{ "abstract": "Purpose:: Limited central nervous system (CNS) bioavailability and pharmacodynamics are obstacles to effective systemic therapies for glioblastoma (GBM). One strategy to overcome these challenges is drug combinations enhancing CNS penetration and/or tumor chemosensitivity. LP-184 (zirdafulven), a synthetic acylfulvene class alkylator, induces DNA damage and inhibits GBM cell viability in preclinical models. LP-184 is a prodrug converted to active metabolites by intracellular oxidoreductase prostaglandin reductase 1 that is overexpressed in >70% of GBM. DNA damage induced by LP-184 is O6-methylguanine-DNA methyltransferase (MGMT) agnostic and reversed by transcription-dependent transcription-coupled nucleotide excision repair (TC-NER).\n\nPatients and Methods:: LP-184 was evaluated in a phase Ia study (NCT05933265) in 63 adult patients with advanced malignancies, including 16 patients with recurrent GBM. All patients with GBM received prior standard-of-care therapy, and most had received one or more additional therapies before enrollment.\n\nResults:: Treatment was overall well tolerated. Patients with GBM experienced frequent grade 1 to 2 nausea and infrequent severe thrombocytopenia and transaminitis. Clinical pharmacokinetic analysis combined with published preclinical intratumoral bioavailability data (∼20% penetration) predicted that LP-184 at the recommended dose for expansion (RDE) would achieve cytotoxic levels if combined with spironolactone, a brain-penetrant ERCC3 degrader and TC-NER inhibitor that sensitizes GBM cells to LP-184 3- to 6-fold. We show that three daily doses of spironolactone deplete orthotopic GBM patient-derived xenograft (PDX) ERCC3 protein by ∼80% and increase tumor LP-184 cytotoxicity 2-fold.\n\nConclusions:: LP-184 is well tolerated at the RDE, and we establish a clinically translatable plan for dosing spironolactone in combination with LP-184 for a future phase Ib/IIa clinical trial.\n\nSignificance:: Treatment failure in GBM reflects inadequate drug brain exposure and DNA repair–mediated resistance. LP-184 (zirdafulven), a novel acylfulvene alkylator, generates MGMT-independent DNA lesions predominantly repaired by TC-NER. In a phase Ia dose-finding trial, LP-184 was well tolerated at the RDE in participants with recurrent GBM. Plasma drug levels achieved predicted effective systemic exposures but not brain concentrations based on projected 20% brain penetrance. Pharmacokinetic modeling indicates that NER inhibition could increase tumor chemosensitivity with the addition of spironolactone. The optimal dosing regimen for spironolactone combined with LP-184 was identified in orthotopic PDX models, facilitating advancement to phase Ib/IIa testing of LP-184 plus spironolactone.\n\nTrial Registration:: ClinicalTrials.gov Identifier: NCT05933265.", "abstract_shown": true, "affiliations": [ "Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.", "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.", "Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland.", "Lantern Pharma Inc., Dallas, Texas." ], "article_type": "research article", "arxiv": null, "author_total": 9, "authors": [ { "affs": [ 0, 1 ], "name": "Karisa C. Schreck", "orcid": "0000-0001-7181-3269" }, { "affs": [ 2 ], "name": "Bachchu Lal", "orcid": "0000-0002-5936-0276" }, { "affs": [ 3 ], "name": "Jianli Zhou", "orcid": "0009-0009-6261-2364" }, { "affs": [ 0, 1, 2 ], "name": "Hernando Lopez-Bertoni", "orcid": "0000-0001-6618-1092" }, { "affs": [ 1 ], "name": "Matthias Holdhoff", "orcid": "0000-0002-3285-3484" }, { "affs": [ 3 ], "name": "Reginald Ewesuedo", "orcid": "0000-0003-3982-9775" }, { "affs": [ 3 ], "name": "Kishor Bhatia", "orcid": "0000-0002-5319-7957" }, { "affs": [ 3 ], "name": "Marc Chamberlain", "orcid": "0009-0009-5285-2807" }, { "affs": [ 0, 1, 2 ], "name": "John Laterra", "orcid": "0000-0002-2983-5365" } ], "bibtex": "https://research.draconitic.com/paper/f53ctfz0z24k7.bib", "cited_by": 0, "doi": "10.1158/2767-9764.crc-26-0518", "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13711432/", "id": "f53ctfz0z24k7", "issns": [ "2767-9764" ], "landing_url": "https://doi.org/10.1158/2767-9764.crc-26-0518", "language": "en", "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "heading", "CNS Cancers" ], [ "heading", "Clinical Trial Results" ], [ "heading", "Dna Damage" ], [ "heading", "Dna Damage And Repair" ], [ "heading", "Gliomas, Glioblastomas" ], [ "heading", "Phase I Clinical Trials" ], [ "heading", "Research Article" ], [ "openalex", "2716|Glioma Diagnosis and Treatment" ] ], "openalex": "W7221031057", "pdf_url": "https://aacrjournals.org/cancerrescommun/article-pdf/doi/10.1158/2767-9764.CRC-26-0518/3837744/crc-26-0518.pdf", "pmcid": "PMC13711432", "pmid": "42849034", "published": "2026-10-27", "publisher": "American Association for Cancer Research", "ris": "https://research.draconitic.com/paper/f53ctfz0z24k7.ris", "sources": [ { "first_seen": "2026-10-31T12:22:12Z", "native_id": "PMC13711432", "source": "pmc", "url": "https://doi.org/10.1158/2767-9764.crc-26-0518" } ], "subjects": [ { "field": "medicine", "origin": "openalex:2716|Glioma Diagnosis and Treatment", "subfield": "human-genetics" } ], "title": "Phase Ia Evaluation of LP-184 in Recurrent Glioblastoma: Safety, Pharmacokinetics, and Translational Optimization of CNS Exposure", "title_text": "Phase Ia Evaluation of LP-184 in Recurrent Glioblastoma: Safety, Pharmacokinetics, and Translational Optimization of CNS Exposure", "type": "peer-reviewed", "updated_at": "2026-10-31T12:22:12Z", "url": "https://research.draconitic.com/paper/f53ctfz0z24k7", "venue": "Cancer Research Communications", "versions": [] }