Download editorial Cancer Cachexia: Emerging Preclinical

JNCI J Natl Cancer Inst (2015) 107(12): djv322
doi:10.1093/jnci/djv322
First published online October 9, 2015
Editorial
editorial
Cancer Cachexia: Emerging Preclinical Evidence and the Pathway
Forward to Clinical Trials
Lisa Martin, Michael B. Sawyer
Affiliations of authors: Department of Agricultural, Food & Nutritional Science (LM) and Department of Oncology, Department of Medical Oncology (MBS),
University of Alberta, Edmonton, AB, Canada
Correspondence to: Michael B. Sawyer, MD, Cross Cancer Institute, 11560 University Ave. NW, Edmonton, AB, Canada, T6G 1Z2 (e-mail: michael.sawyer@
albertahealthservices.ca).
Cancer cachexia is a multifactorial syndrome characterized by
ongoing loss of skeletal muscle (with or without loss of fat) leading to functional decline (1). This loss is driven by variable combinations of reduced food intake and abnormal metabolism (1).
Cachexia affects 60% to 80% of patients with advanced cancer
and results in reduced tolerance to cancer therapies, quality of
life, and survival (1,2). Cachexia is an unmet medical need in
oncology (2) because of its devastating effects on patients, for
which there is no approved therapy.
Cachexia treatment is complex because it cannot be reversed
by nutritional support alone. Cachexia therapy targets have
included stimulation of appetite, regulation of catabolic pathways, and protein synthesis (3). Interventions to prevent, treat,
or support patients with cancer cachexia have been tested in
trials with limited success. Literature reviews suggest trial
design may be partly to blame (4,5). The design of past and
current trials are variable (eg, patient selection criteria, end
points defining effectiveness) and controversial. Fearon et al.
(1) introduced the concept of refractory cachexia, which adds
to our understanding about the abilities of patients to respond
to treatment. The intense catabolism associated with advanced,
chemoresistant disease may be refractory to cachexia therapies,
which must then be deployed earlier in the disease trajectory, at
which time the potential to stimulate anabolism clearly exists
(6). Recognition that anabolism is possible earlier in the disease
trajectory, in addition to other important developments, has
renewed interest toward developing more effective cachexia
therapies.
Cachexia research is building a solid foundation with support from an international society, international conferences,
and an increasingly impactful scientific journal (JCSM). We have
an international consortium of researchers who have: 1) produced a definition and consensus framework for assessing cancer cachexia (1) and 2) contributed data to define and develop
diagnostic criteria for cancer cachexia (7). In addition, there have
been funding initiatives from national agencies (eg, the National
Cancer Institute) to support cachexia research. These efforts
have set the stage for the emergence of a new set of mechanisms
including growth differentiation factor-15 (GDF-15), macrophage
inhibitory cytokine-1 (MIC-1) (8,9), leukemia inhibitory factor
(LIF) (10), myostatin, activin type-2 receptor (ActRIIB) (11), Fn14
(12), signal transducer and activator of transcription 3 (STAT3)
(13,14), and parathyroid hormone-related protein (PTHrP) (14).
In this issue of the Journal, Tseng et al. (15) report on a novel
approach to treat cancer cachexia, the use of histone deacetylase (HDAC) inhibitors. This was a well-designed and comprehensive study that compared and contrasted effects of AR-42
with other HDAC inhibitors such as vorinostat and romidepsin
in two murine models: C-26 colon adenocarcinoma in male
CD2F1 mice and the Lewis lung carcinoma (LLC) in male C57BL/6
mice. In C-26 mouse models, AR-42 protected against weight
loss with AR-42–treated mice at day 15. These mice experienced
a 6% weight loss compared with control mice with greater than
20% weight loss. In addition, despite AR-42 having no effects
on tumor growth, AR-42–treated mice had increased survival
compared with controls. This is a provocative finding; treating
cachexia alone resulted in prolonged survival of tumor-bearing
mice in the absence of direct effects of the cachexia treatment
on the tumor.
This is not the first time that this has been observed. Zhou
et al. (11) showed inhibition of ActRIIB with a decoy receptor
sActRIIB led to prolonged mouse survival in the absence of any
effect on tumor growth. In both C26 and LLC mouse models,
AR-42 protected against muscle wasting whereas other HDAC
inhibitors romidepsin and vorinostat did not. These findings
suggest not all HDAC inhibitors are created equal in terms of
their ability to treat cancer cachexia. Exact mechanisms of AR-42
effects are not entirely clear. HDAC inhibitors are likely to have
pleiotropic effects on many genes as well as their expression.
The authors clearly showed AR-42 affected known mediators of
cancer cachexia including interleukin-6 (IL-6) and LIF. Novel to
this study was the examination of AR-42 on muscle metabolism
Received: October 5, 2015; Accepted: October 7, 2015
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L. Martin et al. | 2 of 2
using metabolomics. Comparing AR-42–treated tumor mice to
control tumor mice and mice without tumors, investigators
showed AR-42 had significant effects on glycolysis and amino
acid metabolism in the muscle, the result being the muscle of
AR-42–treated mice resembled control normal mice more than
tumor-bearing control mice. This suggests AR-42 may preserve
muscle metabolism.
We commend the Tseng et al. for assembling a strong preclinical case for moving AR-42 into trials in cancer patients.
Many agents have had similarly strong preclinical arguments but
have not lived up to their initial promise in the clinic. Reasons
for these failures may not have been because of agents lacking
an intrinsic ability to ameliorate or treat cachexia, but perhaps
they were the right drugs at the wrong time in the disease trajectory of cancer patients. It is now recognized that cachexia
is a continuum with three stages of clinical relevance (eg, precachexia, cachexia, refractory cachexia) (1). In the short term,
we need to understand how these three stages are represented
in animal models used to study cachexia, and to define which
mechanisms result in the best control of cachexia. In addition,
for those undergoing active treatment, these agents should not
interfere with anticancer therapy and as a palliative intervention require a limited side effect profile. In the near future, based
on the preclinical case built by Tseng et al., we foresee a clinical
trial where benefits of AR-42 can be tested in first-line patients
likely to be receiving effective anticancer treatment rather than
end-stage patients.
A major challenge in moving drugs such as AR-42 to the
clinic is identification of functional and other outcomes that
are meaningful to both patients and drug regulators. Functional
outcomes measured in current phase III trials of cachexia
therapy are hand grip strength and stair climb tests. Generally,
regulators have required improvements in lean body mass and
functional outcomes as coprimary endpoints for approval. An
additional measure that has not been often been considered
might be survival, especially if these drugs are moved earlier in
the patient’s disease trajectory.
Note
The authors have no conflicts of interest to disclose.
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