Request for regulatory guidance for cancer cachexia intervention trials

Fearon, Kenneth; Argilés, Josep M.; Baracos, V.; Bernabei, Roberto; Coats, Andrew J.S.; Crawford, Jeffrey; Deutz, NE; Doehner, Wolfram; Evans, William J.; Ferrucci, Luigi; Cabrero‐García, Julio; Gralla, R.; Jatoi, Aminah; Kalantar-Zadeh, Kamyar; Lainščak, Mitja; Je, Morley; Muscaritoli, Maurizio; Polkey, MI; Rosano, Giuseppe; Rossi-Fanelli, Filippo; Schols, AM; Strasser, Florian; Vellas, Bruno; Haehling, Stephan von; Anker, SD

doi:10.1002/jcsm.12083

Cited by 90 publications

(89 citation statements)

References 15 publications

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“…Indeed, on-going trials have a rather heterogeneous design and include an excessively wide span of different types of tumours with different degrees of cachexia. In fact, a unified approach is requested in a recent consensus document [7]. Some of the most promising drug candidates are completely new molecules and, therefore, particular attention has to be focused on safety issues and not just side effects, but also long-term treatment associated problems, together with the issue of interaction with other drugs.…”

Section: Editorialmentioning

confidence: 99%

Searching for the Ideal Therapy for Cancer Cachexia

Argilés¹,

López‐Soriano²,

Busquets³

2017

J Dev Drugs

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EditorialAlthough megestrol acetate and corticosteroids have been, and still are, the universal drug approaches for the treatment of the cancer cachectic syndrome, novel drugs and treatments have lead to promising approaches to counteract wasting thus improving the quality of life and, possibly, survival of cancer patients. Thus, ghrelin agonists, such as anamorelin, that basically act on food intake, nonsteroidal selective androgen receptor modulators (SARMs), such as enobosarm, hold promise as a new class of anabolic therapies for cancer patients that manifest muscle wasting. In addition, betablockers can reduce body energy expenditure and improve efficiency of substrate utilization. Some of them do combine many different pharmacological effects. For instance, espindolol is a non-specific β1/ β2 adrenergic receptor antagonist that exhibits effects through β and central 5-HT1α receptors to demonstrate pro-anabolic, anti-catabolic, and appetite-stimulating actions. Finally, myostatin antagonists, such as bimagrumab or BYM338, seems to be able in pre-clinical models to prevent skeletal muscle mass loss and preserve muscle function facilitating the recovery from muscle atrophy. All of the commented drugs are certainly new promising strategies to fight cancer cachexia [1].However, in order to improve the treatment of cancer cachexia, several considerations have to be made. First, a better understanding of the pathophysiological mechanisms related to skeletal muscle and, in general, body wasting, will enable the development of novel therapeutic approaches. Second, more research should also be devoted to biomarkers for cancer cachexia. Indeed, in many clinical centres, cancer cachexia is treated only when a significant amount of weight loss is detected, or when the patients suffer from certain limitations in daily living activities. Biomarkers could detect the changes before any clinical manifestations arouse, facilitating treatment and, possibly, improving prognosis. Progress has certainly been made concerning biomarkers [2] but more research is needed in this field to find an easy measurable --either blood or urine present and specific muscle wasting biomarker. Third, since cancer cachexia leads to decrease potential for muscle regeneration due to the fact that satellite cells are not able to differentiate into myocells, one new revolutionary concept that will, no doubt, involve further research is that of cell reprogramming to muscle. Therefore, future studies are needed on the potential of stem cell therapy to overcome the problem of muscle cell regeneration. While adult stem cells are tissue-specific and have limited capacity to be expanded ex-vivo, pluripotent stem cells, have the capacity to differentiate into any cell type while possessing unlimited in vitro selfrenewal. Scott et al.[3] described a methodology for large-scale isolation of satellite cells from skeletal muscle. This could then be applied as a therapeutic strategy to stimulate muscle regeneration. Fourth, it is quite clear that a single drug tre...

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Section: Editorialmentioning

confidence: 99%

Searching for the Ideal Therapy for Cancer Cachexia

Argilés¹,

López‐Soriano²,

Busquets³

2017

J Dev Drugs

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“…Among the complex sequelae associated with cachectic progression, compromised muscle function associated with reduced muscle mass is viewed as a primary contributor to patient morbidity and mortality [2,6]. Recognizing this feature of cancer cachexia, regulatory agencies require the demonstration of meaningful improvements in physical function in addition to improvements in patient body composition for successful registration of novel cachexia therapies [7]. Anabolic androgenic steroids or steroidal androgens are among the most well recognized function-promoting therapies [8][9][10] and as such have been extensively evaluated in muscle wasting of diverse etiology [11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Overcoming Resistance to Anabolic Selective Androgen Receptor Modulator (SARM) Therapy in Experimental Cancer Cachexia with Histone Deacetylase Inhibitor AR-42

Tseng

Liva

Dauki

et al. 2017

Preprint

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BackgroundCancer cachexia impacts the majority of advanced cancer patients but no approved anticachexia therapeutic exits. Recent late stage clinical failures of anabolic anti-cachexia therapy revealed heterogeneous responses to anabolic therapies and a limited ability to translate improved body composition into functional benefit. It is currently unclear what governs anabolic responsiveness in cachectic patient populations. Methods We evaluated anabolic androgen therapy combined with the novel anti-cachectic histone deacetylase inhibitor (HDACi) AR-42 in a series of studies using the C-26 mouse model of experimental cachexia. The ability of treatment to suppress tumor-mediated catabolic signaling and promote anabolic effects were characterized. Results Anabolic anti-cachexia monotherapy with the selective androgen receptor modulator (SARM) GTx-024 or enobosarm had no impact on cachectic outcomes in the C-26 model. A minimally effective dose of AR-42 provided mixed anti-cachectic benefits when administered alone but when combined with GTx-024 significantly improved bodyweight (p <0.0001), hind limb muscle mass (p <0.05), and voluntary grip strength (p <0.0001) versus tumor bearing controls. Similar efficacy resulted from the combination of AR-42 with multiple androgens. Anti-cachectic efficacy was associated with the ability to reverse pSTAT3 and atrogene induction in gastrocnemius muscle of tumor-bearing animals in the absence of treatment-mediated changes in serum IL-6 or LIF. Conclusions Anabolic GTx-024 monotherapy is incapable of overcoming catabolic signaling in the C-26 model of experimental cachexia. Anti-cachectic androgen therapy is greatly improved by successful blockade of STAT3 mediated atrophy with AR-42. Combined androgen and HDAC inhibitor administration represents promising approach to improve anabolic response in cachectic patient populations.

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“…For the main JCSM journal, clinical trials,2, 3, 4, 5, 6 disease definition and regulatory issues,7, 8, 9, 10 epidemiological reports of broad interest,11, 12, 13 and significant basic science mechanistic insights14, 15, 16 as well as studies on pathophysiology questions17, 18, 19 will remain the main domain of what we aim to publish, but there are so many more things that deserve to be published and often only by a small margin don't make it into JCSM . We have a rejection rate for original reports that is >80%.…”

mentioning

confidence: 99%