Study of Ruxolitinib in the Treatment of Cachexia in Patients With Tumor-Associated Chronic Wasting Diseases.

Cachexia is a multifactorial syndrome characterized by tissue wasting, loss of body weight, particularly of lean body (muscle) mass (LBM) and to a lesser extent adipose tissue, metabolic alterations, fatigue, reduced performance status, and very often accompanied by anorexia leading to a reduced food intake. Cachexia accompanies the end stage of many chronic diseases and especially cancer and therefore is also termed "cancer-related anorexia/cachexia syndrome" (CACS). Clinically, cachexia is defined as an unintentional 5% resp. 10% loss of body weight over a 6-month resp. 12-month period that is directly associated with an underlying disease. The progressive loss of adipose tissue and skeletal muscle despite adequate feeding results in weakness, reduced ambulation, diminished quality of life, poor response to therapy, and often death due to respiratory failure or infection. At the time of cancer diagnosis, 80% of patients with upper gastrointestinal cancers and 60% of patients with lung cancer have already had substantial weight loss. Currently, there are no approved effective treatments for the treatment of cachexia. Understanding the molecular mechanisms responsible for muscle wasting is necessary to develop targeted therapies that play a central role in signal transduction initiated by cytokines (e.g., interleukin and interferon signaling), growth factors, and hormones for these most vulnerable patients. Key features of CACS are increased resting energy expenditure (REE), increased levels of circulating factors produced by the host immune system in response to the tumor, such as proinflammatory cytokines, or by the tumor itself, such as proteolysis-inducing factor. Inflammation is a unifying mechanism for the entire cluster of sickness behaviours (asthenia, increased slow-wave sleep, mood alteration, lethargy, depression, anorexia, fever, anhedonia, cognitive impairment, hyperalgesia and decreased social interaction), including lipolysis and muscle proteolysis. Inflammation is generated in the brain, by the tumor, by tissues in the locale of the tumor and by a diversity of host cells including skeletal muscle, adipose tissue, cells of the immune system, and liver. The specific identity of the inflammation mediators participating in cancer cachexia is emerging. Both host and tumor-derived factors have been shown experimentally to contribute to muscle wasting. There is evidence that a chronic, low-grade, tumor-induced activation of the host immune system, which shares numerous characteristics with the "acute-phase response" found after major traumatic events, septic shock or chronic inflammatory diseases with an excessive production of proinflammatory cytokines, is involved in CACS. Proinflammatory cytokines interleukin (IL)-1, IL-6, and tumor necrosis factor-alfa (TNF-a) play a central role in the pathophysiology of CACS, although the mechanisms by which they might induce muscle wasting are unknown. A goal of anorexia-cachexia therapy is to interfere with these responses to inflammation and so to restore positive energy balance and to promote the gain of skeletal muscle mass. Understanding the specific management of the initiating inflammatory pathways is crucial to that end. Recently a study reported that a "Signal Transducers and Activators of Transcription (STAT)" protein (STAT3) activation is a common feature of muscle wasting, activated in muscle by IL-6 in vivo and in vitro, by different types of cancer, and by sterile sepsis. Moreover, STAT3 activation is necessary and sufficient for causing muscle wasting. Conversely, the same authors showed that inhibiting STAT3 pharmacologically with Janus kinase (JAK) or STAT3 inhibitors or genetically reduced muscle atrophy downstream of IL-6 or cancer. Epidemiological studies suggest that as many as 25% of all cancers may be due to chronic inflammation. The connection between inflammation and cancer consists of an extrinsic pathway, driven by inflammatory conditions that increase cancer risk, and an intrinsic pathway, driven by oncogenic alterations that result in creation of an inflammatory microenvironment that resolves in neoplasias. Immune cells play key roles in connecting inflammation and cancer by producing various growth or angiogenic factors, proteinases, chemokines, and cytokines that create a pro-inflammatory tumor microenvironment. This milieu stimulates cell migration, proliferation, survival, angiogenesis, and metastasis, and facilitates the subversion of adaptive immunity, thus favoring cancer progression.

These theoretical considerations as well as pharmacological results and data from animal models indicated that the JAK/STAT pathway is a primary mediator of muscle wasting in cancer cachexia and other conditions of high IL-6 family signaling. Thus JAK/STAT pathway could represent a novel therapeutic target for the preservation of skeletal muscle in cachexia. On the basis of this rationale, we want to carry out an open label phase II study with the aim of testing the efficacy and safety of a treatment based on a pharmacologic inhibition of the JAK/STAT3 pathway with Ruxolitinib in patients with CACS. Ruxolitinib represents a novel orally bioavailable, potent, and selective inhibitor of JAK1 and JAK2 developed primarily for the treatment of Myeloproliferative Neoplasms (MPNs). A key feature of MPNs is the dysregulation of JAK/STAT signaling.