{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T06:20:10Z","timestamp":1790058010279,"version":"4.0.1"},"reference-count":36,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100004319","name":"Pfizer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004319","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>In a recent Phase 2 trial in patients with cancer cachexia, the anti\u2010GDF\u201015 antibody ponsegromab resulted in increased body weight, appetite, muscle mass and physical activity. This study provides compelling evidence that targeting the GDF\u201015 pathway may offer a viable therapeutic strategy, while raising new mechanistic questions about how GDF\u201015 neutralization could be optimally integrated with other interventions to reverse the multifactorial cachexia syndrome. This series of experiments aimed to evaluate the effects of anti\u2010GDF\u201015 antibody treatment in combination with muscle anabolic (anti\u2010myostatin antibody) or appetite stimulant (ghrelin receptor agonist anamorelin) modulators using mouse cancer cachexia models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The effects of anti\u2010GDF\u201015 monoclonal antibody alone and in combination with an anti\u2010myostatin antibody or anamorelin fumarate were examined in GDF\u201015\u2010dependent (HT\u20101080 and RENCA) and partially dependent (TOV21G) mouse tumour models. Comprehensive assessments included food intake, body weight, body composition (including fat, lean and muscle mass), muscle function and treadmill running. Circulating myostatin was measured in patient samples from an advanced NSCLC clinical study.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Anti\u2010myostatin antibody treatment had limited efficacy in improving cachexia in mouse tumour models with high circulating GDF\u201015 (HT\u20101080 and RENCA), but improved cachexia (when combined with anti\u2010GDF\u201015 antibody) in a tumour model with low circulating GDF\u201015 levels (TOV21G). In the TOV21G model, combining anti\u2010myostatin and anti\u2010GDF\u201015 antibodies led to even greater increases in body weight and hindlimb muscle mass compared with anti\u2010GDF\u201015 antibody alone (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001 for muscle mass); however, the increase in muscle strength and treadmill running did not reach statistical significance over monotherapy. When anamorelin was combined with anti\u2010GDF\u201015 antibody, body weight was elevated compared with the HT\u20101080 tumour\u2010bearing vehicle group (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001) but did not reach statistical significance over anti\u2010GDF\u201015 antibody alone. Similar observations of the combination treatment were found for food intake, fat mass and gastrocnemius (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). Circulating myostatin was negatively correlated with weight loss in patients with cancer (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These data provide proof\u2010of\u2010principle that mechanistically distinct approaches targeting muscle anabolism and appetite may act additively with GDF\u201015 neutralization, particularly in cancer cachexia settings with lower GDF\u201015 dependence.<\/jats:p>\n                    <jats:p>\n                      <jats:bold>Trial Registration:<\/jats:bold>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/ClinicalTrials.gov\">ClinicalTrials.gov<\/jats:ext-link>\n                      identifier: NCT01360554.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.70312","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T12:24:57Z","timestamp":1778675097000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Targeting Cancer Cachexia: A Mechanistic Evaluation of Anti\u2010GDF\u201015 Antibody\u2010Based Combination Therapies"],"prefix":"10.1002","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6460-8555","authenticated-orcid":false,"given":"Danna M.","family":"Breen","sequence":"first","affiliation":[{"name":"Internal Medicine Research Unit, Pfizer Inc  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Joaquim","sequence":"additional","affiliation":[{"name":"Internal Medicine Research Unit, Pfizer Inc  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brianna 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