EDITORIAL URRENT C OPINION

Discovering and targeting the epigenetic pathways to treat muscle loss: working toward a paradigm shift in cancer therapeutics Martin E. Fernandez-Zapico a, Maite G. Fernandez-Barrena b, David L. Marks a, and Aminah Jatoi c

This issue of Current Opinion in Supportive and Palliative Care includes a diverse group of articles that cover the following topics: the pathophysiology of disease-induced cachexia with discussions of leptin, interleukin-6, and general systemic inflammation as candidate mediators; the potential role of immunomodulating agents to treat cancer cachexia; dehydration as a contributory source of end-of-life distress; the role of corticosteroid therapy to palliate symptoms at the end of life in patients with cachexia; and a discussion of the interventions to improve healthcare providers’ communication, and thereby help patients and their families cope with cancer cachexia and its ramifications. The variety within this compendium illustrates that cachexia, or the wasting of body tissue, is the focus of active investigation, that progress in understanding its pathophysiology is occurring at a rapid pace, but that, nonetheless, patients continue ostensibly to suffer and die from this disease-related complication. To date, however, no interventions have been demonstrated to reverse cachexia and its negative sequelae in their entirety in patients with advanced disease states. In view of this last point, we briefly review in the next few paragraphs the clinical features of cancer cachexia, particularly from the standpoint of muscle loss, and provide our opinion on how the clinical and laboratory investigation of this syndrome could proceed most effectively. We comment here on cancer cachexia because this syndrome is the focus of our own work. Four key observations in patients with cancer cachexia drive efforts to investigate muscle loss. First, it is in fact the loss of muscle – as opposed to loss of any other body compartment – that accounts for much of the observed weight loss in cancer cachexia. Making an early but salient contribution to this field, Cohn et al. [1] examined the body composition in cancer patients with the prompt gamma neutron activation technique, a whole-body potassium counter, and tritiated water assessment. These investigators concluded that the

loss of body weight, the clinical hallmark of cancer cachexia, is the result of attrition of muscle and fat. However, skeletal muscle is predominantly lost, an observation in direct contradistinction to what is seen in simple starvation, in which skeletal muscle remains relatively well preserved. Second, this loss of weight and muscle occurs frequently in patients with metastatic cancer. For example, in as many as 80% of patients with metastatic pancreas cancer, weight loss is observed at diagnosis [2]. Third, this loss of weight and muscle appears to detract from both quality of life and survival. Finkelstein et al. [3] showed that cancer patients who had lost more than 5% of their premorbid weight were more debilitated. Moreover, prospectively collected data from over 3000 cancer patients from the Eastern Cooperative Oncology Group demonstrated that weight loss of more than 5% in the 3 months preceding a cancer diagnosis is a strong independent predictor of poor survival [2]. In a more recent study, Krishnan et al. [4] reported that among 247 pancreas cancer patients, weight loss was associated with a 50% reduction in survival – from 8.5 to 4.2 months. Focusing even further on the negative prognostic effects of muscle loss in cancer patients, Martin et al. [5] observed in a study of over 1400 patients that 53% had muscle loss, as determined by the measurements at the L3 vertebral level on computerized tomography scans, and that these myopenic patients lived shorter lives (P < 0.001). Relying on the autopsy studies, some investigators have described weight or muscle loss as the sole cause of death in as many as 20% of cancer patients [6,7]. a

Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota, USA, bCentro de Investigacion Medica Aplicada, Universidad de Navarra, Pamplona, Spain and cDivision of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA Correspondence to Aminah Jatoi, MD, 200 First Street SW, Rochester, MN 55905, USA. E-mail: [email protected] Curr Opin Support Palliat Care 2014, 8:319–320 DOI:10.1097/SPC.0000000000000103

1751-4258 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

www.supportiveandpalliativecare.com

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Relative expression

Cachexia, nutrition and hydration

MURF1 2 1 0

SOCS3 2 1 0

2

EGR1

2

IER5

2

SLC25A37

2

1

1

1

1

0

0

0

0

PROXI

3

HINT3

2

Control Patient

1 0

FIGURE 1. Expression of key genes relevant to muscle loss in cancer patients and healthy controls. RNA was extracted from muscle biopsies from normal control individuals (n ¼ 10) and cancer patients (n ¼ 3). RNA was converted to cDNA and realtime PCR was performed for MuRF1 (a muscle-specific E3 ubiquitin ligase), SOCS3, and EGR1 (known STAT3 targets), IER5 (an early response gene upregulated in muscle loss and a possible STAT3 target), and IER5 (an early response gene upregulated in muscle loss) and SLC25A37, PROX1 and HINT3 (genes known to be downregulated during myolysis). Data show relative expression normalized by b-actin levels. Graphs show mean values with standard errors.

Fourth, investigators have begun to delve further into these tight associations between loss of weight or muscle and poor clinical outcomes. Our group observed that myolytic pathways are overactivated in the muscle of cancer patients (Fig. 1). Taken together, these four observations underscore the significance of targeting muscle in an effort to improve outcomes in weight-losing cancer patients. Although a dearth of scientific investigations has sought to examine the muscle of weight-losing cancer patients with the goal of identifying druggable targets to prevent and treat muscle loss, the few that have indicate that alterations in gene expression (overexpression/underexpression) undoubtedly regulate muscle loss [8–10]. For example, Gallagher et al. [11] serially examined the muscle transcriptome in 12 cancer patients who underwent muscle biopsies at the time of cancer resection and in 6 healthy controls. Making comparisons between thousands of genes, these investigators observed that 1868 genes were either upregulated or downregulated over time in cancer patients. Both catabolic and anabolic genes were to a great extent downregulated at baseline compared with after operation. Surprisingly, postoperative muscle gene profiles in cancer patients appeared very similar to those observed in healthy controls. In effect, Gallagher and others have shown that the cancer-related changes we see in muscle can be reversed with successful cancer therapy – in this case surgery – thereby spawning hope that the muscle changes we see in incurable cancer patients can one day also be reversed. This study further suggests that muscle loss occurs independently of the genetic alterations through mechanisms affecting gene transcription and chromatin dynamics. The study of inherited changes in gene expression is known as epigenetics, a critical and largely unexplored aspect of many human disease states and syndromes, including cachexia. Impugning epigenetics is therapeutically relevant because realistically genetic mutations cannot be repaired, whereas epigenetic events potentially can be. Thus, it is critical 320

www.supportiveandpalliativecare.com

that further investigations are undertaken to understand the epigenetic pathways that lead to muscle loss in order to define targets for new pharmacological approaches. Our hope is that one day soon a future issue of Current Opinion in Supportive and Palliative Care will provide a large compendium of articles that describe muscle-targeted therapies along with a description of their well proven clinical benefits of better quality of life and longer survival in cachectic patients with incurable malignancies. Acknowledgements None. Conflicts of interest The authors report no conflicts of interest.

REFERENCES 1. Cohn SH, Gertenhaus W, Sawitsky A, et al. Compartment body composition of cancer patients by measurement of total body nitrogen, potassium, and water. Metabolism 1981; 30:222–229. 2. Dewys WD, Begg C, Lavin PT, et al. Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group. Am J Med 1980; 69:491–497. 3. Finkelstein DM, Cassileth BR, Bonomi PD, et al. A pilot study of the Functional Living Index-Cancer Scale for the assessment of quality of life for metastatic lung cancer patients. An Eastern Cooperative Oncology Group study. Am J Clin Oncol 1988; 11:630–633. 4. Krishnan S, Rana V, Janjan NA, et al. Prognostic factors in patients with unresectable locally advanced pancreatic adenocarcinoma treated with chemoradiation. Cancer 2006; 107:2589–2596. 5. Martin L, Birdsell L, Macdonald N, et al. Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful prognostic factor independent of body mass index. J Clin Oncol 2013; 31:1539–1547. 6. Ambrus JL, Ambrus CM, Mink IB, Pickren JW. Causes of death in cancer patients. J Med 1975; 6:61–64. 7. Warren S. The immediate causes of death in cancer. Am J Med Sci 1932; 184:610–615. 8. Stephens NA, Gallagher IJ, Rookackers O, et al. Using transcriptomics to identify and validate novel biomarkers of human skeletal muscle cancer cachexia. Genome Med 2010; 2:1. 9. Williams A, Sun X, Fischer JE, Hasselgren PO. The expression of genes in the ubiquitin–proteasome pathway is increased in skeletal muscle from patients with cancer. Surgery 1999; 126:744–749. 10. Tan BHL, Ross JA, Kaasa S, et al. Identification of possible genetic polymorphisms involved in cancer cachexia: a systemic review. J Genet 2011; 90:165–177. 11. Gallagher IJ, Stephens NA, MacDonald AJ, et al. Suppression of skeletal muscle turnover in cancer cachexia: evidence from the transcriptome in sequential human muscle biopsies. Clin Cancer Res 2012; 18:2817–2827.

Volume 8  Number 4  December 2014

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Discovering and targeting the epigenetic pathways to treat muscle loss: working toward a paradigm shift in cancer therapeutics.

Discovering and targeting the epigenetic pathways to treat muscle loss: working toward a paradigm shift in cancer therapeutics. - PDF Download Free
150KB Sizes 0 Downloads 5 Views