Preclinical NCI-MPACT: prospective modeling of the mutation-based NCI-MPACT clinical trial therapeutic strategy in patient-derived xenograft models
PurposeThe 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 xe...
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Frontiers Media S.A.
2025-05-01
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| Series: | Frontiers in Oncology |
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| author | Yvonne A. Evrard Sergio Y. Alcoser Michael Mullendore Li Chen Chih-Jian Lih Vishnuprabha Rahul Kannan Vivekananda Datta Lindsay Dutko Shahanawaz Jiwani Lawrence V. Rubinstein Yingdong Zhao P. Mickey Williams Alida Palmisano Alida Palmisano Laura Kuhlmann Mel Simpson Shivaani Kummar Biswajit Das Chris Karlovich Eric Polley Ming-Chung Li Alice P. Chen Melinda G. Hollingshead James H. Doroshow James H. Doroshow |
| author_facet | Yvonne A. Evrard Sergio Y. Alcoser Michael Mullendore Li Chen Chih-Jian Lih Vishnuprabha Rahul Kannan Vivekananda Datta Lindsay Dutko Shahanawaz Jiwani Lawrence V. Rubinstein Yingdong Zhao P. Mickey Williams Alida Palmisano Alida Palmisano Laura Kuhlmann Mel Simpson Shivaani Kummar Biswajit Das Chris Karlovich Eric Polley Ming-Chung Li Alice P. Chen Melinda G. Hollingshead James H. Doroshow James H. Doroshow |
| author_sort | Yvonne A. Evrard |
| collection | DOAJ |
| description | PurposeThe 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).MethodsFifty-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.ResultsEleven 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 erlotinib. Follow-up studies demonstrated that temozolomide drove the activity of the veliparib plus temozolomide combination and drug sensitivity to temozolomide correlated with MGMT deficiency.ConclusionThis 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. |
| format | Article |
| id | doaj-art-a9fe3168269e4a14b69b13a85a5ee659 |
| institution | OA Journals |
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| language | English |
| publishDate | 2025-05-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Oncology |
| spelling | doaj-art-a9fe3168269e4a14b69b13a85a5ee6592025-08-20T02:25:12ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2025-05-011510.3389/fonc.2025.15716351571635Preclinical NCI-MPACT: prospective modeling of the mutation-based NCI-MPACT clinical trial therapeutic strategy in patient-derived xenograft modelsYvonne A. Evrard0Sergio Y. Alcoser1Michael Mullendore2Li Chen3Chih-Jian Lih4Vishnuprabha Rahul Kannan5Vivekananda Datta6Lindsay Dutko7Shahanawaz Jiwani8Lawrence V. Rubinstein9Yingdong Zhao10P. Mickey Williams11Alida Palmisano12Alida Palmisano13Laura Kuhlmann14Mel Simpson15Shivaani Kummar16Biswajit Das17Chris Karlovich18Eric Polley19Ming-Chung Li20Alice P. Chen21Melinda G. Hollingshead22James H. Doroshow23James H. Doroshow24Applied and Developmental Research Directorate (ADRD), Frederick National Laboratory for Cancer Research, Frederick, MD, United StatesDivision of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, United StatesApplied and Developmental Research Directorate (ADRD), Frederick National Laboratory for Cancer Research, Frederick, MD, United StatesMolecular Characterization Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United StatesMolecular Characterization Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United StatesMolecular Characterization Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United StatesMolecular Characterization Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United StatesMolecular Characterization Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United StatesMolecular Characterization Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United StatesDivision of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, United StatesDivision of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, United StatesMolecular Characterization Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United StatesDivision of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, United StatesGeneral Dynamics Information Technology (GDIT), Falls Church, VA, United StatesDivision of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, United StatesApplied and Developmental Research Directorate (ADRD), Frederick National Laboratory for Cancer Research, Frederick, MD, United StatesDivision of Hematology/Medical Oncology, School of Medicine, Oregon Health & Science University, Portland, OR, United StatesMolecular Characterization Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United StatesMolecular Characterization Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United StatesDepartment of Public Health Sciences, University of Chicago, Chicago, IL, United StatesDivision of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, United StatesDivision of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, United StatesDivision of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, United StatesDivision of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, United StatesCenter for Cancer Research, National Cancer Institute, Bethesda, MD, United StatesPurposeThe 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).MethodsFifty-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.ResultsEleven 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 erlotinib. Follow-up studies demonstrated that temozolomide drove the activity of the veliparib plus temozolomide combination and drug sensitivity to temozolomide correlated with MGMT deficiency.ConclusionThis 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.https://www.frontiersin.org/articles/10.3389/fonc.2025.1571635/fullprecision medicineNCI-MPACTpatient-derived modelsDNA damage repairnext-generation sequencingtargeted agents |
| spellingShingle | Yvonne A. Evrard Sergio Y. Alcoser Michael Mullendore Li Chen Chih-Jian Lih Vishnuprabha Rahul Kannan Vivekananda Datta Lindsay Dutko Shahanawaz Jiwani Lawrence V. Rubinstein Yingdong Zhao P. Mickey Williams Alida Palmisano Alida Palmisano Laura Kuhlmann Mel Simpson Shivaani Kummar Biswajit Das Chris Karlovich Eric Polley Ming-Chung Li Alice P. Chen Melinda G. Hollingshead James H. Doroshow James H. Doroshow Preclinical NCI-MPACT: prospective modeling of the mutation-based NCI-MPACT clinical trial therapeutic strategy in patient-derived xenograft models Frontiers in Oncology precision medicine NCI-MPACT patient-derived models DNA damage repair next-generation sequencing targeted agents |
| title | Preclinical NCI-MPACT: prospective modeling of the mutation-based NCI-MPACT clinical trial therapeutic strategy in patient-derived xenograft models |
| title_full | Preclinical NCI-MPACT: prospective modeling of the mutation-based NCI-MPACT clinical trial therapeutic strategy in patient-derived xenograft models |
| title_fullStr | Preclinical NCI-MPACT: prospective modeling of the mutation-based NCI-MPACT clinical trial therapeutic strategy in patient-derived xenograft models |
| title_full_unstemmed | Preclinical NCI-MPACT: prospective modeling of the mutation-based NCI-MPACT clinical trial therapeutic strategy in patient-derived xenograft models |
| title_short | Preclinical NCI-MPACT: prospective modeling of the mutation-based NCI-MPACT clinical trial therapeutic strategy in patient-derived xenograft models |
| title_sort | preclinical nci mpact prospective modeling of the mutation based nci mpact clinical trial therapeutic strategy in patient derived xenograft models |
| topic | precision medicine NCI-MPACT patient-derived models DNA damage repair next-generation sequencing targeted agents |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2025.1571635/full |
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