{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:24:12Z","timestamp":1785284652601,"version":"3.55.0"},"reference-count":68,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Ruesch Center for the Cure of Gastrointestinal Cancers"},{"DOI":"10.13039\/100008064","name":"Georgetown University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100008064","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NIH\/NCI","award":["P30-CA051008"],"award-info":[{"award-number":["P30-CA051008"]}]},{"name":"Georgetown clinical trials office"},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health","doi-asserted-by":"publisher","award":["UL1-TR001409"],"award-info":[{"award-number":["UL1-TR001409"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: The primary aim of this Phase 1 clinical trial was to study the safety and dose of a cholecystokinin receptor antagonist, proglumide, in combination with gemcitabine\/nab-paclitaxel (GEM-NAB-P) in patients with metastatic pancreatic cancer. The secondary aim was to study the effects of proglumide with GEM-NAB-P on the tumor microenvironment (TME) with tumor biopsies and a blood biomarker assay. An exploratory aim studied the effects of proglumide treatment on cancer-related pain. Methods: Gemcitabine-na\u00efve patients were treated with GEM-NAB-P plus proglumide 1200 mg\/day. Tumor biopsies and a liquid biopsy serum sample for analysis of a microRNA biomarker panel were collected pre- and on-treatment to study the TME. McGill pain surveys were done at baseline, week 8 and at the end of treatment. The study was approved and registered (NCT05827055). Results: The mean age of the patients was 68.2 years (range 54\u201374 years). The starting dose was well-tolerated with no unexpected treatment-related adverse events observed. Multiplex immunohistochemical analysis of tumor biopsies at baseline and week 8 revealed a significant reduction in Ki67+ cells, collagen1\u03b11, and M2-polarized tumor-associated macrophages (TAMs). Week 8 tumor biopsies demonstrated a significant increase in CD8+ T-cells and natural killer cells compared to baseline. The blood biomarker panel showed a significant inverse change in microRNAs associated with decreasing fibrosis and metastasis. The McGill pain scores showed less pain at week 24 or end-of-treatment compared to baseline. Conclusions: Proglumide demonstrates a favorable safety profile when combined with standard chemotherapy for metastatic pancreatic cancer. Its unique ability to remodel TME and alleviate cancer-related pain highlights its potential, warranting further research.<\/jats:p>","DOI":"10.3390\/pharmaceutics18030379","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T11:50:36Z","timestamp":1773921036000},"page":"379","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Effects of Proglumide with Chemotherapy on the Pancreatic Tumor Microenvironment: Phase 1 PROGEM Trial"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0835-4802","authenticated-orcid":false,"given":"Jill P.","family":"Smith","sequence":"first","affiliation":[{"name":"Department of Medicine, Georgetown University Medical Center, Washington, DC 20007, USA"},{"name":"Department of Oncology, Georgetown University Medical Center, Washington, DC 20007, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2238-8980","authenticated-orcid":false,"given":"Gakiza C.","family":"Nkulikiyimana","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Molecular & Cellular Biology, Georgetown University, Washington, DC 20007, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Medicine, Georgetown University Medical Center, Washington, DC 20007, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6864-9932","authenticated-orcid":false,"given":"Wenqiang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medicine, Georgetown University Medical Center, Washington, DC 20007, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1298-2983","authenticated-orcid":false,"given":"Bhaskar","family":"Kallakury","sequence":"additional","affiliation":[{"name":"Department of Pathology, MedStar Georgetown University Hospital, Washington, DC 20007, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Kwagyan","sequence":"additional","affiliation":[{"name":"Department of Statistics, Howard University College of Medicine, Washington, DC 20059, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anju","family":"Duttargi","sequence":"additional","affiliation":[{"name":"Department of Oncology, Georgetown University Medical Center, Washington, DC 20007, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0408-4817","authenticated-orcid":false,"given":"Benjamin A.","family":"Weinberg","sequence":"additional","affiliation":[{"name":"Department of Oncology, Georgetown University Medical Center, Washington, DC 20007, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1001\/jama.2021.13027","article-title":"Pancreatic Cancer: A Review","volume":"326","author":"Park","year":"2021","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1053\/j.gastro.2022.03.056","article-title":"Pancreatic Cancer: Pathogenesis, Screening, Diagnosis, and Treatment","volume":"163","author":"Wood","year":"2022","journal-title":"Gastroenterology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1016\/S0140-6736(25)00261-2","article-title":"Pancreatic cancer","volume":"405","author":"Stoop","year":"2025","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1056\/NEJMoa1011923","article-title":"FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer","volume":"364","author":"Conroy","year":"2011","journal-title":"N. 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