{"doi":"10.3389/fonc.2025.1571635","title":"Preclinical NCI-MPACT: prospective modeling of the mutation-based NCI-MPACT clinical trial therapeutic strategy in patient-derived xenograft models","abstract":"Purpose: The National Cancer Institute's Molecular Profiling-Based Assignment of Cancer Therapy (NCI-MPACT) randomized phase 2 clinical trial assessed the utility of applying tumor DNA sequencing to treatment selection. Here, we report the results of a companion preclinical study in patient-derived xenograft (PDX) models to evaluate how each tumor responded to each of the treatment regimens studied in the NCI-MPACT trial instead of simply to the specific regimen targeting the study-actionable mutation of interest (aMOI). Methods: Fifty-one PDX models (46 with and 5 without NCI-MPACT aMOIs) were tested against both the arm that would have been assigned in the NCI-MPACT trial as well as every other study regimen: (1) veliparib plus temozolomide or (2) adavosertib plus carboplatin (targeting the DNA repair pathway); (3) everolimus (targeting the PI3K pathway); and (4) trametinib (targeting the RAS/RAF/MEK pathway). Durability of response was measured by relative median time to tumor quadrupling event-free survival (EFSx4 ≥ 2), and duration of tumor regression. Results: Eleven of 50 models (22%) treated with veliparib plus temozolomide responded according to one or both metrics, as did 2/47 models (4.2%) treated with adavosertib plus carboplatin, and 2/46 models (4.3%) treated with trametinib; no models responded to everolimus. Follow-up studies demonstrated that temozolomide drove the activity of the veliparib plus temozolomide combination and drug sensitivity to temozolomide correlated with MGMT deficiency. Conclusion: This prospective preclinical study confirmed the modest response rates in the NCI-MPACT clinical trial. Substantial responses to temozolomide suggest that this drug represents an effective treatment for patients with MGMT deficiency, regardless of cancer type.","journal":"Frontiers in Oncology","year":2025,"id":552827,"datarank":0.11989572852928784,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.01592365144529604,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.01592365144529604,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":1,"citers_with_citation_signal":1,"citers_with_endowment":1,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9155,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":739299,"name":"Sergio Y. 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