models of cachexia are able to recapitulate the clinical findings from human disease and have provided a much-needed means of testing the efficacy of prospective therapies. Objective: This review focuses on animal models of cachexia caused by cancer, chronic heart failure and chronic kidney disease, including the features of these models, their implementation and commonly followed outcome measures. Conclusion: Given the dire clinical need for effective treatments of cachexia, animal models will continue to play a vital role in assessing the efficacy and safety of potential treatments prior to testing in humans. Also important in the future will be the use of animal models to assess the durability of effects from anti-cachexia treatments and their effect on prognosis of the underlying disease states.