Current Therapeutic Targets in Cancer Cachexia: A Pathophysiologic Approach

Abstract

Significant progress in our understanding of cancer cachexia has occurred in recent years. Despite these advances, no pharmacologic agent has achieved US Food and Drug Administration approval for this common and highly morbid syndrome. Fortunately, improved understanding of the molecular basis of cancer cachexia has led to novel targeted approaches that are in varying stages of drug development. This article reviews two major thematic areas that are driving these pharmacologic strategies, including those targeting signal mediators at the level of the CNS and skeletal muscle. Additionally, pharmacologic strategies are being tested in combination with targeted nutrients, nutrition therapy, and exercise to treat cancer cachexia. To this end, we highlight recently published and ongoing trials evaluating cancer cachexia therapies in these specific areas.

FIG 1.

Interorgan relationships in cancer cachexia: Where do the therapeutic targets reside? Cachexia is initiated by a complex mixture of tumor-derived catabolic factors and proinflammatory molecules generated through tumor crosstalk with associated stromal cells and the immune system. Some of these factors act directly on muscles and adipose tissues to elicit excess catabolism (eg, lipolysis inducers adrenomedullin, zinc α2 glycoprotein). Skeletal muscle catabolism is induced by proinflammatory cytokines, eicosanoids, and transforming growth factor-β (TGFβ) family effectors (eg, activin A, myostatin). Alteration of CNS functions further induces catabolism. Altered CNS outputs are neural (eg, activation of sympathetic output to adipocytes) and neuroendocrine (activation of adrenal with increased catabolic glucocorticoid signaling to muscle). Behavioral changes associated with malignant disease include reduced food intake and lethargy, reducing anabolic growth factor, nutrient, and contractile activity signaling. Systemic therapy–associated wasting is a powerful impetus to the overall loss of skeletal muscle, via specific toxic actions at the cellular level. GDF15, growth differentiation factor 15; miR, microRNA; TNF, tumor necrosis factor; TNFRSF12A, TNF receptor superfamily member 12A; TRAF6, TNF receptor–associated factor 6; TWEAK, TNF-related weak inducer of apoptosis.

FIG 2.

CNS-mediated mechanisms of cancer cachexia. Anorexia and excessive peripheral catabolism originate in part by tumor-induced and inflammatory changes in specific regions of the hypothalamus and brainstem. Cytokines (eg, IL1, TNFα) exert a profound inflammatory effect on the hypothalamus resulting in activation of anorexigenic neurons (ie, POMC) and inhibition of orexigenic neurons (ie, NPY). NPY neurons stimulate food intake in response to a variety of mediators including ghrelin. Ghrelin is a multifaceted gut hormone which activates the growth hormone secretagogue receptor (GHS-R). Ghrelin’s hallmark functions are its stimulatory effects on food intake, fat deposition, and growth hormone release. POMC neurons inhibit food intake by the production of α-MSH, a neuropeptide of the melanocortin family, which acts via type 4 melanocortin receptors (MC4R) in the paraventricular nucleus (PVN). Small molecular weight, orally active agonists of GHS-R, and antagonists of MC4R have been developed for the indication of anorexia/cancer cachexia. Growth differentiation factor (GDF15) is overexpressed by some cancers and inhibits food intake by activating the GFRAL-RET signaling pathway in the brainstem area postrema and nucleus tractus solitarii. Advanced stage cancers may be associated with persistent non–chemotherapy-related nausea, and clinical management of these symptoms with antiemetic regimens is recommended to enable food intake. High-dose corticosteroids activate NPY neurons and inhibit POMC neurons; however, this is limited as a therapeutic approach because of secondary toxicity including muscle atrophy, poor glycemic control, and thrombosis. AGRP, agouti-related peptide; GDF15, growth differentiation factor 15; IL1, interleukin-1; NPY, neuropeptide Y; POMC, pro-opiomelanocortin; TNFα, tumor necrosis factor-α; α-MSH, α-melanocyte–stimulating hormone.

FIG 3.

Signaling pathways involved in tumor-induced skeletal muscle atrophy. Signaling pathways involved in the control of muscle anabolism and catabolism. Protein synthesis, cell growth, and proliferation are normally maintained by growth factors, nutrients, and contractile activity. Anabolism is activated by downstream pathways that converge at the mTOR complex 1, a multicomplex protein able to activate transcription of hypertrophy genes. Phosphorylated AKT also blunts catabolic signaling via inhibition of FoxO and its downstream signaling to transcription of atrophy genes. Omega-3 PUFA suppress the dissociation of NF-κB/IκB and decrease the translation of atrophy genes in the nucleus induced by NF-κB. Protein breakdown is regulated by transcriptional regulation of atrophy genes, mediated by NF-kB, STAT3, C/EBPβ, and SMAD2/3 transcription factors. Tumor products and products of activated host immune cells induce atrophy, TNF-α, and TWEAK acting via downstream signaling that induces a dissociation of NF-κB/IκB complex and NF-κB translocation to the nucleus. IL-6 and LIF induce STAT3 and C/EBPβ signaling pathways, and TGF-β superfamily members (eg, myostatin, activin-A) activate SMAD2/SMAD3. ACVR2, activin receptor type 2; AKT, serine/threonine protein kinase; C/EBPβ, CCAAT/enhancer-binding protein-β; FoxO, forkhead box protein O complex; IκB, inhibitory subunit of NF-κB; IGF1, insulin-like growth factor-1; IGFR, IGF receptor; IL-6, interleukin-6; IL-6R, IL-6 receptor; LIF, leukocyte inhibitory factor, mTOR, mammalian target of rapamycin; mTORC1, mammalian target of rapamycin complex 1; PI3K, phosphatidylinositol-3 kinase; PUFA, polyunsaturated fatty acid; STAT3, signal transducer and activator of transcription 3; TGFBR2, TGF-β receptor type 2; TNF, tumor necrosis factor; TNFR, TNF receptor; TNFRSF12A, TNF receptor superfamily member 12A; TWEAK, TNF-related weak inducer of apoptosis.

FIG 4.

A summary of recent reports of muscle loss rates during systemic cancer therapies. Data are for muscle loss reported during standard regimens. Because of variations in scan interval, for purposes of comparison, author-reported mean muscle loss was converted to % lost per 100 days on treatment. Data are from existing studies.^,,– ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; AC, anthracycline and cyclophosphamide; BEP, bleomycin, etoposide, platinum; BEV, bevacizumab; DCF, docetaxel, cisplatin, fluorouracil; DCTP, docetaxel, carboplatin, trastuzumab, and pertuzumab; FLOT, fluorouracil, leucovorin, oxaliplatin, and docetaxel; FOLFIRINOX, leucovorin, fluorouracil, irinotecan, oxaliplatin; FOLFOX, leucovorin, fluorouracil, oxaliplatin; FU, fluorouracil; GE, gastroesophageal; Gem, gemcitabine.

FIG 5.

Signaling pathways involved in antineoplastic therapy–induced skeletal muscle atrophy. Cytotoxic cancer therapies induce transcriptional activation of pathways of myofibrillar destruction by the ubiquitin proteasome system, autophagy, and catabolism of amino acids. Apoptosis, necroptosis, and death receptor signaling are also activated, along with mitochondrial dysfunction and overproduction of reactive oxygen species. ACVR2, activin receptor type 2; AKT, serine/threonine protein kinase; C/EBPβ, CCAAT/enhancer-binding protein-β; FoxO, forkhead box protein O complex; IκB, inhibitory subunit of NF-κB; IGF1, insulin-like growth factor-1; IGFR, IGF receptor; IL-6, interleukin-6; IL-6R, IL-6 receptor; LIF, leukocyte inhibitory factor; mTORC1, mammalian target of rapamycin complex 1; PI3K, phosphatidylinositol-3 kinase; PUFA, polyunsaturated fatty acid; STAT3, signal transducer and activator of transcription 3; TGFBR2, TGF-β receptor type 2; TNF, tumor necrosis factor; TNFR, TNF receptor; TNFRSF12A, TNF receptor superfamily member 12A; TWEAK, TNF-related weak inducer of apoptosis.

FIG 6.

Pathways of nutrient-related, growth factor–related, and contraction-related signaling activate muscle protein synthesis. The growth factor–sensitive and nutrient-sensitive mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator anabolism in muscle cells. Signaling pathways activated by nutrients, growth factors, and contractile work are convergent to mTORC1, and activation of the complex requires both nutrients and growth factors to be present. Muscle protein biosynthesis requires availability of 20 amino acids, which are the substrate for the formation of protein. However, the branched chain amino acids, particularly leucine, also have a signaling action. Leucine sensing proteins, such as leucyl t-RNA synthetase, participate in the activation of mTORC1 via the activation of RagB/RagD. Contractile activity that is either high load (resistance training) or high torque (eccentric contraction) signals mTORC1 activation via formation of phosphatidic acid, the ζ isoform of diacylglycerol kinase is necessary for the mechanically induced increase in phosphatidic acid. On activation, mTORC1 will phosphorylate P70S6 kinase, which goes on to phosphorylate ribosomal protein S6 and initiate RNA translation. Akt, serine/threonine protein kinase; AMPK, AMP-dependent protein kinase; ATP/AMP, adenosine triphosphate/adenosine monophosphate; ERK, extracellular signal–regulated kinase; GDP, guanosine diphosphate; GTP, guanosine triphosphate; MEK, mitogen-activated protein kinase; mLST8, mammalian lethal with SEC13 protein 8; mTORC1, mammalian target of rapamycin complex 1; PI3K, phosphatidylinositol-3 kinase; PRAS40, proline-rich Akt substrate of 40 kDa; Raf, rapidly accelerated fibrosarcoma; Rag, recombination-activating genes; Ras, rat sarcoma; Rheb, RAS homolog enriched in brain; RSK, ribosomal S6 kinase; TSC1/2, tuberous sclerosis complex.