{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T22:55:17Z","timestamp":1791327317669,"version":"4.3.1"},"reference-count":121,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2023,8,9]],"date-time":"2023-08-09T00:00:00Z","timestamp":1691539200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Urothelial carcinoma (UC), the sixth most common cancer in Western countries, includes upper tract urothelial carcinoma (UTUC) and bladder carcinoma (BC) as the most common cancers among UCs (90\u201395%). BC is the most common cancer and can be a highly heterogeneous disease, including both non-muscle-invasive (NMIBC) and muscle-invasive (MIBC) forms with different oncologic outcomes. Approximately 80% of new BC diagnoses are classified as NMIBC after the initial transurethral resection of the bladder tumor (TURBt). In this setting, intravesical instillation of Bacillus Calmette\u2013Guerin (BCG) is the current standard treatment for intermediate- and high-risk patients. Unfortunately, recurrence occurs in 30% to 40% of patients despite adequate BCG treatment. Radical cystectomy (RC) is currently considered the standard treatment for NMIBC that does not respond to BCG. However, RC is a complex surgical procedure with a recognized high perioperative morbidity that is dependent on the patient, disease behaviors, and surgical factors and is associated with a significant impact on quality of life. Therefore, there is an unmet clinical need for alternative bladder-preserving treatments for patients who desire a bladder-sparing approach or are too frail for major surgery. In this review, we aim to present the strategies in BCG-unresponsive NMIBC, focusing on novel molecular therapeutic targets.<\/jats:p>","DOI":"10.3390\/ijms241612596","type":"journal-article","created":{"date-parts":[[2023,8,9]],"date-time":"2023-08-09T10:08:59Z","timestamp":1691575739000},"page":"12596","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer: Current Treatment Landscape and Novel Emerging Molecular Targets"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2812-5553","authenticated-orcid":false,"given":"Francesco","family":"Claps","sequence":"first","affiliation":[{"name":"Urological Clinic, Department of Medicine, Surgery and Health Sciences, University of Trieste, 34149 Trieste, Italy"},{"name":"Department of Surgical Oncology (Urology), Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7355-7625","authenticated-orcid":false,"given":"Nicola","family":"Pavan","sequence":"additional","affiliation":[{"name":"Department of Surgical, Oncological, and Oral Sciences, University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5649-4095","authenticated-orcid":false,"given":"Luca","family":"Ongaro","sequence":"additional","affiliation":[{"name":"Urological Clinic, Department of Medicine, Surgery and Health Sciences, University of Trieste, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Tierno","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, University of Trieste, 34127 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9704-6651","authenticated-orcid":false,"given":"Gabriele","family":"Grassi","sequence":"additional","affiliation":[{"name":"Department of Medical, Surgery and Health Sciences, Hospital of Cattinara, University of Trieste, Strada di Fiume 447, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0237-544X","authenticated-orcid":false,"given":"Carlo","family":"Trombetta","sequence":"additional","affiliation":[{"name":"Urological Clinic, Department of Medicine, Surgery and Health Sciences, University of Trieste, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5797-3351","authenticated-orcid":false,"given":"Gabriele","family":"Tulone","sequence":"additional","affiliation":[{"name":"Department of Surgical, Oncological, and Oral Sciences, University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9513-4869","authenticated-orcid":false,"given":"Alchiede","family":"Simonato","sequence":"additional","affiliation":[{"name":"Department of Surgical, Oncological, and Oral Sciences, University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0021-0302","authenticated-orcid":false,"given":"Riccardo","family":"Bartoletti","sequence":"additional","affiliation":[{"name":"Department of Translational Research and New Technologies, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura S.","family":"Mertens","sequence":"additional","affiliation":[{"name":"Department of Surgical Oncology (Urology), Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bas W. G.","family":"van Rhijn","sequence":"additional","affiliation":[{"name":"Department of Surgical Oncology (Urology), Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Carmen","family":"Mir","sequence":"additional","affiliation":[{"name":"Department of Urology, Hospital Universitario La Ribera, 46600 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8662-138X","authenticated-orcid":false,"given":"Bruna","family":"Scaggiante","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, University of Trieste, 34127 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17","DOI":"10.3322\/caac.21763","article-title":"Cancer Statistics, 2023","volume":"73","author":"Siegel","year":"2023","journal-title":"CA Cancer J. 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