{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T12:57:05Z","timestamp":1783947425206,"version":"3.55.0"},"reference-count":31,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T00:00:00Z","timestamp":1766448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NCI-CTEP","award":["GR139237"],"award-info":[{"award-number":["GR139237"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Decitabine efficacy in acute myeloid leukemia (AML) may be enhanced by the pharmacologic upregulation of microRNA miR-29b, a regulator of DNA methyltransferase (DNMT) expression. Bortezomib and sorafenib have been shown preclinically to increase miR-29b levels, providing a biologically informed strategy to sensitize leukemic blasts to DNMT inhibition. Objectives: To evaluate the safety, tolerability, biological activity, and preliminary efficacy of combining bortezomib and sorafenib followed by decitabine in patients with newly diagnosed or relapsed\/refractory AML. Methods: This phase I, dose-escalation study enrolled 15 patients (11 untreated, 4 relapsed\/refractory) who received fixed-dose bortezomib and sorafenib across three dose levels prior to decitabine. Dose escalation was guided by dose-limiting toxicities (DLTs) and an increase in miR-29b expression. Results: The regimen was generally well tolerated with the most frequent grade \u22653 adverse events of hypertension and febrile neutropenia. At the highest dose level, a \u22652-fold increase in miR-29b expression was observed in two of the six evaluable patients. The overall response rate was 33.3%, with clinical responses observed in both newly diagnosed and relapsed\/refractory patients. However, changes in miR-29b expression did not consistently correlate with clinical response. Conclusions: Sequential treatment with bortezomib and sorafenib followed by decitabine is feasible and demonstrates acceptable safety in AML. Although the biologic modulation of miR-29b was variable, this trial provides a proof of concept for pharmacodynamic-guided dose finding in epigenetic therapy combinations.<\/jats:p>","DOI":"10.3390\/cancers18010045","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T14:27:47Z","timestamp":1766500067000},"page":"45","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Pharmacologic Targeting of miR29b with Bortezomib and Sorafenib to Improve Decitabine Sensitivity in Patients with Acute Myeloid Leukemia: Results from a Phase 1 Dose-Escalation Trial"],"prefix":"10.3390","volume":"18","author":[{"given":"Shivani","family":"Handa","sequence":"first","affiliation":[{"name":"The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin","family":"Koenig","sequence":"additional","affiliation":[{"name":"Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuhong","family":"Zhao","sequence":"additional","affiliation":[{"name":"The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice S.","family":"Mims","sequence":"additional","affiliation":[{"name":"The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumithira","family":"Vasu","sequence":"additional","affiliation":[{"name":"The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramiro","family":"Garzon","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamanna","family":"Haque","sequence":"additional","affiliation":[{"name":"Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Don","family":"Benson","sequence":"additional","affiliation":[{"name":"The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca B.","family":"Klisovic","sequence":"additional","affiliation":[{"name":"University Hospitals Seidman Cancer Center, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido","family":"Marcucci","sequence":"additional","affiliation":[{"name":"The City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison R.","family":"Walker","sequence":"additional","affiliation":[{"name":"Moffitt Cancer Center, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4869-0712","authenticated-orcid":false,"given":"Bhavana","family":"Bhatnagar","sequence":"additional","affiliation":[{"name":"West Virigina University Cancer Institute, Wheeling Hospital, Wheeling, WV 26003, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1182\/blood-2016-08-733196","article-title":"Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel","volume":"129","author":"Estey","year":"2017","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1016\/S1470-2045(17)30416-3","article-title":"Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukemia: A multicenter, first-in-human, open-label, phase 1-2 study","volume":"18","author":"Perl","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2386","DOI":"10.1056\/NEJMoa1716984","article-title":"Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML","volume":"378","author":"DiNardo","year":"2018","journal-title":"N. 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