Author: Palus, Sandra ; Pötsch, Mareike S. ; Tschirner, Anika ; Springer, Jochen ; Anker, Stefan D. ; Ishida, Junichi ; von Haehling, Stephan ; Doehner, Wolfram

AbstractBackgroundCachexia, a common manifestation of malignant cancer, is associated with wasting of skeletal muscle and fat tissue. In this study, we investigated the effects of a new first in class anabolic catabolic transforming agent on skeletal muscle in a rat model of cancer cachexia.MethodsYoung male Wistar Han rats were intraperitoneally inoculated with 108 Yoshida hepatoma AH‐130 cells and once daily treated with 0.3 mg kg−1, 3 mg kg−1 MT‐102, or placebo by gavage.ResultsThree mg kg−1d−1 MT‐102 not only prevented progressive loss of fat mass (−6 ± 2 g vs ‐12 ± 1 g; P < 0.001); lean mass (+1 ± 10 g vs. −37 ± 2 g; P < 0.001) and body weight (+1 ± 13 g vs. −60 ± 2 g; P < 0.001) were remained. Quality of life was also improved as indicated by a higher food intake 12.9 ± 3.1 g and 4.3 ± 0.5 g, 3 mg kg−1d−1 MT‐102 vs. placebo, respectively, P < 0.001) and a higher spontaneous activity (52 369 ± 6521 counts/24 h and 29 509 ± 1775 counts/24 h, 3 mg·kg‐1d‐1 MT‐102 vs. placebo, respectively, P < 0.01) on Day 11. Most importantly, survival was improved (HR = 0.29; 95% CI: 0.16–0.51, P < 0.001). The molecular mechanisms behind these effects involve reduction of overall protein degradation and activation of protein synthesis, assessed by measurement of proteasome and caspase‐6 activity or Western blot analysis, respectively.ConclusionsThe present study shows that 3 mg kg−1 MT‐102 reduces catabolism, while inducing anabolism in skeletal muscle leading to an improved survival.

01 Dec 2014·Expert Opinion on Investigational DrugsQ2 · MEDICINE

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

Q2 · MEDICINE

Review

Author: Anne-Marie C. Dingemans ; Annemie M. W. Schols ; Judith de Vos-Geelen ; Ramon Langen

INTRODUCTIONCachexia 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 COVEREDThe 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 OPINIONThe 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.

01 Aug 2013·Supportive Care in Cancer

Emerging new therapeutic alternatives for the management of cancer cachexia: recent insights

Letter

Author: Shailendra Kapoor

To the Editor: Garcia et al. have provided interesting data in their recent article [1]. New compounds have been identified recently that may play a significant role in mitigating cancer cachexia. BL-6020/979 has recently been shown to attenuate cancer cachexia. It mediates its effect by antagonizing melanocortin-4 receptor function [2]. Its administration significantly improves food intake. At the same time, energy expenditure is attenuated significantly. In addition, it is orally effective and demonstrates depression mitigating properties. Another drug with considerable potential is ARA286. It is an erythropoietin analogue that significantly attenuates muscle loss in cancer cachexia models [3]. Another drug that has shown effectiveness in mitigating cancer cachexia is theophylline; it mediates its effect by attenuating cachexia-associated proteolysis [4]. As a result there is a reduction in serum TNF-alpha levels. MT-102 is another emerging alternative with considerable efficacy. It is an anabolic/ catabolic transforming agent that reduces muscle loss in cancer cachexia. The ACT-ONE study is currently underway to see if these anabolic effects can be illustrated in humans also [5]. Similarly, rosiglitazone has recently been shown to attenuate cancer-associated cachexia; it results in marked improvement in adipose tissue mass. It also restores PPARdelta in muscles to their normal levels [6]. A similar effect is seen on muscle PDK4 levels. As a result, it delays cachexia-associated weight loss. Another recent alternative is tocilizumab. It is an antiinterleukin-6 receptor antibody that has shown effectiveness in reducing the signs and symptoms of cancer-associated cachexia [7]. It enhances retinol-binding protein levels. At the same time, pre-albumin levels are also accentuated. Ursolic acid has also been recently shown to reduce cancer cachexia. It is a natural triterpene that mediates its effect by accentuating skeletal muscle insulin: IGF-1 signaling [8]. At the same time, it attenuates the expression of atrophy related mRNAs. The above-mentioned agents have shown considerable promise so far. Hopefully, the coming few years will see further research to fully evaluate their role in mitigating cancer cachexia.

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Indication	Highest Phase	Country/Location	Organization	Date
Inflammatory Bowel Diseases	Phase 1	KR	Mthera PharmaStartup	25 Apr 2023

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