{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T03:37:34Z","timestamp":1789097854692,"version":"build-2803163510"},"reference-count":39,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T00:00:00Z","timestamp":1737936000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Thyroid\u00ae"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>Medullary thyroid cancer (MTC) is a frequently metastatic tumor of the thyroid that develops from the malignant transformation of C-cells. These tumors most commonly have activating mutations within the RET or RAS proto-oncogenes. Germline mutations within RET result in C-cell hyperplasia, and cause the MTC pre-disposition disorder, multiple endocrine neoplasia, type 2A (MEN2A). Single-agent therapies for MTC, including vandetanib (VAN) and cabozantinib for all MTCs and selpercatinib (SEL) for RET-mutated MTC, lead to partial responses but are not curative.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>To identify new therapeutic targets for MTC, we conducted proteomic profiling of normal C-cells, MTC cells, pre-malignant MEN2A patient samples, and MTC tumors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      From this analysis, we identified CAPN1, a member of the CALPAIN (CAPN) family endopeptidases, as widely upregulated in MTC samples. We found that short hairpin RNA-mediated depletion of CAPN1 or inhibitors of CAPN1 significantly reduced MTC cell growth, colony formation, and xenograft tumor growth\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      . In addition, we show that CAPN1 inhibitors synergize with VAN and SEL\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      , maximizing apoptosis. Mechanistic experiments implicate CAPN1 in inhibiting neurofibromin, encoded by NF1, and CAPN1 inhibitors stabilize NF1 protein levels and diminish downstream RAS\/RET activation of AKT and ERK.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>Our data suggest that increased CAPN1 levels support RET and RAS-fueled growth by reducing NF1 levels. We find that combinatorial therapies between CAPN1 inhibitors and VAN or SEL show maximal efficacy in MTC cells.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1089\/thy.2024.0102","type":"journal-article","created":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T09:15:01Z","timestamp":1737969301000},"page":"177-187","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":3,"title":["Proteomic Profiling of Medullary Thyroid Cancer Identifies CAPN1 as a Key Regulator of NF1 and RET Fueled Growth"],"prefix":"10.1177","volume":"35","author":[{"given":"Eshan","family":"Khan","sequence":"first","affiliation":[{"name":"Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio, USA."},{"name":"The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Hylton","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio, USA."},{"name":"The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neel","family":"Rajan","sequence":"additional","affiliation":[{"name":"The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA."},{"name":"Department of Molecular Medicine and Therapeutics, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie J.","family":"Bouley","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jalal K.","family":"Siddiqui","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio, USA."},{"name":"The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swetha","family":"Rajasekaran","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio, USA."},{"name":"The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ganesh R.","family":"Koshre","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio, USA."},{"name":"The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1945-4536","authenticated-orcid":false,"given":"Hayden","family":"Storts","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio, USA."},{"name":"The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anisley","family":"Valenciaga","sequence":"additional","affiliation":[{"name":"The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA."},{"name":"Department of Molecular Medicine and Therapeutics, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Misbah","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio, USA."},{"name":"The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandya","family":"Liyanarachchi","sequence":"additional","affiliation":[{"name":"The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA."},{"name":"Department of Molecular Medicine and Therapeutics, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Fernandez","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuguang","family":"Zheng","sequence":"additional","affiliation":[{"name":"The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8482-2137","authenticated-orcid":false,"given":"John","family":"Phay","sequence":"additional","affiliation":[{"name":"Division of Surgical Oncology, Ohio State University Comprehensive Cancer Center and Ohio State University Wexner Medical Center, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1884-408X","authenticated-orcid":false,"given":"Priya H.","family":"Dedhia","sequence":"additional","affiliation":[{"name":"Division of Surgical Oncology, Ohio State University Comprehensive Cancer Center and Ohio State University Wexner Medical Center, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5145-1156","authenticated-orcid":false,"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology and 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